nuevos escenarios para nab-paclitaxel: de la … · gem, gemcitabine; hr, hazard ratio; kps,...

Nuevos escenarios para nab-paclitaxel: de la

neoadyuvancia al paciente frágil

Dra. T. Macarulla

Hospital Vall d´Hebrón

• High mortality, PC constitutes the fourth leading cause of cancer-related deaths in US.

• 6.000 cases/year in Spain.

• Overall survival at 5 years: <10%

• -Less than 1cm with curative resection:100%

• -Stage I: 58%

• -Stage IIb:17%

• Curative resection: 10-15%.

Cáncer de páncreas

Projecting Cancer Incidence and Deaths to 2030

Rahib et al, Cancer Res 2014

Cáncer de páncreas: Estadiage

Nab-Paclitaxel + Gemcitabine: phase III study (MPACT)

Von Hoff DD et al. NEJM. 2013

Tumor resecable

TC: Tronco celiaco; AMS: arteria mesentérica superior; AHC: arteria hepática común; VMS: vena mesentérica superior ; VP: vena porta

Hidalgo et al, Clin and Transl Oncol 2017

Tratamiento adyuvante en el cáncer de páncreas


Adjuvant Qta: Ro/R1, pT1-4/No-1M0

Tratamiento adyuvante en el cáncer de páncreas: Estudio APACT

Resultados esperados para 2018…

Tumor borderline


Objective: - Ro resection -Early tto of microM1 -Avoid IQ in early PD

-No randomized phase 3 -QTA associated with higher RR in M1

Tumor borderline

Lelpo et al, European Journal of Surgical Oncology

N 25 potentially resectable PA (R 14, BR 11) Resection rate N 17/25 (68%) (DPC 10, DP 4, TP 3) R0 17 (100%), 13/17(76.5%) major pathological regressions Vascular resection 6/17(35%) (PV 2, SMV 4)

Tumor borderline

OS in resected patients: 31 m, OS in unresected patients 12.5 m, p 0.0002 DFS resected patients: 22.6 m

Lelpo et al, European Journal of Surgical Oncology 2016

Promising data that should be confirmed in larger, randomized studies. ..

Tumor irresecable

-No randomized clinical trials -Goal: Improve Survival

LAPACT: Interim Phase II Results of nab-Paclitaxel + Gemcitabine for Patients With LAPC

Previously untreated,

unresectable LAPC

Planned N = 110

Induction Phase

nab-Paclitaxel 125 mg/m2 qw 3/4

+ gemcitabine

1000 mg/m2 qw 3/4

Maximum of 6 cyclesa

Investigator’s Choice

For patients without disease progression or unacceptable

toxicity • nab-Paclitaxel +

gemcitabine • Chemoradiationb

• Surgical resection

Periodic follow-up

for PFS and OS

Primary endpoint

TTF: time from first dose of study therapy to treatment failure (treatment failure defined as discontinuation of study therapy due to disease

progression, death by any cause, or the start of a nonprotocol-defined therapy)

a Surgical intervention was allowed prior to completing 6 cycles of nab-paclitaxel plus gemcitabine if deemed operable by the treating medical team. b Concurrent capecitabine or gemcitabine plus radiation according to institutional practice.

c Combined incidence of CR, PR, and SD measured at the end of the treatment visit.

Lacy J, et al. Poster at ASCO GI 2017 [abstract 358].

Secondary endpoints

• DCRc (after 6 cycles of therapy) • ORR • PFS • OS • Safety • QoL (EORTC QLQ-C30 and QLQ-PAN26)

N 47

LAPC definition

Unresectable pancreatic cancer according to radiographic criteria (MRI or CT) or exploration:

Occlusion, thrombosis, or encasement (extending several centimeters) of the superior mesenteric vein and portal vein

Tumor abutment > 180° or thrombosis of superior mesenteric artery

Abutment or encasement of the celiac axis

Lymph node involvement

Key exclusion criteria

Endocrine/mixed-origin pancreatic tumors

Prior anticancer therapy for pancreatic carcinoma

Borderline resectable disease



Completeda Discontinued

Reasons for Discontinuation

Adverse event Progressive disease Physician decision Nonadherence to study drug Other

28 patients (60%) completed the nab-P + Gem induction phase and 19 (40%) discontinued (due to AEs in a majority of cases)

a Patients who had a surgical intervention prior to completing 6 cycles of nab-paclitaxel plus gemcitabine were

considered to have completed induction therapy.


The median number of cycles received during the nab-P plus Gem induction phase was 5


Adverse Event (n = 47), n (%)a All-Grade Grade 3 - 4

Patients with ≥ 1 adverse event 47 (100) 36 (77)

Neutropenia 31 (66) 21 (45)

Anemia 23 (49) 6 (13)

Fatigue 21 (45) 5 (11)

• No new safety signals were observed with nab-P + Gem treatment

• Other relevant AEs (all-grade; grade 3 - 4) included diarrhea (47%; 2%), thrombocytopenia (28%; 2%); peripheral sensory neuropathy (15%; 2%), and febrile neutropenia (2% for both)

a Reported grade 3 - 4 events in > 10% of patients.



Best Response by RECIST v1.1, n (%) Efficacy Population (n = 45)a

CR 0

PR 14 (31)

All SDb

SD ≥ 16 weeks

28 (62)

22 (49)

DCR [SD ≥ weeks + CR + PR] 36 (80)

PD 3 (7)

a Includes patients who had a baseline and ≥ 1 postbaseline assessment. b Six patients had a best response of SD at 8 weeks, but response at 16 weeks could not be confirmed.



Chemotherapy

Chemoradiation

Surgical resection

R0

R1

R2

Deemed unresectable

during surgery

Patients (n = 21) who received investigator’s choice intervention

Six of the 47 patients (13%) had surgical tumor resection after nab-P + Gem induction

1 of 6 (17%) had an R0 resection margin

4 (67%) had an R1 resection margin

1 (17%) had an R2 resection margin



• Results from this interim analysis suggest a tolerable safety profile for nab-paclitaxel plus gemcitabine; no new safety signals were identified thus far, and most patients (60%) completed the induction phase

• The 80% disease control rate for the first 47 patients to complete the nab-paclitaxel plus gemcitabine induction phase is promising and indicative of antitumor activity in patients with locally advanced pancreatic cancer

• Notably, all patients were identified as unresectable at baseline, yet 13% were resectable after the nab-paclitaxel plus gemcitabine induction phase

• Most patient-reported symptoms stabilized or improved during the induction phase


Enfermedad metastásica


Gemcitabina + nab-paclitaxel en la población “con limitaciones” a la QTA

Datos de eficacia

Gem, gemcitabine; HR, hazard ratio; KPS, Karnofsky performance status; MPC, metastatic pancreatic cancer; nab-P, nab-paclitaxel; NE, not evaluable; OS, overall survival.

Tabernero J, et al. Oncologist. 2015 Jan 12..

Gemcitabina + nab-paclitaxel en la población “con limitaciones” a la QTA

Datos de reducciones de dosis

Factor nab-P + Gem Gem

n nab-P DR, % Gem DR, % n DR, %

Age

< 65 years 246 40 45 225 32

≥ 65 years 175 42 50 177 33

KPS

90 - 100 246 42 50 248 36

70 - 80 174 40 43 153 28

• In patients with markers of poor prognosis, similar rates of dose reductions occurred in older vs younger patients (age ≥ 65 vs < 65 years) and higher vs lower KPS (90 - 100 vs 70 - 80) in each treatment arm

Scheithauer W, Von Hoff DD, Ramanathan RK, et al. Dose Delivery in a Phase III Trial (MPACT) of Weekly nab-Paclitaxel (nab-P) Plus Gemcitabine (Gem) vs Gem Alone for Patients With Metastatic Adenocarcinoma of the Pancreas [abstract 2.586]. Poster presented at: European Cancer Congress 2013 (ECCO-ESMO-ESTRO); September 27-October 1; Amsterdam, The Netherlands.

Impact of nab-paclitaxel plus gemcitabine vs Gemcitabine alone on Karnofsky Performance Status in Metastatic

Pancreatic Cancer pts with Good or Poor Performance Status at Baseline: a Post-hoc Analysis of the MPACT Trial

Poor KPS

Good KPS

Overall, all analyses indicate that pts on nab-P+G had better preservation of KPS score than pts on G alone regardless of the baseline KPS

score. This benefit wassomewhat more pronounced in those with poor KPS at

baseline.

Chiorean et al, ESMO 2015

A phase I/II trial to evaluate the efficacy and safety of nab-paclitaxel in combination with gemcitabine for the treatment of

frail patients with advanced or metastatic pancreatic cancer: Safety results of the Phase I trial

Presented in ESMO 2014

A phase I/II trial to evaluate the efficacy and safety of nab-paclitaxel in combination with gemcitabine for the treatment of

frail patients with advanced or metastatic pancreatic cancer: Safety results of the Phase I trial

Presented in ESMO 2014

A phase I and randomized phase II trial to evaluate the efficacy and safety of nab-paclitaxel (nab-P) in combination with gemcitabine (G) for the treatment of patients with ECOG 2

advanced pancreatic cancer (PDAC).

Next steps…Abstract has been sent to ESMO 2017

Gemcitabina + nab-paclitaxel en la población “con limitaciones” a la QTA Recomendaciones en GUÍAS

Hidalgo et al, Clin Transl Oncol 2017


Selected PS 2 due to heavy tumour load: consider gem-Nab

Ducreux, Ann Oncol 2015

Gemcitabina + nab-paclitaxel en la población “con limitaciones” a la QTA: Recomendaciones en GUÍAS

Gemcitabine + albumin-bound paclitaxel is reasonable for patients with KPS ≥ 70


Fig. 1 *Comorbidities, cognition, mental health status and support, fatigue, assessment of

polypharmacy, and the

presence of geriatric syndromes.

**The efficacy of GEM/nabpaclitaxel over gemcitabine in this specific subgroup of patients is

currently insufficient

Vera et al, Clin Trans Oncol 2016

Conclusiones

• El cáncer de páncreas presenta alta mortalidad, constituyendo la cuarta causa de muerte por cáncer.

• En los últimos años dos nuevos esquemas de tratamiento han demostrado un aumento de la supervivencia respecto a la gemcitabina: FOLFIRINOX y nab-paclitaxel+gemcitabina.

• El papel de nab-paclitaxel en adjuvancia está pendiente de los resultados del estudio APACT.

• Experiencias unicéntricas han demostrado eficacia de gemcitabina y nab-paclitaxel en el contexto de la neoadjuvancia: necesidad de estudios clínicos multicéntricos y randomizados en este contexto.

Conclusiones

• Datos preliminares del estudio LAPACT demuestran eficacia de la combinación de gemcitabina y nab-paclitaxel en el CP LA. Resultados completos en ESMO 2017.

• Sub-análisis del estudio MPACT indican igual eficacia y tolerabilidad de gemcitabina y nab-paclitaxel en los pacientes “con limitaciones” que la población general del estudio.

• Datos del estudio fragance (ESMO 2017) nos permitirán tener datos de la combinación en la población ECOG 2 (dosis, eficacia y tolerabilidad).

• Todas las guías de manejo de cáncer de páncreas incluyen la población “ con limitaciones a la quimioterapia” y consideran la acción de que esta población se trate con gemcitabina y nab-paclitaxel.

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