paradigms on immunotherapy combinations with chemotherapy · 2021. 3. 12. · immunogenic cell...

JUNE 2021 CANCER DISCOVERY | OF1

Paradigms on Immunotherapy Combinations with Chemotherapy Diego Salas-Benito1,2, José L. Pérez-Gracia1,2, Mariano Ponz-Sarvisé1,2, María E. Rodriguez-Ruiz1,2, Iván Martínez-Forero3, Eduardo Castañón1,2, José M. López-Picazo1,2, Miguel F. Sanmamed1,2,4,5,6, and Ignacio Melero2,4,5,6,7

Review

1Oncology Department, Clínica Universidad de Navarra, Pamplona, Spain. 2Clinical Trials Unit, Clínica Universidad de Navarra, Pamplona, Spain. 3Sen-ior Director, Clinical Research, MSD, Madrid, Spain. 4Center for Medical Applied Research (CIMA), Universidad de Navarra, Pamplona, Spain. 5Nav-arra Institute for Health Research (IDISNA), Pamplona, Spain. 6Biomedical Research Network in Oncology (CIBERONC), Pamplona, Spain. 7Immunol-ogy Department, Clínica Universidad de Navarra, Pamplona, Spain.Note: Supplementary data for this article are available at Cancer Discovery Online (http://cancerdiscovery.aacrjournals.org/).M.F. de Sanmamed and I. Melero share senior authorship of this review.Corresponding Authors: Diego Salas-Benito, University of Navarra and Instituto de Investigacion Sanitaria de Navarra (IdISNA), Av. Pio XII, 55, Pamplona, Navarra 31008, Spain. Phone: 34948194700; E-mail: [email protected]; and Ignacio Melero, Pamplona 31009, Spain. Phone: 34948255400; E-mail: [email protected] Discov 2021;11:1–15doi: 10.1158/2159-8290.CD-20-1312©2021 American Association for Cancer Research.

abstRact Checkpoint inhibitors are being added to standard-of-care chemotherapy in multi-ple clinical trials. Success has been reported in non–small and small cell lung carci-

nomas and urothelial, head and neck, gastric, and esophageal cancers, and promising results are already available in triple-negative breast and pancreatic malignancies. The potential mechanisms of synergy include immunogenic tumor cell death, antiangiogenesis, selective depletion of myeloid immunosup-pressive cells, and lymphopenia, which reduces regulatory T cells and makes room for proliferation of effector T cells. However, chemotherapy regimens have not been optimized for such combinations, perhaps explaining some recent clinical trial disappointments. Approaches to make the most of chemo-immunotherapy include neoadjuvant and adjuvant schemes.

Significance: Immunotherapy of cancer based on PD-1/PD-L1 blockade has prompted a revolution in cancer clinical management. Evidence in phase III clinical trials already supports combinations of immuno-therapy with standard-of-care chemotherapy for a number of malignant diseases. This review focuses on such evidence and provides an overview of the potential synergistic mechanisms of action and the opportunities to optimize chemoimmunotherapy regimens.

canceR chemotheRapyFinding the Achilles’ heel of metastatic cancer is a for-

midable task. The first pharmacologic answer comes from the search for chemicals that would selectively damage rep-licating cells. Compounds achieving such an effect mainly include DNA-damaging agents, those interfering with the DNA enzymatic replicative machinery, and those impairing nucleotide synthesis or mitotic mechanisms. The develop-ment of chemotherapy started in the 1950s with remarkable

success for Hodgkin lymphoma (1), testicular cancer (2), and acute lymphoid leukemia (3). Curative effects against such diseases were discovered with the realization that synergistic combinations of several drugs were required, and that efficacy comes at the cost of significant toxicity. Over the years, cyto-toxic compounds for cancer therapy have been developed in an empiric quest to attain survival advantage for patients in myriads of disease-by-disease clinical trial efforts.

Unfortunately, for the most prevalent epithelial solid malignancies at metastatic stages, chemotherapy at its best offers only modest prolongation of survival. Indeed, the best effects of chemotherapy are obtained when it is delivered in a complementary fashion to radical surgery, either before the operation (neoadjuvant treatment) or after surgery (adjuvant treatment).

Cellular biology observations indicate that most chemo-therapy agents in the clinic ultimately trigger the proapop-totic suicidal machinery of cancer cells. However, resistance mechanisms are most often induced as a result of the expres-sion of multidrug transporters that pump out the chemicals, and genetic and epigenetic adaptations to the selective Dar-winian pharmacologic pressure.

The current state of the art is that aggressive and poorly tolerated chemotherapy schemes are instigated in induc-tion and maintenance regimens until radiologic cancer progression involving tumor masses thriving or newly appearing in spite of treatment. Doses and intervals have been chosen under the maximal tolerated dose paradigm.

Cancer Research. on September 9, 2021. © 2021 American Association forcancerdiscovery.aacrjournals.org Downloaded from

Published OnlineFirst March 12, 2021; DOI: 10.1158/2159-8290.CD-20-1312

http://crossmark.crossref.org/dialog/?doi=10.1158/2159-8290.CD-20-1312&domain=pdf&date_stamp=2021-01-13

http://cancerdiscovery.aacrjournals.org/

Salas-Benito et al.REVIEW

OF2 | CANCER DISCOVERY JUNE 2021 AACRJournals.org

More recently, therapies to attain selective chemotherapy by nano-formulated drugs such as albumin-conjugated taxanes (nab-paclitaxel) or the liposomal formulation of anthracy-clines (liposomal doxorubicin), or antibody–drug conjugates (ADC; such as TDM-1) have been developed. In line with this, tumor selectivity of the ADC can be further attained by optimized linkers that release the chemotherapy moiety selectively in the tumor cell context, as in the case of trastu-zumab-deruxtecan (4), or by protease activatable precursor forms of the antibodies (probodies) conjugated to chemo-therapy agents (5).

Unfortunately, despite its potency, chemotherapy largely lacks a bystander tumor-killing effect, and escape and resist-ance are most frequently possible for the remaining malignant cells at tolerable doses. Paradoxically, full-dose chemotherapy is known to affect replicating immune system cells. Indeed, chemotherapy at high doses can cause immunosuppression (6), and drugs that were originally devised to treat cancer are currently mainly used for autoimmune disorders or to pre-vent allograft rejection. Nonetheless, a therapeutic window exists that contradicts the dogmatic interpretation that was taught until recently in medical school classrooms, stating that the mechanisms targeted by chemotherapy were exactly

the same as those required for adaptive immune responses, which are dependent on clonal lymphocyte expansions.

mechanismsFollowing obscure years of intensive research to harness

the power of the cytotoxic immune response against cancer, we are witnessing a revolution in cancer therapeutics exploit-ing the tumor recognition and destruction capabilities of the immune system. Two approaches have yielded unprecedented success: checkpoint inhibitors (7) and adoptive T-cell therapy with chimeric antigen receptors for B cell–derived malignan-cies (8). Importantly, the most striking therapeutic effects of checkpoint inhibitors have been observed upon combination with chemotherapy or antiangiogenic drugs, whereas adoptive T-cell therapy requires preconditioning regimens of non-mye-loablative chemotherapy or total body irradiation (9, 10). A summary of the main mechanisms at the interface of chemo-therapy and immunotherapy is shown graphically in Fig. 1.

Tumor Debulking by ChemotherapyTumor masses are active producers of immunosuppressive

substances that inhibit immune responses systemically (11).

Figure 1. Postulated mechanisms of synergy between chemotherapy and immunotherapy. In the upper part, the pros and cons mechanisms of chemo-therapy with regard to the immune response are depicted with emphasis on the fact that the pros must outbalance the cons. In the lower part, the main invoked mechanisms of action are schematically represented with the main supportive literature references. MDSC, myeloid-derived suppressor cell; Treg, regulatory T cell.

ConsPros

• Chemotherapy-drivenimmunosuppressionToxicity/tolerabilityCumulative orsynergistic toxicity

••

• Immunogenic cell deathTreg depletionHomeostatic T-cellproliferationMyeloid-derivedsuppressor cell depletion

••

•

Immunotherapy

Chemotherapy

Treg depletion

MDSC depletion

Tumor cell death:(a) immunogenic cell death(b) reduction of tumor cellsproducing immunosupressivemediators

Gut barrier disruption

Homeostatic proliferation of T cells

Refs. 12, 13

Refs. 37, 38

Refs. 21, 22

Ref. 25

Ref. 28




Chemoimmunotherapy REVIEW


Hence, any treatment that would cause tumor tissue debulk-ing (surgery, chemotherapy, or radiotherapy) may have a ben-eficial impact on the overall antitumor immune response and its efficacy (12). Additionally, the bulk and numbers of tumor cells to be cleared by the immune system are likely to have limitations. Reducing tumor mass leaves fewer tumor cells to be cleared by the immune system, thereby also reducing the chances for immunoescape variants.

Immunogenic Cell Death: Chemotherapy Meets Immunology

Apoptosis was perceived as an immunologically silent form of cell death and turnover. However, the group of G. Kroemer realized that tumor cells apoptotically killed under the influ-ence of certain chemotherapeutic drugs or ionizing radia-tion vaccinated mice against a subsequent lethal inoculi of viable tumor cells (13). Such ensuing immunity is mainly dependent on CD8 T lymphocytes (13). Incisive research on the mechanisms underlying these effects concluded that the immunogenicity of cell death is a function of premortem reticular stress (14) and release of tissue damaging–denoting substances (alarmins) that alert the immune system. Ulti-mately, tumor cell debris uptake by professional antigen-pre-senting dendritic cells and their activation/maturation state seem to determine the immune outcome (15). Several hall-marks of immunogenic cell death have been proposed, includ-ing exposure of calreticulin on the outer cell surface; release of ATP, Annexin-1, and HMGB1; autophagy; inflammasome activation; induction of type 1 IFN signaling, and release of mitochondrial formyl peptides (16). Interestingly, in vivo or in vitro measurements of such hallmark mechanisms allow drugs to be ranked as inducers of immunogenic cell death (17, 18). It must be acknowledged that most of the evidence corresponds to imperfect mouse models and to correlative studies in human cell line samples. Ultimately, the contribu-tion of these mechanisms needs to be addressed in patient tis-sues under treatment. An excellent recent review summarizes specific knowledge on immunogenic cell death and immune mechanisms elicited in mouse models by anticancer agents, listing most conventional chemotherapy drugs (18).

The postulated train of events in immunogenic cell death includes release of antigens from the dying or dead cells that is taken up, processed, and presented by specialized antigen-presenting cells termed conventional type 1 dendritic cells (cDC1). Maturation/activation of such cDC1 cells is induced by factors released by the surrounding stressed cells under the influence of toxics. Such phenomena are collectively termed as cross-priming of tumor antigens (19), but it must be acknowledged that formal experimental proof for chemo-therapy-enhanced tumor antigen cross-priming in humans remains to be published.

The most exploitable consequence of these immunogenic cell death phenomena is that chemotherapy may result in mechanisms that unleash immunity to tackle malignant cells that could be intrinsically resistant to the chemotherapeutic agent. Nonetheless, the most immunogenic form of cell death is probably far less immunogenic than the immunogenicity following detection of microbial presence (20). Microbial moie-ties detected by innate pathogen recognition receptors are the physiologic triggers of immunity. Therefore, further combina-

tion with locally given or systemically delivered TLR agonists, STING agonists, or virotherapy could be advisable to make the most of the proimmune effects of chemotherapy (21). Of note, off-target effects of chemotherapy may provide adjuvanticity to raise the immunogenicity of tumor antigens, for instance, the reported TLR4 agonist activity of paclitaxel (22).

Depletion of Myeloid-Derived Suppressor Cells, Cancer-Associated Neutrophils, and Macrophages

Not all cells of the immune system fight cancer. In fact, there are leukocyte populations that depress cytotoxic antitumor immunity. Tumors favor a form of leukocyte hematopoiesis that yields myeloid cells phenotypically similar to immature macrophages and neutrophils that in culture and in vivo dampen antitumor T-cell immunity (23, 24). Such myeloid-derived suppressor cells (MDSC) are known to be sensitive to chemotherapeutic agents in mice and humans, which include platinum compounds and DNA alkylating agents (25, 26). The mechanisms that such immunosuppressive myeloid cells deploy to impair T-cell function are multifarious, encompass-ing production of growth and proangiogenic factors, T-cell damaging enzymatic functions, and neutrophil extracellular trap formation, among others. For instance, cancer vaccines are more effective under the influence of cyclophosphamide or platinum-based regimens (25, 26), because of attenuation of MDSC. Of note, gemcitabine and 5-FU are also reported to effectively deplete MDSCs (27, 28). Intratumoral mac-rophages with transcriptomic features conceptualized as M2 are clearly protumoral, whereas those conceptualized as M1 may mediate antitumor function. Chemotherapy drugs such as cyclophosphamide and doxorubicin reportedly favor M1 differentiation (29). Another possible explanation is that by damaging or killing malignant cells, chemotherapeutic drugs downregulate or reduce factors derived from tumor cells that otherwise may favor M2 differentiation, thereby potentially acting through indirect effects.

Tumors promote the formation of tumor-supportive mye-loid leukocytes with growth factors (i.e., GM-CSF, G-CSF, M-CSF, HGF, etc.) and attraction with chemokines (i.e., CXCL1, CXCL8, CCL2, etc.; refs. 24, 30). Ironically, the fre-quently prescribed recombinant G-CSF to treat or prevent chemotherapy-induced neutropenia is likely to be deleterious for the proimmune effects of chemotherapy.

Homeostatic Proliferation of Effector T Cells, and Treg Depletion

T lymphocytes enter the cell cycle as a result of two types of stimuli. On the one hand, cognate antigen recognition spurs rapid clonal expansion, while on the other hand, T-cell num-bers are homeostatically maintained by a competition for promitotic growth factors such as IL7 and IL15. Accordingly, lymphopenia results in homeostatic proliferation of antigen-naïve and central memory T cells.

Hence, lymphotoxic chemotherapy might result in a paradox-ical reshaping of the T-cell repertoire and the differentiation into tumor-attacking cytotoxic T cells. Of note, the window of doses and dose intervals becomes crucial, because too much chemo-therapy would destroy lymphocytes undergoing expansion, but at optimal doses may foster specific immunity. This is best perceived in the context of adoptive T-cell therapy approaches,






where chemotherapy drugs (usually cyclophosphamide and fludarabine) make room for homeostatic proliferation of adop-tively infused cells (9). This mechanism is considered crucial, and efficacy has been correlated to the circulating levels of homeo-static cytokines and the achieved lymphopenia (9, 31).

Among T cells, a CD4+ subset is specialized at reduc-ing the activation and expansion of effector T lymphocytes. Such a subset differentiates in the thymus and is driven by the transcription factor FOXP3. In cancer, such regulatory T cells (Treg) interfere with tumor immunity in mouse models, and their presence in the tumor microenvironment has been correlated with a poorer prognosis (32). Moreover, FOXP3+ Treg cell differentiation can be induced as a result of local factors in the tumor tissue microenvironment, such as TGFβ (33). Tregs are probably specific to self-antigens conferring a certain level of self-tolerance and are frequently engaged in the cell cycle. Interestingly, some chemotherapies such as cyclo-phosphamide seem to be selective to some extent at killing these FOXP3+ subpopulations (34). However, clinical studies have questioned whether cyclophosphamide could actually induce relevant levels of Treg depletion (35). Dosing and tim-ing may be critical to the immunomodulatory effects of cyclo-phosphamide, and the concept of medium-dose intermittent chemotherapy has been suggested as optimal (36). In any case, cyclophosphamide is an imperfect Treg-depleting agent, and more precise and effective ways to target this immunosuppres-sive population are under clinical investigation.

All considered, predosing with low-dose cyclophospha-mide is a common adjuvant procedure in experimental cancer vaccines (37). Treg depletion by chemotherapy is also likely to explain the favorable effects on lymphodepletion in TIL adoptive therapy. It must be remembered that efficient Treg depletion in tumor tissues is a pending issue in cancer immu-notherapy. Of note, low-dose regimens of cyclophosphamide such as metronomic or oral schedules might derive their benefit from these immune-mediated mechanisms. Nonethe-less, clinical proof for the efficacy of cyclophosphamide as an immunotherapy-potentiating tool remains to be established and is matter of debate.

AntiangiogenesisImmunotherapy with PD-1/PD-L1–blocking checkpoint

inhibitors induces striking clinical benefit upon combina-tion with VEGF–VEGFR antagonists for metastatic renal cell carcinoma (RCC; refs. 38, 39) and hepatocellular car-cinoma (HCC; ref. 40). Indeed, the multityrosine kinase inhibitor axitinib + pembrolizumab or avelumab and the combination of bevacizumab + atezolizumab are market-approved for first-line treatment of advanced RCC and HCC, respectively. These combined therapeutic mechanisms were originally translated to the clinic for melanoma by S. Hodi’s team (41) and are related not only to angiogenesis inhibition, but also to the reshaping of myeloid populations and to VEGF effects on innate lymphocytes (42). Although VEGF–VEGFR-targeted inhibitors cannot be considered as chemotherapy, they illustrate the concept that antiangio-genesis in combination with immunotherapy may result in synergistic effects.

In this regard, proliferating vascular cells can be the prey of a variety of chemotherapeutic agents even at low metro-

nomic doses (43) that thereby cause solid-tumor hypoxia and nutrient deprivation. This is a double-edged sword for cancer immunity. It is intriguing that a relative degree of hypoxia increases the activity of cytotoxic T cells (44) while it may also result in a more hostile myeloid cell environment (44). Furthermore, tissue penetration of T lymphocytes across endothelial barriers could be altered for the better or for the worse by chemotherapy pretreatment (42).

Disruption of the Gut Microbiome BarrierThe importance of the abundance and species composi-

tion of the gut microbiome for immunotherapy has been intensively studied and found to exert a significant effect on therapeutic outcomes in response to immunotherapies with potential for therapeutic interventions (45). Chemotherapy agents very actively destroying replicating enterocytes result in disruption of the gut mucosal barrier leading to bacilli and microbial biomolecules that reach otherwise sterile tis-sues (46). Such barrier disruption is also induced by total body irradiation and may exert important effects on cancer immunity, in part depending on the control of the matura-tion state of dendritic cells even if they are located distant from the gut (47).

It is worth mentioning that chemotherapy often causes febrile neutropenia as a side effect that is frequently treated with broad-spectrum antibiotics, which severely modify the gut microbiota. When considering the potential effects on concomitant immunotherapy, this could be deleterious, neutral, or favorable with regard to antitumor effects. These phenomena deserve attention in chemoimmunotherapy tri-als and will most probably be deleterious for patients’ out-comes (48).

Recently, attention has focused on the presence of bac-teria or their nucleic acids in tumor lesions, particularly in metastasis from digestive cancers (49, 50). It would not be surprising that such levels of microbial colonization could be increased by chemotherapy drugs, thereby exerting anticancer or procancer immune effects.

Deleterious Effects of Chemotherapy on ImmunityHigh-dose chemotherapy beyond a poorly understood

threshold results in overall immune functional depression (51). This is presumably the result of elimination of antican-cer effector components or the demise of stem-like T cells able to restore the antigen-recognition repertoire. Such an undesirable effect may come from dose levels and continu-ous dosing without intervals for immune recovery. Certainly, dose and schedules of chemotherapy have not been chosen for being immune system-friendly.

For instance, in an attempt to deal with these immuno-suppressive side effects, strategies of extraction, expansion, preservation, and reinfusion of polyclonal peripheral blood T cells have been clinically tested in patients undergoing chemo-therapy to improve overall immunocompetence and tumor immune responsiveness (52). These approaches might be espe-cially suitable for combination with checkpoint inhibitors.

In addition, it must be considered that the approach of combining chemotherapy and immunotherapy also leads to increased toxicity, as observed with most combination therapies. For example, in the lung cancer KEYNOTE-189






trial, despite a similar overall rate of adverse events, the discontinuation rate for all treatments or any treatment component was higher in the chemoimmunotherapy com-bination arm (53).

Disease-by-Disease expeRienceExamples of already available phase III evidence support-

ing the notion of chemoimmunotherapy combinations can be found and have been published or recently released in congresses in multiple oncology conditions [Table 1, includ-ing HR and P data evidence for overall survival (OS) or progression-free survival (PFS)]. Moreover, hundreds of clini-cal trials are ongoing or are in the plan/preparation phases in which immunotherapy agents are combined with chemo-therapy regimens again across multiple malignant indica-tions (Supplementary Table). Furthermore, many studies on neoadjuvant settings are ongoing with evidence for enhanced pathologic responses on chemoimmunotherapy that remain to be validated in terms of OS consequences. A general appraisal of these types of combinations is quite favorable, and they will likely expand to numerous diseases and disease stages. However, benefit is not universally found, and there are trials failing to report superiority of chemoimmunother-apy over standard-of-care options.

For this approach, the accepted standard-of-care chemo-therapy regimen has been chosen as such in most cases. We have elected not to present a catalog of immune-related effects of chemotherapy agents as published by Galluzzi and colleagues (18), because in the best of cases it would be incomplete and probably inaccurate. Indeed, the immune-effect profile of chemotherapy drugs commonly used in the clinic needs to be investigated in mouse models and in humans over a broad range of doses.

Chemoimmunotherapy of Lung CancerThe first and foremost success of chemotherapy being

combined with immunotherapy came in the field of non–small cell lung cancer (NSCLC). Following approval of PD-1 and PD-L1 antagonists in second-line metastatic or locally advanced NSCLC, a race for approvals as the first line of treatment with immunotherapy agents began. Single-agent immunotherapy found efficacy in first-line therapy against tumors with high (>50%) PD-L1 expression versus platinum-based chemotherapy doublets (54, 55). In this scenario, an obvious approach was to add immunotherapy to the stand-ard chemotherapy regimens and maintenance with anti–PD-1/PD-L1 immunotherapy as suggested by phase II trials. Amazing unprecedented efficacy in terms of OS as compared with chemotherapy was observed for a pembrolizumab + chemotherapy combination either for adenocarcinoma (HR 0.49; P < 0.001; ref. 53) or for squamous histologies (HR 0.64; P < 0.001; ref. 56). Intriguingly, a parallel trial of chemo-therapy with nivolumab failed in its primary endpoint of OS to beat chemotherapy with the chemoimmunotherapy com-bination in the first-line setting (HR 0.86; P = 0.1859; ref. 57). Nonetheless, results from a randomized phase III clinical trial comparing the addition or not of nivolumab to carboplatin + paclitaxel + bevacizumab for first-line nonsquamous NSCLC have recently disclosed superiority for the nivolumab-con-

taining arm in terms of PFS (HR 0.56; P = 0.0001), while the study is yet immature for OS (58).

The anti–PD-L1 monoclonal antibody atezolizumab com-bined with carboplatin/cisplatin and pemetrexed for first-line metastatic nonsquamous NSCLC improved PFS compared with chemotherapy alone (HR 0.596; P < 0.0001; ref. 59). Similar benefit in PFS for a chemoimmunotherapy combi-nation with atezolizumab in squamous NSCLC came from another phase III trial (HR 0.71; P = 0.0001), but OS was no longer in the chemoimmunotherapy arm (60). Most recently, ipilimumab + nivolumab combined with chemotherapy sur-passed chemotherapy alone as a first-line treatment (HR 0.69; P = 0.0006; ref. 61).

Frequent crossover from chemotherapy to immunotherapy did not prevent improved survival, thus supporting the notion that sequencing both approaches is less beneficial. Impor-tantly, benefit extended to patients with tumors presenting low or no expression of PD-L1. Safety profiles of the combina-tion were tolerable, and >grade 3 adverse events were similar in percentages to chemotherapy + placebo (53, 56). However, as mentioned, the discontinuation rate was higher in the chemo-immunotherapy arm in the Keynote-189 trial (53).

Other PD-1/PD-L1–blocking-based combinations, includ-ing those with anti-CTLA4 antibodies and VEGF blockade, have also recently obtained FDA approval for first-line treat-ment of NSCLC. In this regard, the field has widened with the use of ipilimumab + nivolumab that surpasses chemotherapy, especially in those patients with a high tumor mutational bur-den (62), and atezolizumab + bevacizumab + chemotherapy, which is better than bevacizumab + chemotherapy (HR 0.78; P = 0.02; ref. 63). As mentioned above, nivolumab in combina-tion with chemotherapy + bevacizumab also rendered benefit over standard chemotherapy + bevacizumab (58).

The most astonishing results of immunotherapy in lung cancer have been observed in the neoadjuvant setting, where nivolumab achieved pathologic complete responses in 45% of cases (64). Several phase III clinical trials are evaluating the added benefit of combining immunotherapy and chemo-therapy in the neoadjuvant setting (Supplementary Table).

In small cell lung cancer (SCLC), recent results have also documented in first-line treatment that the addition of PD-L1 blockade with atezolizumab (65) or durvalumab (66) to standard platinum + etoposide yields better results than chemotherapy alone (HR 0.70, P = 0.007; HR 0.73, P = 0.0047, respectively, for atezolizumab or durvalumab). The benefit for pembrolizumab with etoposide + carboplatin over chemo-therapy alone has been reported in a phase III trial in terms of PFS (HR 0.75; P = 0.0023), but with a final analysis for OS that did not reach the significance boundary, even if a favorable tendency was observed (HR 0.80; P = 0.0164; ref. 67).

The clinical success of these combinations in the NSCLC and SCLC arenas has not been followed by deep mechanistic insight or the identification of predictive or pharmacody-namic biomarkers. The discovery and validation of such markers is crucial and the focus of ongoing efforts.

Chemoimmunotherapy of Breast CancerFrom the different types of carcinoma of the breast, HER2-

negative hormone receptor–negative [triple-negative breast cancer (TNBC)] remains a formidable clinical challenge. In






tabl

e 1.

Che

moi

mm

unot

hera

py c

linic

al p

hase

III t

rial

s w

ith

disc

lose

d ef

fica

cy re

sult

s

Indi

catio

nSt

age

Chem

othe

rapy

ag

ent

Imm

unot

hera

py

agen

tNC

TRe

f.Cl

inic

al ef

ficac

y (C

htIO

/Cht

)St

atis

tical

evid

ence

FDA

appr

oval

Clin

ical

be

nefit

NSCL

CM

TS 1

LPl

atin

um/P

emPe

mbr

oliz

umab

KEYN

OTE-

189

(NCT

0257

8680

)53

ORR

47.6

vs. 1

8.9%

; PF

S: 8

.8 m

vs. 4

.9 m

; OS

at 1

2 m

onth

s 69

.2%

vs. 4

9.4%

OS:

HR

0.49

(CI 0

.38–

0.64

);

P <

0.00

1Ye

sYe

s

NSCL

CM

TS 1

LPl

atin

um-b

ased

+

Pem

Atez

oliz

umab

IMpo

wer 1

32

(NCT

0265

7434

)59

ORR

47%

vs. 3

2%; P

FS

7.6

m vs

. 5.2

m; O

S 18

.1 m

vs. 1

3.6

m

PFS:

HR

0.59

6 (C

I 0.4

94–

0.71

9); P

< 0

.000

1No

Yes

NSCL

CM

TS 1

LHi

stol

ogy-

base

d Ch

TNi

volu

mab

Chec

kMat

e 22

7 (N

CT02

4778

26)

57OR

R 48

.1 vs

. 29.

3%;

PFS

8.7

vs. 5

.8 m

; OS

18.8

vs. 1

5.6

m

OS:

HR

0.86

(CI 0

.69–

1.08

); P

= 0

.185

9No

No

NSCL

CM

TS 1

LHi

stol

ogy-

base

d Ch

TNi

volu

mab

+

ipili

mum

abCh

eckM

ate

9LA

(NCT

0321

5706

)61

ORR

38 vs

. 25%

; PFS

6.

7 vs

. 5 m

; OS

15.6

vs

. 10.

9 m

; OS

at

1-ye

ar 6

3% vs

. 47%

OS:

HR

0.69

(CI 0

.55–

0.87

); P

= 0

.000

6Ye

sYe

s

NSCL

CM

TS 1

LCa

rb +

Pac

l +

Bev

Nivo

lum

abTA

SUKI

-52

(O

NO-4

538-

52)

58PF

S 12

.12

vs. 8

.11

m;

OS n

ot m

atur

ePF

S: H

R 0.

56 (C

I 0.4

3–0.

71);

P =

0.0

001

NoYe

s

NSCL

CM

TS 1

LCa

rb +

Pac

l +

Bev

Atez

oliz

umab

IMpo

wer1

50

(NCT

0236

6143

)63

ORR

63.5

vs. 4

8%; P

FS

8.3

vs. 8

.6 m

; OS

19.2

vs

. 14.

7 m

OS:

HR

0.78

(CI: 0

.64–

0.96

); P

= 0

.02

Yes

Yes

NSCL

Csq

MTS

1L

Carb

+ N

ab-

Pacl

/Pac

lPe

mbr

oliz

umab

KEYN

OTE-

407

(NCT

0277

5435

)56

ORR

57.9

vs. 3

8.4%

; PF

S 6.

4 vs

. 4.8

m; O

S 15

.9 vs

. 11.

3 m

OS:

HR

0.64

(CI 0

.49–

0.85

); P

< 0

.001

Yes

Yes

NSCL

Csq

MTS

1L

Carb

+ P

acl/

Nab-

Pacl

Atez

oliz

umab

IMpo

wer1

31

(NCT

0236

7794

)60

ORR

49 vs

. 41%

; PFS

6.

3 m

vs. 5

.6 m

; OS

14.2

m vs

. 13.

5 m

PFS:

HR

0.71

(CI 0

.60–

0.85

);

P =

0.00

01No

No

SCLC

MTS

1L

Carb

+ E

top

Atez

oliz

umab

IMpo

wer1

33

(NCT

0276

3579

)65

ORR

60.2

vs. 6

4.4%

; PF

S 5.

2 vs

. 4.3

m; O

S 12

.3 vs

. 10.

3 m

OS:

HR

0.70

(CI 0

.54–

0.91

); P

= 0

.007

Yes

Yes

SCLC

MTS

1L

Carb

+ E

top

Durv

alum

abCA

SPIA

N (N

CT03

0438

72)

66OR

R 68

vs. 5

8%; O

S 13

vs

. 10.

3 m

OS:

HR

0.73

(CI 0

.59–

0.91

); P

= 0

.004

7Ye

sYe

s

SCLC

MTS

1L

Carb

/Cis

+ E

top

Pem

brol

izum

abKE

YNOT

E-60

4 (N

CT03

0667

78)

67OR

R 70

.6 vs

. 61.

8%;

PFS

4.5

vs. 4

.3 m

; OS

10.8

vs. 9

.7 m

PFS:

HR

0.75

(CI 0

.61–

0.91

); P

= 0.

0023

. OS:

HR

0.80

(0

.64–

0.98

); P

= 0.

0164

NoYe

s?






Brea

st T

NM

TS 1

LNa

b-Pa

clAt

ezol

izum

abIM

pass

ion

130

(NCT

0242

5891

)68

, 69,

70

PFS:

7.2

vs. 5

.5 m

; OS

(ITT)

: 21

vs. 1

8.7

m;

OS (P

D-L1

>1%

): 25

.4

vs. 1

7.9

m

PFS:

HR

0.80

(CI 0

.69–

0.92

); P

= 0.

002

OS

(ITT

): HR

0.8

7 (C

I 0.7

2–1.

02); P

= 0.

078

OS

(PD

-L>1

%):

HR 0

.67

(CI

0.53

–0.8

6)

Yes,

PD-L

1 (+

)No

Brea

st T

NM

TS 1

LPa

clAt

ezol

izum

abIM

pass

ion

131

(NCT

0312

5902

)71

ORR

54 vs

. 47%

; PFS

5.

7 vs

. 5.6

m; O

S 19

.2

vs. 2

2.8

m

OS:

HR

1.12

(CI 0

.76–

1.65

) PF

S: H

R 0.

82 (C

I 0.6

0–1.

12)

NoNo

Brea

st T

NM

TS 1

LNa

b-Pa

cl o

r Pac

l or

Car

b +

Gem

Pem

brol

izum

abKE

YNOT

E-35

5 (N

CT02

8195

18)

72PF

S (C

PS>1

0) 9

.7 vs

. 5.

6 m

; PFS

(CPS

>1)

7.6

vs. 5

.6 m

PFS

(CPS

>10)

: HR

0.65

(CI

0.49

–0.8

6) P

= 0

.004

11Ye

s (PD

-L1

CPS>

10)

Yes

Brea

st T

NNe

oAd

Pacl

+ C

yclo

ph +

Do

xor/

Epi

Pem

brol

izum

abKE

YNOT

E-52

2 (N

CT03

0364

88)

75pC

R 64

.8%

vs. 5

1.2%

pCR

: Inc.

13.6

%; C

I 5.4

to 2

1.8;

P

< 0.

001

NoYe

s

Brea

st T

NNe

oAd

Carb

+ N

ab-P

acl

Atez

oliz

umab

NeoT

RIPa

PDL1

(N

CT02

6202

80)

76pC

R 43

.5%

vs. 4

0.8%

Not a

vaila

ble

NoNo

Brea

st T

N ea

rlyNe

oAd

Pacl

+ C

yclo

ph +

Do

xor

Atez

oliz

umab

IMpa

ssio

n031

(N

CT03

1979

35)

77pC

R 57

.6%

vs. 4

1.1%

pCR

: Inc.

16.5

% (5

.9, 2

7.1)

; 1-

side

d P

= 0.

0044

NoYe

s

Blad

der

MTS

1L

Gem

+ C

is/C

arb

Avel

umab

(mai

nte-

nanc

e)JA

VELI

N Bl

adde

r 10

0 (N

CT02

6034

32)

87OS

21.

4 m

vs. 1

4.3

mO

S: H

R 0.

69 (C

I 0.5

6–0.

86);

1-si

ded P

= 0.

0005

Yes

Yes

Blad

der

MTS

1L

Gem

+ C

is/C

arb

Pem

brol

izum

abKE

YNOT

E-36

1 (N

CT02

8533

05)

89OR

R 54

.7 vs

. 44.

9%;

PFS

8.3

vs. 7

.1 m

; OS

17 vs

. 14.

3 m

PFS:

HR

0.78

(IC

0.65

–0.9

3);

P =

0.00

33. O

S: H

R 0.

86 (I

C 0.

72–1

.02)

; P =

0.0

407

NoNo

HNC

MTS

1L

Carb

/Cis

+ 5

-FU

or C

arb/

Cis +

5-

FU +

Cet

ux

Pem

brol

izum

abKE

YNOT

E-04

8 (N

CT02

3580

31)

92OR

R 35

vs. 1

9%; O

S (IT

T): 1

3 vs

. 10.

7 m

. OS

(CPS

≥1):

13.6

vs.

10.4

m. O

S (C

PS≥2

0):

14.7

vs. 1

1 m

OS

(ITT

): HR

0.7

7 (C

I 0.

63–0

.93)

; P =

0.0

034.

O

S (C

PS≥1

): HR

0.6

5 (C

I 0.

53–0

.80)

; P <

0.0

001.

O

S (C

PS≥2

0): 0

.60

(CI

0.45

–0.8

2); P

= 0

.000

4

Yes C

PS≥1

Yes

Gast

ricM

TS 1

LCi

s + 5

-FU/

Cape

Pem

brol

izum

abKE

YNOT

E-06

2 (N

CT02

4945

83)

101

ORR

52.5

% vs

. 36.

7%;

PFS

(CPS

≥1) 6

.9 m

vs

. 6.4

m; O

S (C

PS≥1

) 12

.5 vs

. 11.

1 m

OS

(CPS

≥10)

12.

3 vs

. 10

.8 m

OS

(CPS

≥1):

HR, 0

.85

(CI

0.70

–1.0

3); P

= 0

.05.

OS

(CPS

≥10)

: HR,

0.8

5 (C

I 0.

62–1

.17)

; P =

0.1

6

NoNo

Gast

ric/E

s-op

hage

alM

TS 1

LCa

pe +

Oxa

li/

5-FU

+ O

xali

Nivo

lum

abCh

eckM

ate-

649

(NCT

0287

2116

)10

2PF

S (P

D-L1

CPS

≥5)

7.6

vs. 6

.1 m

; OS

(all)

13

.8 vs

. 11.

6 m

OS

(all)

: HR

0.80

(C

I 0.6

8–0.

94); P

= 0.

0002

. PF

S (C

PS≥5

): HR

0.6

8

(CI 0

.56–

0.81

); P

< 0.

0001

NoYe

s

(continued)






Indi

catio

nSt

age

Chem

othe

rapy

ag

ent

Imm

unot

hera

py

agen

tNC

TRe

f.Cl

inic

al ef

ficac

y (C

htIO

/Cht

)St

atis

tical

evid

ence

FDA

appr

oval

Clin

ical

be

nefit

Gast

ricM

TS 1

LS-

1 +

Oxal

i/Ca

pe +

Oxa

liNi

volu

mab

ATTR

ACTI

ON

(ONO

-453

8–37

)10

3OR

R 57

.5 vs

. 47.

8%;

PFS

10.5

vs. 8

.3 m

; OS

17.

5 vs

. 17.

2 m

PFS:

HR

0.68

(CI 0

.51–

0.90

);

P =

0.00

07 O

S: H

R 0.

90

(CI 0

.75–

1.08

); P

= 0.

257

NoYe

s

Esop

hage

alAd

juva

ntCR

TNi

volu

mab

Chec

kMat

e 57

7 (N

CT02

7434

94)

104

DFS

22.4

vs. 1

1 m

DFS

: HR

0.69

(CI 0

.56–

0.86

); P

= 0

.000

3No

Yes

Esop

hage

alM

TS 1

LCi

s + 5

-FU

Pem

brol

izum

abKE

YNOT

E-59

0 (N

CT03

1897

19)

105

ORR

(all)

45

vs. 2

9.3%

; PF

S (a

ll) 6

.3 vs

. 5.8

m;

OS (a

ll) 1

2.4

vs. 9

.8 m

PFS

(all)

: HR

0.65

(CI,

0.55

–0.7

6); P

< 0

.000

1. O

S (a

ll): H

R, 0

.73

(CI 0

.62–

0.86

); P

< 0.

0001

NoYe

s

Glio

blas

tom

aM

TS 1

LTe

moz

+ R

TNi

volu

mab

Chec

kMat

e-54

8 (N

CT02

6675

87)

[pre

ss re

leas

e].

Prin

ceto

n, N

J: BM

S; M

ay 9

, 201

9

PFS

not i

mpr

oved

, OS

not m

atur

eRe

sults

not

pub

lishe

dNo

No

Ovar

ian

NeoA

d/Ad

Carb

+ P

acl +

Be

vAt

ezol

izum

abIM

agyn

050

(NCT

0303

8100

)An

n On

col.

2020

;31:

S1

161–

S116

2.

PFS

(ITT)

19.

5 vs

. 18.

6 m

; PFS

(PD-

L1+)

20.

8 vs

. 18.

5 m

; OS

not

mat

ure

PFS

(ITT

): HR

0.9

2 (C

I 0.

79–1

.07)

. PFS

(PD

-L1+

): HR

0.8

0 (C

I 0.6

5–0.

99)

NoNo

NOTE

: Eac

h cl

inic

al tr

ial i

s ref

erre

d to

acc

ordi

ng to

text

bib

liogr

aphy

. Ab

brev

iatio

ns: 5

-FU,

5-F

luor

oura

cile

; Bev

, bev

aciz

umab

; Cap

e, ca

peci

tabi

ne; C

arb,

carb

opla

tin; C

etux

, cet

uxim

ab; C

hT, c

hem

othe

rapy

; Cis

, cis

plat

in; C

PS, P

D-L1

com

bine

d po

sitiv

e sc

ore;

CRT

, che

mor

adio

-th

erap

y; C

yclo

ph, c

yclo

phos

pham

ide;

Dox

or, d

oxor

ubic

in; D

FS, d

isea

se-f

ree

surv

ival

; Epi

, epi

rubi

cin;

Eto

p, e

topo

side

; Gem

, gem

cita

bine

; ITT,

inte

ntio

n-to

-tre

at; H

NC, h

ead

and

neck

canc

er; M

TS, m

etas

tatic

; Na

b-Pa

cl, n

ab-p

aclit

axel

; Neo

Ad, n

eoad

juva

nt; N

eoAd

/Ad,

neo

adju

vant

and

/or a

djuv

ant;

NSCL

C, n

on–s

mal

l cel

l lun

g ca

ncer

squa

mou

s and

non

-squ

amou

s; NS

CLCs

q, sq

uam

ous n

on–s

mal

l cel

l lun

g ca

ncer

; OR

R, o

bjec

tive

resp

onse

rate

; OS,

ove

rall

surv

ival

; Oxa

li, o

xalip

latin

; Pac

l, pac

litax

el; P

em, p

emet

rexe

d; P

FS, p

rogr

essi

on-f

ree

surv

ival

; pCR

, pat

holo

gic c

ompl

ete

resp

onse

; RT,

radi

othe

rapy

; Tem

oz, t

emo-

zola

mid

e; T

N, tr

iple

neg

ativ

e.

tabl

e 1.

Che

moi

mm

unot

hera

py c

linic

al p

hase

III t

rial

s w

ith

disc

lose

d ef

fica

cy re

sult

s (C

onti

nued

)






the absence of targeted therapy, the standard of care includes several lines of chemotherapy.

Much enthusiasm and expectation were originally raised by the published results of a clinical trial testing first-line treatment of metastatic TNBC using a combination of nab-paclitaxel + atezolizumab that conferred a better PFS for the combination arm over chemotherapy alone (HR 0.80; P = 0.002), which was higher in the PD-L1–positive tumors (68). However, the final results for OS were negative for the intention-to-treat population (HR 0.87; P = 0.078; refs. 69, 70). The clinical benefit has been described to be almost restricted to patients with PD-L1 > 1% (HR 0.67; refs. 69, 70). Given these results, the field underwent a significant degree of confusion, and the FDA issued an alert regarding the mar-keting approval. Furthermore, a trial that tested paclitaxel in combination with atezolizumab versus paclitaxel in mono-therapy also for first-line TNBC has rendered negative results [HR (OS) 1.12; HR (PFS) 0.82; ref. 71]. In this case, the need for immunosuppressive steroids to permit administration of the weekly taxane might have been involved in the lack of superiority for the chemoimmunotherapy.

A phase III clinical trial comparing pembrolizumab in combination with chemotherapy (paclitaxel, nab-paclitaxel, or carboplatin/gemcitabine) versus chemotherapy alone has shown a significant benefit for the chemoimmunotherapy combination in those patients with combined positive score (CPS) ≥ 10 (HR 0.65; P = 0.00411), leading to FDA approval, but results were not statistically significant for patients with CPS ≤ 1 (72). Of important note, numerous phase I–II clinical trials are exploiting chemoimmunotherapy combinations in patients with metastatic TNBC (Supplementary Table).

In early-stage TNBC following diagnostic biopsy, neoadjuvant chemotherapy regimens have been shown to be highly beneficial to avoid relapse (73). Recently, combination results with pem-brolizumab added to the neoadjuvant chemotherapy regimens in two randomized phase II–III trials enhanced the percentage of pathologic complete responses. In this phase II trial (I-SPY2), the pathologic complete response rate in the combination arm was 60% compared with 20% in the chemotherapy-alone arm (74). In the phase III clinical trial, the pathologic complete response rate was 64.8% in the pembrolizumab + chemotherapy arm and 51.2% in the chemotherapy arm (estimated treatment difference 13.6%; P < 0.001; ref. 75) and will be probably conducive to a survival benefit. A randomized study with atezolizumab + chemotherapy in a similar neoadjuvant setting was, however, negative (from 40.8% to 43.5%), even in the PD-L1–positive population (76). Nonetheless, a phase III clinical trial of atezolizumab + chemo-therapy in early-stage TNBC has concluded benefit for chemo-immunotherapy, with pathologic complete responses seen in 57.6% versus 41.1% (P = 0.0044; ref. 77). Whether these findings translate into OS and PFS benefit needs longer follow-up.

A phase II randomized clinical trial in the neoadjuvant setting that combines durvalumab versus placebo plus chemo therapy (nab-paclitaxel sequenced to epirubicine + cyclophosphamide) did not show a significant improvement in pCR, although those patients who had received durvalumab alone two weeks before starting chemotherapy had a better and significant pCR advantage versus those who did not receive durvalumab (61.0% vs. 41.4%; OR 2.22; 95% CI 1.06–4.64; P = 0.035; ref. 78). These results stress again the importance of an adequate treatment

sequencing of chemo and immunotherapy to achieve the best from such combinations.

At present, the field of TNBC awaits clarification on whether there is a benefit of chemoimmunotherapy versus chemother-apy alone. It could be that the type of chemotherapy, the level of expression of PD-L1, and the vast genetic/transcriptomic heterogeneity of TNBC subtypes matter (79). In this regard, taxanes are considered weak inducers of immunogenic cell death, whereas anthracyclines and alkylating agents are con-sidered to be more proimmunogenic (16). Only further trans-lational research will be able to clarify these points.

Chemoimmunotherapy of Genitourinary TumorsPD-1/PD-L1 immunotherapy is standard therapy in RCC

(80). Prior to the advent of checkpoint blockade, the standard of care for first-line clear cell RCC (ccRCC) treatment was not chemotherapy, but rather antiangiogenic tyrosine kinase inhibitors (TKI). Following the usual paradigm of adding immunotherapy to standard-of-care therapy, first-line treat-ment of metastatic ccRCC now includes combinations of anti–PD-1 with antiangiogenic agents such as axitinib + pem-brolizumab (38), avelumab + axitinib (39), and nivolumab + ipilimumab (81), which in all cases outperformed sunitinib. In this disease, further addition of chemotherapy would be complicated because of its lack of efficacy on its own and the potential for increased toxicity.

In contrast, metastatic urothelial carcinoma has clearly benefited to some extent from platinum-based chemotherapy (82). Pembrolizumab and atezolizumab are approved for sec-ond-line treatment of metastatic urothelial carcinoma (83, 84, 85) and as first-line treatment for patients who are ineligible for cisplatin (86). Recently, a phase III clinical trial comparing avelumab as maintenance after an induction phase of chemo-therapy versus best supportive care resulted in overwhelm-ingly better results for the immunotherapy over placebo (HR 0.69; one-sided P = 0.0005), thus leading to FDA approval (87). More recently, exploratory biomarkers in biopsies indicated that those patients with indicators of lymphocyte activity ben-efited the most with avelumab maintenance, whereas benefit was negatively associated with markers of chronic inflamma-tion (88). By contrast, recently released results from a phase III clinical trial in first line failed to meet the statistical thresh-olds for the benefit of pembrolizumab combined with chemo-therapy as compared with chemotherapy alone, even though there was a clear tendency in favor of chemoimmunotherapy [HR (PFS) 0.78; P = 0.0033; HR (OS) 0.86; P = 0.0407; ref. 89]. This trial (KEYNOTE 361) is very interesting in its three-arm design because it compares chemotherapy alone with chemoimmunotherapy and includes a third immunotherapy-alone arm. However, the comparison with the pembrolizumab single-treatment arm is not available yet.

In castration-resistant metastatic prostate cancer, a ben-eficial effect of checkpoint inhibitors remains to be seen, although taxane chemotherapy is indicated following hor-monal therapy failure. Perhaps subgroups of patients such as those with microsatellite-unstable or BRCA-mutant pros-tate cancer may benefit from the addition of checkpoint inhibitors to chemotherapy, as is being tested in clinical trials (NCT03834506). As mentioned, one of the potential prob-lems for taxanes is the need for them to be accompanied by






steroids, which in pharmacodynamics terms may be at odds with checkpoint inhibitors.

Chemoimmunotherapy of Squamous Head and Neck Cancer

Nivolumab and pembrolizumab are approved for second-line treatment of head and neck cancers (90, 91). Conven-tional first-line treatment involves the use of chemotherapy and anti-EGFR (cetuximab). Pembrolizumab monotherapy is also approved for first-line treatment of patients whose tumors are CPS > 20 (92). In the same trial (KEYNOTE-048), chemotherapy + pembrolizumab was found to be superior to cetuximab + chemotherapy in the intention-to-treat, in CPS > 1, and in CPS > 20 populations in OS (HR 0.77, 0.65, and 0.60, respectively; P = 0.0034, P < 0.0001, P = 0.0004, respectively), although chemoimmunotherapy did not show superior PFS (92). In this regard, it is worth mentioning that immuno-therapy seems to enable more durable objective responses in this setting. The nature of this disease offers many opportuni-ties for neoadjuvant or adjuvant chemoimmunotherapy treat-ments that are already under intensive investigation in early stages of the disease (Supplementary Table).

Chemoimmunotherapy for Gastrointestinal Tumors

Immunotherapy with checkpoint inhibitors has demon-strated clinical benefit in patients with metastatic microsat-ellite-unstable colorectal cancer (93), gastric cancer (94), and HCC (95). PD-1/PD-L1 immunotherapy alone minimally affects disease response in patients with pancreatic ductal adenocar-cinoma (PDAC; ref. 96); even in microsatellite instability–high (MSI-H) cases the response rate is below 20% (97). Chemo-therapy regimens are considered first-line standard of care for colorectal cancer (in combination with cetuximab or bevaci-zumab), gastric cancer, esophageal cancer, and PDAC.

Colorectal Cancer

In metastatic microsatellite-stable (MSS) colorectal cancer, the use of checkpoint inhibitors thus far offers only anecdotal evidence of clinical activity, despite the fact that T-cell infil-tration of primary tumors very much determines prognosis (98). However, recent evidence shows that PD-1 blockade in neoadjuvant regimens prior to removal of resectable primary MSS tumors achieves frequent pathologic responses (99). This disease arena might become fertile for combination regimens including novel immunotherapy agents that are postulated to synergize with chemotherapy regimens. As mentioned, for MSI-H metastatic colorectal cancer, pembrolizumab mono-therapy has demonstrated improved PFS over standard of care (chemotherapy plus bevacizumab or cetuximab), supporting recent FDA approval for the indication (100).

Gastric and Esophageal Cancer

Recent data released at the European Society for Medical Oncology (ESMO) Virtual Congress 2020 regarding gastro-esophageal junction (GEJ) and gastric cancer provide evi-dence for chemoimmunotherapy in the first-line setting of these diseases. Publication of such evidence in metastatic or advanced gastric cancer is eagerly awaited because com-munications in congresses seem to be conflicting to some

extent with previous observations. A randomized phase III trial (101) concluded that the addition of chemotherapy to pembrolizumab apparently worsens survival over pem-brolizumab or chemotherapy as single treatments (ref. 101; Table 1). Although there may be issues in this trial of patient selection, these results alert us to the fact that chemoimmu-notherapy will not be universally beneficial. In line with this, it is possible that agents such as 5-fluorouracile, commonly used in digestive tumor regimens, might be deleterious for anticancer immune responses (51), even more so when used as an add-on rather than in sequential strategies. In striking contrast, recent results from another phase III trial evaluating chemoimmunotherapy combination in first line for advanced cancer of the GEJ/gastric cancer with nivolumab have shown benefit in PFS and OS in the prespecified interim analysis in those patients who received the combination and expressed PD-L1 CPS ≥ 5 [HR (OS) 0.80; P = 0.0002, and HR (PFS CPS ≥ 5) 0.68; P < 0.0001; ref. 102], leading to FDA marketing approval. In the same regard, another study in Asian patients comparing nivolumab + chemotherapy versus chemotherapy for first-line advanced GEJ/gastric cancer showed benefit for chemoimmunotherapy in PFS (HR 0.68; P = 0.0007; ref. 103).

In the localized setting of GEJ/gastric cancer following neoadjuvant chemoradiation and post-resection, adjuvant treatment with nivolumab resulted in a disease-free sur-vival benefit as compared with placebo (HR 0.69; P = 0.003; ref. 104).

In advanced esophageal cancer, more specifically in squamous with PD-L1 CPS > 10, there was a very clear benefit for chemoim-munotherapy over chemotherapy alone (HR 0.57; P < 0.0001), although these positive outcomes favoring chemoimmuno-therapy are also expanded to the intention-to-treat population (HR 0.73; P < 0.0001; ref. 105). It would have been very interest-ing to have an immunotherapy-alone arm in this study.

HCC

In the case of HCC, chemotherapy has never been first-line standard of care, whereas TKIs (sorafenib and lenvatinib) still are. However, chemoembolization is often used for local-ized disease. In advanced stages, PD-L1 blockade has shown remarkable results in combination with VEGF blockade with bevacizumab over sorafenib (40), changing standard of care. In this disease scenario, considered to be off-limits for chemo-therapy, the incorporation of moderate doses of chemo-therapy to instigate anticancer immunity is to be explored to further increase efficacy.

PDAC

Metastatic and locally advanced PDAC remains a daunting challenge for clinical oncology. As mentioned, immunother-apy with checkpoint inhibitors has not yielded any valuable results, even in MSI-H cases (96, 97). Chemotherapy of differ-ent kinds offers very limited OS benefit (106). In the context of chemoimmunotherapy, a phase II clinical trial combining gemcitabine + nab-paclitaxel with or without durvalumab + tremelimumab has recently disclosed no PFS or OS benefit (107). However, there are reasons for hope because radiologic responses were achieved in 32% of 23 metastatic patients given a regimen encompassing pembrolizumab + 5-FU/leucovorin + Onyvide (liposomal pegylated irinotecan) chemotherapy






together with an antagonist of the CXCR4 chemokine recep-tor (108). Further development of this strategy is warranted and should advance to earlier localized stages of this deadly disease.

cRitical peRspectiveChemoimmunotherapy combinations are changing several

paradigms in clinical practice. This approach has been sim-ple and consisted merely of standard-of-care chemotherapy regimens being added to immunotherapy and then being compared with chemotherapy plus placebo. Although this is the most feasible and convenient way to clinically develop this approach, we must remember that the elements in the combination have not been optimized at all. This means that doses, sequence of agents, drugs, and schedules are most likely suboptimal with much potential for improvement (Fig. 2). Knowing that chemotherapy was developed on the basis of a maximal tolerated dosing philosophy, it is likely that at such levels chemotherapy agents are causing some degree of immune cell toxicity. This could be affecting the long-term effects of immunotherapy working against the plateau of the tail in the survival curve, which is so dear to patients and physicians. Whenever possible, an immunotherapy-alone arm should be considered as an additional comparator in clinical

trials to really ascertain the benefit of chemoimmunotherapy combinations.

To move forward, these issues should be reexamined in preclinical models testing the concept that, at least in certain cases, less chemotherapy in combination with immunotherapy might be conducive to better efficacy. Considering the mecha-nisms of synergy between chemotherapy and immunotherapy (Fig. 1), sequential approaches might be useful, and these need to be empirically developed in animal models and subsequently in clinical trials. In this regard, a detailed characterization in preclinical models of the profile of immune effects exerted by each chemotherapy agent should be undertaken as has been done for immunogenic cell death (18), but also considering direct or indirect effects on immune system cells.

Unconventional exploratory clinical trial designs can be undertaken, as has been done in the TONIC trial for meta-static TNBC, in which preconditioning chemotherapy and radiotherapy regimens were compared, followed by PD-1 blockade with nivolumab. This trial recruited small rand-omized cohorts of about 10 to 15 patients. Interestingly, doxorubicin showed better objective response rate (ORR) than cisplatin, radiotherapy, or cyclophosphamide (109). Fur-thermore, presurgical treatments will allow using pathologic responses and time-to-progression as potential surrogate endpoints to eventually determine patient survival benefit.

Figure 2. Road map with the main points of improvement in chemotherapy approaches. Schematic representation of the main criteria and elements to further improve the efficacy of chemoimmunotherapy combinations. TCR, T-cell receptor.

Drug selection

Dose

Chemoimmunologicbiomarkers:Pre and post

• Standard of careImmunogenic cell deathT-lymphocyte friendly

••

• Standard-of-care dose • Maximal tolerated dose • Most beneficial

immunotherapy dose

• Concomitant • Chemotherapy first • Immunotherapy first • Chemotherapy maintenance • Immunotherapy maintenance

• Overall survival vs.progression-free survivalDuration of response vs.overall response rateDifferent statisticalmethods to assess theresponsePercentage of long-termsurvivorsReductions ofhyperprogression cases

•

•

•

•

• Tumor: T-cell infiltration, myeloidinfiltration, tumor cell apoptosis,pathologic complete response

• Blood: ctDNA, T-cell activation,circulating cytokines, TCR clonality

Schedule and sequencing

Assessing response

Optimizingchemoimmunotherapy






This issue of sequencing becomes further complicated by the advent of new immunotherapy agents that will be tested in the arena of the new chemoimmunotherapy standards of care. Nonetheless, concomitancy of treatments may allow chemotherapy to prevent cases of hyperprogression upon exposure to checkpoint inhibitors. This is particularly rel-evant considering that single-agent immunotherapy has been consistently associated with hyperprogressive disease in cer-tain solid malignancies (110).

The role of surgery remains to be reexamined in the context of chemoimmunotherapy (111), because, contrary to general beliefs, debulking in metastatic stages may be beneficial for immunotherapy as a consequence of removing immunosup-pressive factors dependent on tumor mass and reducing the amount of disease to be prey of the immune system.

In our opinion, chemoimmunotherapy regimens should advance to first-line treatment in a number of diseases at metastatic stages. The safety profile of chemoimmunother-apy will probably allow the development of combinations in neoadjuvant settings, in which reductions in chemotherapy intensity might be tested. Importantly, it should not be for-gotten that improvements in ORR and PFS do not necessarily lead to longer OS, and ultimately the long-term tail under the Kaplan–Meier curve is the most striking value of immu-notherapy, and unfortunately the one that potentially can be curtailed by chemotherapeutics.

It is of note that there are abundant reports from experi-ence outside clinical trials that speak of the unexpected objec-tive responses that do occur upon use of subsequent lines of chemotherapy in patients who had recently progressed to checkpoint inhibitors (68).

In chemoimmunotherapy trials, biomarker studies are to be encouraged, even as substudies in larger randomized stud-ies. In our quest to make the most of chemoimmunotherapy, we need to exploit biomarkers in sequential blood and tumor samples. This should provide suitable pharmacodynamic parameters for optimization of dose, schedule, and drug regimens. For instance, benefit of nab-paclitaxel + atezoli-zumab in TNBC seemed to depend on PD-L1 expression in the tumor microenvironment (69). However, in NSCLC such a correlation is much weaker, and nonexistent for the com-bination of chemotherapy with pembrolizumab (53) and the combination of ipilimumab + nivolumab + chemotherapy (61). The room for future treatment individualization of chemoimmunotherapies is therefore huge.

All things considered, chemoimmunotherapy has arrived in the clinical setting and will stay for years to come. How-ever, the field is to be considered in its infancy with regard to understanding mechanisms as well as to optimizing/indi-vidualizing treatments. Because of our imperfect knowledge, there will be mixtures of successes and failures in large rand-omized clinical trials. This overall strategy deserves attention back on the laboratory bench and in translational research-oriented clinical trials, because efficacy could most likely be further improved in a meaningful fashion.

Authors’ DisclosuresD. Salas-Benito reports being employed at the clinical trial unit

of Clínica Universidad de Navarra. J.L. Pérez-Gracia reports grants, personal fees, and non-financial support from Roche, BMS, MSD,

and Seattle Genetics, grants and personal fees from Ipsen, grants from Eisai, Incyte, and Janssen outside the submitted work. M. Ponz-Sarvisé reports grants and personal fees from BMS and Roche and personal fees from Incyte outside the submitted work. I. Martínez-Forero reports personal fees from MSD during the conduct of the study. E. Castañón reports personal fees from AstraZeneca, Roche, BMS, and MSD outside the submitted work. M.F. Sanmamed reports grants from Roche outside the submitted work. I. Melero reports grants and personal fees from Roche, Alligator, AstraZeneca, Gen-mab, and Bristol Myers and personal fees from F-Star, Numab, Phar-mamar, Gossamer, and Merck Serono outside the submitted work. No disclosures were reported by the other authors.

AcknowledgmentsThis work was supported by Miniserio de ciencia e innovación

(SAF2017-83267-C2-1-R), Asociación Española contra el cáncer GCB15152947MELE, and PROCROP European commission HORIZON 2020. We are grateful for healthy discussion with Dr. Jesús San Miguel, Dr. Antonio González, Dr. Ignacio Gil Bazo, and Dr. Carlos de Andrea. Professional English editing by Dr. Paul Miller is also acknowledged.

Received September 16, 2020; revised November 21, 2020; accepted January 4, 2021; published first March 12, 2021.

REFERENCES 1. Cannellos GP, Young RC, DeVita VT. Combination chemotherapy

for advanced Hodgkin’s disease in relapse following extensive radio-therapy. Clin Pharmacol Ther13:750–4.

2. Peckham MJ, Barrett A, Liew KH, Horwich A, Robinson B, Dobbs HJ, et al. The treatment of metastatic germ-cell testicular tumours with bleomycin, etoposide and cisplatin (BEP). Br J Cancer 1983;47: 613–9.

3. Spiers AS, Roberts PD, Marsh GW, Parekh SJ, Franklin AJ, Galton DA, et al. Acute lymphoblastic leukaemia: cyclical chemotherapy with three combinations of four drugs (COAP-POMP-CART regimen). Br Med J 1975;4:614–7.

4. Nagai Y, Oitate M, Shiozawa H, Ando O. Comprehensive preclini-cal pharmacokinetic evaluations of trastuzumab deruxtecan (DS-8201a), a HER2-targeting antibody-drug conjugate, in cynomolgus monkeys. Xenobiotica 2019;49:1086–96.

5. Johnson ML, El-Khoueiry AB, Hafez N, Lakhani NJ, Mamdani H, Rodon Ahnert J, et al. CX-2029, a PROBODY drug conjugate tar-geting CD71 (transferrin receptor): Results from a first-in-human study (PROCLAIM-CX-2029) in patients (Pts) with advanced cancer. J Clin Oncol 2020;38:3502.

6. Rasmussen L, Arvin A. Chemotherapy-induced immunosuppres-sion. Environ Health Perspect 1982;43:21–5.

7. Ribas A, Wolchok JD. Cancer immunotherapy using checkpoint blockade. Science 2018;359:1350–5.

8. June CH, O’Connor RS, Kawalekar OU, Ghassemi S, Milone MC. CAR T cell immunotherapy for human cancer. Science 2018;359: 1361–5.

9. Rosenberg SA, Restifo NP. Adoptive cell transfer as personalized immunotherapy for human cancer. Science 2015;348:62–8.

10. Goff SL, Dudley ME, Citrin DE, Somerville RP, Wunderlich JR, Danforth DN, et al. Randomized, prospective evaluation comparing intensity of lymphodepletion before adoptive transfer of tumor-infiltrating lymphocytes for patients with metastatic melanoma. J Clin Oncol 2016;34:2389–97.

11. Rabinovich GA, Gabrilovich D, Sotomayor EM. Immunosuppres-sive strategies that are mediated by tumor cells. Annu Rev Immunol 2007;25:267–96.

12. Russ AJ, Wentworth L, Xu K, Rakhmilevich A, Seroogy CM, Sondel PM, et al. Suppression of T-cell expansion by melanoma is exerted on resting cells. Ann Surg Oncol 2011;18:3848–57.






13. Casares N, Pequignot MO, Tesniere A, Ghiringhelli F, Roux S, Chaput N, et al. Caspase-dependent immunogenicity of doxoru-bicin-induced tumor cell death. J Exp Med 2005;202:1691–701.

14. Bruno PM, Liu Y, Park GY, Murai J, Koch CE, Eisen TJ, et al. A sub-set of platinum-containing chemotherapeutic agents kills cells by inducing ribosome biogenesis stress. Nat Med 2017;23:461–71.

15. Vanmeerbeek I, Sprooten J, De Ruysscher D, Tejpar S, Vandenberghe P, Fucikova J, et al. Trial watch: chemotherapy-induced immuno-genic cell death in immuno-oncology. Oncoimmunology 2020;9: 1703449.

16. Galluzzi L, Buqué A, Kepp O, Zitvogel L, Kroemer G. Immuno-genic cell death in cancer and infectious disease. Nat Rev Immunol 2017;17:97–111.

17. Menger L, Vacchelli E, Adjemian S, Martins I, Ma Y, Shen S, et al. Cardiac glycosides exert anticancer effects by inducing immuno-genic cell death. Sci Transl Med 2012;4:143ra99.

18. Galluzzi L, Humeau J, Buqué A, Zitvogel L, Kroemer G. Immuno-stimulation with chemotherapy in the era of immune checkpoint inhibitors. Nat Rev Clin Oncol 2020;17:725–41.

19. Sánchez-Paulete AR, Teijeira A, Cueto FJ, Garasa S, Pérez-Gracia JL, Sánchez-Arráez A, et al. Antigen cross-presentation and T-cell cross-priming in cancer immunology and immunotherapy. Ann Oncol Off J Eur Soc Med Oncol 2017;28:xii74.

20. Medzhitov R, Janeway CA. Decoding the patterns of self and nonself by the innate immune system. Science 2002;296:298–300.

21. Vanpouille-Box C, Hoffmann JA, Galluzzi L. Pharmacological mod-ulation of nucleic acid sensors – therapeutic potential and persisting obstacles. Nat Rev Drug Discov 2019;18:845–67.

22. Wanderley CW, Colón DF, Luiz JPM, Oliveira FF, Viacava PR, Leite CA, et al. Paclitaxel reduces tumor growth by reprogramming tumor-associated macrophages to an M1 profile in a TLR4-dependent manner. Cancer Res 2018;78:5891–900.

23. Bronte V, Brandau S, Chen S-H, Colombo MP, Frey AB, Greten TF, et al. Recommendations for myeloid-derived suppressor cell nomen-clature and characterization standards. Nat Commun 2016;7:12150.

24. Gabrilovich DI. Myeloid-derived suppressor cells. Cancer Immunol Res 2017;5:3–8.

25. Welters MJ, van der Sluis TC, van Meir H, Loof NM, van Ham VJ, van Duikeren S, et al. Vaccination during myeloid cell depletion by cancer chemotherapy fosters robust T cell responses. Sci Transl Med 2016;8:334ra52.

26. Melief CJM, Welters MJP, Vergote I, Kroep JR, Kenter GG, Ottevanger PB, et al. Strong vaccine responses during chemotherapy are associated with prolonged cancer survival. Sci Transl Med 2020;12:eaaz8235.

27. Suzuki E. Gemcitabine selectively eliminates splenic Gr-1+/CD11b+ myeloid suppressor cells in tumor-bearing animals and enhances antitumor immune activity. Clin Cancer Res 2005;11:6713–21.

28. Vincent J, Mignot G, Chalmin F, Ladoire S, Bruchard M, Chevriaux A, et al. 5-Fluorouracil selectively kills tumor-associated myeloid-derived suppressor cells resulting in enhanced T cell-dependent antitumor immunity. Cancer Res 2010;70:3052–61.

29. Buhtoiarov IN, Sondel PM, Wigginton JM, Buhtoiarova TN, Yanke EM, Mahvi DA, et al. Anti-tumour synergy of cytotoxic chemother-apy and anti-CD40 plus CpG-ODN immunotherapy through repolarization of tumour-associated macrophages. Immunology 2011;132:226–39.

30. Bonavita E, Galdiero MR, Jaillon S, Mantovani A. Phagocytes as cor-rupted policemen in cancer-related inflammation. Adv Cancer Res 2015;128:141–71.

31. Gattinoni L, Finkelstein SE, Klebanoff CA, Antony PA, Palmer DC, Spiess PJ, et al. Removal of homeostatic cytokine sinks by lym-phodepletion enhances the efficacy of adoptively transferred tumor-specific CD8+ T cells. J Exp Med 2005;202:907–12.

32. Sakaguchi S, Mikami N, Wing JB, Tanaka A, Ichiyama K, Ohkura N. Regulatory T cells and human disease. Annu Rev Immunol 2020;38:541–66.

33. Chen W, Jin W, Hardegen N, Lei K-J, Li L, Marinos N, et al. Conver-sion of peripheral CD4+CD25-naive T cells to CD4+CD25+ regula-

tory T cells by TGF-beta induction of transcription factor Foxp3. J Exp Med 2003;198:1875–86.

34. Zhao J, Cao Y, Lei Z, Yang Z, Zhang B, Huang B. Selective depletion of CD4+CD25+Foxp3+ regulatory T cells by low-dose cyclophospha-mide is explained by reduced intracellular ATP levels. Cancer Res 2010;70:4850–8.

35. Ge Y, Domschke C, Stoiber N, Schott S, Heil J, Rom J, et al. Met-ronomic cyclophosphamide treatment in metastasized breast can-cer patients: immunological effects and clinical outcome. Cancer Immunol Immunother 2012;61:353–62.

36. Wu J, Waxman DJ. Immunogenic chemotherapy: dose and schedule dependence and combination with immunotherapy. Cancer Lett 2018;419:210–21.

37. Le DT, Jaffee EM. Regulatory T-cell modulation using cyclophos-phamide in vaccine approaches: a current perspective. Cancer Res 2012;72:3439–44.

38. Rini BI, Plimack ER, Stus V, Gafanov R, Hawkins R, Nosov D, et al. Pembrolizumab plus axitinib versus sunitinib for advanced renal-cell carcinoma. N Engl J Med 2019;380:1116–27.

39. Motzer RJ, Penkov K, Haanen J, Rini B, Albiges L, Campbell MT, et al. Avelumab plus axitinib versus sunitinib for advanced renal-cell carcinoma. N Engl J Med 2019;380:1103–15.

40. Finn RS, Qin S, Ikeda M, Galle PR, Ducreux M, Kim T-Y, et al. Atezolizumab plus bevacizumab in unresectable hepatocellular car-cinoma. N Engl J Med 2020;382:1894–905.

41. Wu X, Li J, Connolly EM, Liao X, Ouyang J, Giobbie-Hurder A, et al. Combined anti-VEGF and anti-CTLA-4 therapy elicits humoral immunity to galectin-1 which is associated with favorable clinical outcomes. Cancer Immunol Res 2017;5:446–54.

42. Fukumura D, Kloepper J, Amoozgar Z, Duda DG, Jain RK. Enhanc-ing cancer immunotherapy using antiangiogenics: opportunities and challenges. Nat Rev Clin Oncol 2018;15:325–40.

43. Hanahan D, Bergers G, Bergsland E. Less is more, regularly: metro-nomic dosing of cytotoxic drugs can target tumor angiogenesis in mice. J Clin Invest 2000;105:1045–7.

44. Labiano S, Palazon A, Melero I. Immune response regulation in the tumor microenvironment by hypoxia. Semin Oncol 2015;42:378–86.

45. Finlay BB, Goldszmid R, Honda K, Trinchieri G, Wargo J, Zitvogel L. Can we harness the microbiota to enhance the efficacy of cancer immunotherapy? Nat Rev Immunol 2020;20(9):522–8.

46. Viaud S, Saccheri F, Mignot G, Yamazaki T, Daillère R, Hannani D, et al. The intestinal microbiota modulates the anticancer immune effects of cyclophosphamide. Science 2013;342:971–6.

47. Viaud S, Daillère R, Boneca IG, Lepage P, Langella P, Chamaillard M, et al. Gut microbiome and anticancer immune response: really hot Sh*t! Cell Death Differ 2015;22:199–214.

48. Elkrief A, Derosa L, Kroemer G, Zitvogel L, Routy B. The negative impact of antibiotics on outcomes in cancer patients treated with immunotherapy: a new independent prognostic factor? Ann Oncol Off J Eur Soc Med Oncol 2019;30:1572–9.

49. Geller LT, Barzily-Rokni M, Danino T, Jonas OH, Shental N, Nejman D, et al. Potential role of intratumor bacteria in mediating tumor resistance to the chemotherapeutic drug gemcitabine. Science 2017; 357:1156–60.

50. Walker SP, Tangney M, Claesson MJ. Sequence-based characteriza-tion of intratumoral bacteria—a guide to best practice. Front Oncol 2020;10:179.

51. Kazmers IS, Daddona PE, Dalke AP, Kelley WN. Effect of immu-nosuppressive agents on human T and B lymphoblasts. Biochem Pharmacol 1983;32:805–10.

52. Rapoport AP, Stadtmauer EA, Aqui N, Badros A, Cotte J, Chrisley L, et al. Restoration of immunity in lymphopenic individuals with cancer by vaccination and adoptive T-cell transfer. Nat Med 2005;11:1230–7.

53. Gandhi L, Rodríguez-Abreu D, Gadgeel S, Esteban E, Felip E, De Angelis F, et al. Pembrolizumab plus chemotherapy in metastatic non-small-cell lung cancer. N Engl J Med 2018;378:2078–92.

54. Reck M, Rodríguez-Abreu D, Robinson AG, Hui R, Csőszi T, Fülöp A, et al. Pembrolizumab versus chemotherapy for PD-L1-positive non-small-cell lung cancer. N Engl J Med 2016;375:1823–33.






55. Reck M, Rodríguez-Abreu D, Robinson AG, Hui R, Csőszi T, Fülöp A, et al. Updated analysis of KEYNOTE-024: pembrolizumab versus platinum-based chemotherapy for advanced non-small-cell lung cancer with PD-L1 tumor proportion score of 50% or greater. J Clin Oncol 2019;37:537–46.

56. Paz-Ares L, Luft A, Vicente D, Tafreshi A, Gümüş M, Mazières J, et al. Pembrolizumab plus chemotherapy for squamous non-small-cell lung cancer. N Engl J Med 2018;379:2040–51.

57. Paz-Ares L, Ciuleanu TE, Yu X, Salman P, Pluzanski A, Nagrial A, et al. LBA3 nivolumab (NIVO) + platinum-doublet chemotherapy (chemo) vs chemo as first-line (1L) treatment (tx) for advanced non-small cell lung cancer (aNSCLC): CheckMate 227 – part 2 final analysis. Ann Oncol 2019;30:xi67–8.

58. Lee J-S, Sugawara S, Kang JH, Kim HR, Inui N, Hida T, et al. LBA54 Randomized phase III trial of nivolumab in combination with carboplatin, paclitaxel, and bevacizumab as first-line treatment for patients with advanced or recurrent non-squamous NSCLC. Ann Oncol 2020;31:S1184–5.

59. Papadimitrakopoulou V, Cobo M, Bordoni R, Dubray-Longeras P, Szalai Z, Ursol G, et al. OA05.07 IMpower132: PFS and safety results with 1L atezolizumab + carboplatin/cisplatin + pemetrexed in stage IV non-squamous NSCLC. J Thorac Oncol. 2018;13:S332–3.

60. Jotte R, Cappuzzo F, Vynnychenko I, Stroyakovskiy D, Rodríguez-Abreu D, Hussein M, et al. Atezolizumab in combination with carboplatin and nab-paclitaxel in advanced squamous NSCLC (IMpower131): results from a randomized phase III trial. J Thorac Oncol 2020;15:1351–60.

61. Reck M, Ciuleanu T-E, Dols MC, Schenker M, Zurawski B, Menezes J, et al. Nivolumab (NIVO) + ipilimumab (IPI) + 2 cycles of platinum-doublet chemotherapy (chemo) vs 4 cycles chemo as first-line (1L) treatment (tx) for stage IV/recurrent non-small cell lung cancer (NSCLC): CheckMate 9LA. J Clin Oncol 2020;38:9501.

62. Hellmann MD, Ciuleanu TE, Pluzanski A, Lee JS, Otterson GA, Aud-igier-Valette C, et al. Nivolumab plus ipilimumab in lung cancer with a high tumor mutational burden. N Engl J Med 2018;378:2093–104.

63. Socinski MA, Jotte RM, Cappuzzo F, Orlandi F, Stroyakovskiy D, Nogami N, et al. Atezolizumab for first-line treatment of metastatic nonsquamous NSCLC. N Engl J Med 2018;378:2288–301.

64. Forde PM, Chaft JE, Smith KN, Anagnostou V, Cottrell TR, Hell-mann MD, et al. Neoadjuvant PD-1 blockade in resectable lung cancer. N Engl J Med 2018;378:1976–86.

65. Horn L, Mansfield AS, Szczęsna A, Havel L, Krzakowski M, Hoch-mair MJ, et al. First-line atezolizumab plus chemotherapy in exten-sive-stage small-cell lung cancer. N Engl J Med 2018;379:2220–9.

66. Paz-Ares L, Dvorkin M, Chen Y, Reinmuth N, Hotta K, Trukhin D, et al. Durvalumab plus platinum-etoposide versus platinum-etoposide in first-line treatment of extensive-stage small-cell lung cancer (CASPIAN): a randomised, controlled, open-label, phase 3 trial. Lancet 2019;394:1929–39.

67. Rudin CM, Awad MM, Navarro A, Gottfried M, Peters S, Csőszi T, et al. Pembrolizumab or placebo plus etoposide and platinum as first-line therapy for extensive-stage small-cell lung cancer: rand-omized, double-blind, phase III KEYNOTE-604 study. J Clin Oncol 2020;38:2369–79.

68. Schmid P, Adams S, Rugo HS, Schneeweiss A, Barrios CH, Iwata H, et al. Atezolizumab and nab-paclitaxel in advanced triple-negative breast cancer. N Engl J Med 2018;379:2108–21.

69. Schmid P, Rugo HS, Adams S, Schneeweiss A, Barrios CH, Iwata H, et al. Atezolizumab plus nab-paclitaxel as first-line treatment for unre-sectable, locally advanced or metastatic triple-negative breast cancer (IMpassion130): updated efficacy results from a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol 2020;21:44–59.

70. Emens LA, Adams S, Barrios CH, Dieras VC, Iwata H, Loi S, et al. LBA16 IMpassion130: Final OS analysis from the pivotal phase III study of atezolizumab + nab-paclitaxel vs placebo + nab-paclitaxel in previously untreated locally advanced or metastatic triple-nega-tive breast cancer. Ann Oncol 2020;31:S1148.

71. Miles DW, Gligorov J, André F, Cameron D, Schneeweiss A, Barrios CH, et al. LBA15 Primary results from IMpassion131, a double-blind

placebo-controlled randomised phase III trial of first-line paclitaxel (PAC) ± atezolizumab (atezo) for unresectable locally advanced/meta-static triple-negative breast cancer (mTNBC). Ann Oncol 2020;31: S1147–8.

72. Cortes J, Cescon DW, Rugo HS, Nowecki Z, Im S-A, Yusof MM, et al. KEYNOTE-355: Randomized, double-blind, phase III study of pembrolizumab + chemotherapy versus placebo + chemotherapy for previously untreated locally recurrent inoperable or metastatic triple-negative breast cancer. J Clin Oncol 2020;38:1000.

73. Cortazar P, Zhang L, Untch M, Mehta K, Costantino JP, Wolmark N, et al. Pathological complete response and long-term clinical benefit in breast cancer: the CTNeoBC pooled analysis. Lancet 2014;384:164–72.

74. Nanda R, Liu MC, Yau C, Shatsky R, Pusztai L, Wallace A, et al. Effect of pembrolizumab plus neoadjuvant chemotherapy on path-ologic complete response in women with early-stage breast cancer: an analysis of the ongoing phase 2 adaptively randomized I-SPY2 trial. JAMA Oncol 2020;6:676–84.

75. Schmid P, Cortes J, Pusztai L, McArthur H, Kümmel S, Bergh J, et al. Pembrolizumab for early triple-negative breast cancer. N Engl J Med 2020;382:810–21.

76. Gianni L, Huang C-S, Egle D, Bermejo B, Zamagni C, Thill M, et al. Abstract GS3-04: Pathologic complete response (pCR) to neoadju-vant treatment with or without atezolizumab in triple negative, early high-risk and locally advanced breast cancer. NeoTRIPaPDL1 Michel-angelo randomized study. Gen Sess Abstr AACR; 2020:GS3-04– GS3-04.

77. Harbeck N, Zhang H, Barrios CH, Saji S, Jung KH, Hegg R, et al. LBA11 IMpassion031: Results from a phase III study of neoadju-vant (neoadj) atezolizumab + chemotherapy in early triple-negative breast cancer (TNBC). Ann Oncol 2020;31:S1144.

78. Loibl S, Untch M, Burchardi N, Huober J, Sinn BV, Blohmer J-U, et al. A randomised phase II study investigating durvalumab in addi-tion to an anthracycline taxane-based neoadjuvant therapy in early triple-negative breast cancer: clinical results and biomarker analysis of GeparNuevo study. Ann Oncol 2019;30:1279–88.

79. Baird RD, Caldas C. Genetic heterogeneity in breast cancer: the road to personalized medicine? BMC Med 2013;11:151.

80. Motzer RJ, Escudier B, McDermott DF, George S, Hammers HJ, Srinivas S, et al. Nivolumab versus everolimus in advanced renal-cell carcinoma. N Engl J Med 2015;373:1803–13.

81. Motzer RJ, Tannir NM, McDermott DF, Arén Frontera O, Melichar B, Choueiri TK, et al. Nivolumab plus ipilimumab versus sunitinib in advanced renal-cell carcinoma. N Engl J Med 2018;378:1277–90.

82. Logothetis CJ, Dexeus FH, Finn L, Sella A, Amato RJ, Ayala AG, et al. A prospective randomized trial comparing MVAC and CISCA chemotherapy for patients with metastatic urothelial tumors. J Clin Oncol 1990;8:1050–5.

83. Bellmunt J, de Wit R, Vaughn DJ, Fradet Y, Lee J-L, Fong L, et al. Pembrolizumab as second-line therapy for advanced urothelial car-cinoma. N Engl J Med 2017;376:1015–26.

84. Fradet Y, Bellmunt J, Vaughn DJ, Lee JL, Fong L, Vogelzang NJ, et al. Randomized phase III KEYNOTE-045 trial of pembrolizumab versus paclitaxel, docetaxel, or vinflunine in recurrent advanced urothelial cancer: results of >2 years of follow-up. Ann Oncol Off J Eur Soc Med Oncol 2019;30:970–6.

85. Rosenberg JE, Hoffman-Censits J, Powles T, van der Heijden MS, Balar AV, Necchi A, et al. Atezolizumab in patients with locally advanced and metastatic urothelial carcinoma who have progressed following treatment with platinum-based chemotherapy: a single-arm, multicentre, phase 2 trial. Lancet 2016;387:1909–20.

86. Balar AV, Galsky MD, Rosenberg JE, Powles T, Petrylak DP, Bellmunt J, et al. Atezolizumab as first-line treatment in cisplatin-ineligible patients with locally advanced and metastatic urothelial carcinoma: a single-arm, multicentre, phase 2 trial. Lancet 2017;389:67–76.

87. Powles T, Park SH, Voog E, Caserta C, Valderrama BP, Gurney H, et al. Maintenance avelumab + best supportive care (BSC) versus BSC alone after platinum-based first-line (1L) chemotherapy in advanced urothelial carcinoma (UC): JAVELIN Bladder 100 phase III interim analysis. J Clin Oncol 2020;38:LBA1–LBA1.






88. Powles TB, Loriot Y, Bellmunt J, Sternberg CN, Sridhar S, Petrylak DP, et al. 699O Avelumab first-line (1L) maintenance + best supportive care (BSC) vs BSC alone for advanced urothelial carcinoma (UC): association between clinical outcomes and exploratory biomarkers. Ann Oncol 2020;31:S552–3.

89. Alva A, Csőszi T, Ozguroglu M, Matsubara N, Geczi L, Cheng S.-S, et al. LBA23 Pembrolizumab (P) combined with chemotherapy (C) vs C alone as first-line (1L) therapy for advanced urothelial carci-noma (UC): KEYNOTE-361. Ann Oncol 2020;31:S1155.

90. Ferris RL, Blumenschein G, Fayette J, Guigay J, Colevas AD, Licitra L, et al. Nivolumab for recurrent squamous-cell carcinoma of the head and neck. N Engl J Med 2016;375:1856–67.

91. Cohen EEW, Soulières D, Le Tourneau C, Dinis J, Licitra L, Ahn M-J, et al. Pembrolizumab versus methotrexate, docetaxel, or cetuximab for recurrent or metastatic head-and-neck squamous cell carcinoma (KEYNOTE-040): a randomised, open-label, phase 3 study. Lancet (London, England) 2019;393:156–67.

92. Burtness B, Harrington KJ, Greil R, Soulières D, Tahara M, de Castro G, et al. Pembrolizumab alone or with chemotherapy versus cetuximab with chemotherapy for recurrent or metastatic squa-mous cell carcinoma of the head and neck (KEYNOTE-048): a randomised, open-label, phase 3 study. Lancet 2019;394:1915–28.

93. Le DT, Uram JN, Wang H, Bartlett BR, Kemberling H, Eyring AD, et al. PD-1 blockade in tumors with mismatch-repair deficiency. N Engl J Med 2015;372:2509–20.

94. Shitara K, Özgüroğlu M, Bang Y-J, Di Bartolomeo M, Mandalà M, Ryu M-H, et al. Pembrolizumab versus paclitaxel for previously treated, advanced gastric or gastro-oesophageal junction cancer (KEYNOTE-061): a randomised, open-label, controlled, phase 3 trial. Lancet 2018;392:123–33.

95. El-Khoueiry AB, Sangro B, Yau T, Crocenzi TS, Kudo M, Hsu C, et al. Nivolumab in patients with advanced hepatocellular carci-noma (CheckMate 040): an open-label, non-comparative, phase 1/2 dose escalation and expansion trial. Lancet 2017;389:2492–502.

96. Brahmer JR, Tykodi SS, Chow LQM, Hwu W-J, Topalian SL, Hwu P, et al. Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N Engl J Med 2012;366:2455–65.

97. Marabelle A, Le DT, Ascierto PA, Di Giacomo AM, De Jesus-Acosta A, Delord J-P, et al. Efficacy of pembrolizumab in patients with non-colorectal high microsatellite instability/mismatch repair-deficient cancer: results from the phase II KEYNOTE-158 study. J Clin Oncol 2020;38:1–10.

98. Pagès F, Mlecnik B, Marliot F, Bindea G, Ou F-S, Bifulco C, et al. International validation of the consensus Immunoscore for the clas-sification of colon cancer: a prognostic and accuracy study. Lancet 2018;391:2128–39.

99. Chalabi M, Fanchi LF, Dijkstra KK, Van den Berg JG, Aalbers AG, Sikorska K, et al. Neoadjuvant immunotherapy leads to patho-logical responses in MMR-proficient and MMR-deficient early-stage colon cancers. Nat Med 2020;26:566–76.

100. Andre T, Shiu K-K, Kim TW, Jensen BV, Jensen LH, Punt CJA, et al. Pembrolizumab versus chemotherapy for microsatellite instability-high/mismatch repair deficient metastatic colorectal cancer: the phase 3 KEYNOTE-177 study. J Clin Oncol 2020;38:LBA4–LBA4.

101. Shitara K, Van Cutsem E, Bang Y-J, Fuchs C, Wyrwicz L, Lee K-W, et al. Efficacy and safety of pembrolizumab or pembrolizumab plus chemotherapy vs chemotherapy alone for patients with first-line, advanced gastric cancer. JAMA Oncol 2020;6:1571.

102. Moehler M, Shitara K, Garrido M, Salman P, Shen L, Wyrwicz L, et al. LBA6_PR Nivolumab (nivo) plus chemotherapy (chemo) versus chemo as first-line (1L) treatment for advanced gastric cancer/gastroesopha-geal junction cancer (GC/GEJC)/esophageal adenocarcinoma (EAC): first results of the CheckMate 649 study. Ann Oncol 2020;31:S1191.

103. Boku N, Ryu MH, Oh D-Y, Oh SC, Chung HC, Lee K-W, et al. LBA7_PR Nivolumab plus chemotherapy versus chemotherapy alone in patients with previously untreated advanced or recurrent gastric/gastroesophageal junction (G/GEJ) cancer: ATTRACTION-4 (ONO-4538-37) study. Ann Oncol 2020;31:S1192.

104. Kelly RJ, Ajani JA, Kuzdzal J, Zander T, Van Cutsem E, Piessen G, et al. LBA9_PR Adjuvant nivolumab in resected esophageal or gas-troesophageal junction cancer (EC/GEJC) following neoadjuvant chemoradiation therapy (CRT): first results of the CheckMate 577 study. Ann Oncol 2020;31:S1193–4.

105. Kato K, Sun J-M, Shah MA, Enzinger PC, Adenis A, Doi T, et al. LBA8_PR Pembrolizumab plus chemotherapy versus chemotherapy as first-line therapy in patients with advanced esophageal cancer: the phase 3 KEYNOTE-590 study. Ann Oncol 2020;31:S1192–3.

106. Singh RR, O’Reilly EM. New treatment strategies for metastatic pancreatic ductal adenocarcinoma. Drugs 2020;80:647–69.

107. Renouf DJ, Knox JJ, Kavan P, Jonker D, Welch S, Couture F, et al. LBA65 The Canadian Cancer Trials Group PA.7 trial: Results of a randomized phase II study of gemcitabine (GEM) and nab-pacli-taxel (Nab-P) vs GEM, nab-P, durvalumab (D) and tremelimumab (T) as first line therapy in metastatic pancreatic ductal adenocarci-noma (mPDAC). Ann Oncol 2020;31:S1195.

108. Bockorny B, Semenisty V, Macarulla T, Borazanci E, Wolpin BM, Stemmer SM, et al. BL-8040, a CXCR4 antagonist, in combination with pembrolizumab and chemotherapy for pancreatic cancer: the COMBAT trial. Nat Med 2020;26:878–85.

109. Voorwerk L, Slagter M, Horlings HM, Sikorska K, van de Vijver KK, de Maaker M, et al. Immune induction strategies in metastatic triple-negative breast cancer to enhance the sensitivity to PD-1 blockade: the TONIC trial. Nat Med 2019;25:920–8.

110. Champiat S, Dercle L, Ammari S, Massard C, Hollebecque A, Postel-Vinay S, et al. Hyperprogressive disease is a new pattern of progres-sion in cancer patients treated by anti-PD-1/PD-L1. Clin Cancer Res 2017;23:1920–8.

111. Melero I, Berraondo P, Rodríguez-Ruiz ME, Pérez-Gracia JL. Mak-ing the most of cancer surgery with neoadjuvant immunotherapy. Cancer Discov 2016;6:1312–4.




Published OnlineFirst March 12, 2021.Cancer Discov Diego Salas-Benito, José L. Pérez-Gracia, Mariano Ponz-Sarvisé, et al. ChemotherapyParadigms on Immunotherapy Combinations with

Updated version

10.1158/2159-8290.CD-20-1312doi:

Access the most recent version of this article at:

Material

Supplementary

http://cancerdiscovery.aacrjournals.org/content/suppl/2021/01/09/2159-8290.CD-20-1312.DC1

Access the most recent supplemental material at:

E-mail alerts related to this article or journal.Sign up to receive free email-alerts

Subscriptions

Reprints and

[email protected] at

To order reprints of this article or to subscribe to the journal, contact the AACR Publications

Permissions

Rightslink site. Click on "Request Permissions" which will take you to the Copyright Clearance Center's (CCC)

.http://cancerdiscovery.aacrjournals.org/content/early/2021/03/12/2159-8290.CD-20-1312To request permission to re-use all or part of this article, use this link



http://cancerdiscovery.aacrjournals.org/lookup/doi/10.1158/2159-8290.CD-20-1312

http://cancerdiscovery.aacrjournals.org/content/suppl/2021/01/09/2159-8290.CD-20-1312.DC1

http://cancerdiscovery.aacrjournals.org/cgi/alerts

mailto:[email protected]

http://cancerdiscovery.aacrjournals.org/content/early/2021/03/12/2159-8290.CD-20-1312


paradigms on immunotherapy combinations with chemotherapy · 2021. 3. 12. · immunogenic cell...

Documents