Impact of Genomic Changes on the Treatment of Lung Cancer
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Impact of Genomic Changes on the Treatment of Lung Cancer June 13, 2015 Bruce E. Johnson, MD Chief Clinical Research Officer Dana-Farber Cancer Institute ASCO Review 2015
Impact of Genomic Changes on the Treatment of Lung Cancer
June 13, 2015 Bruce E. Johnson, MD
Chief Clinical Research Officer Dana-Farber Cancer Institute
ASCO Review 2015
Presenter
Presentation Notes
I wanted to present information about the impact of epidermal growth factor receptor mutations on the treatment of non-small cell lung cancer.
Serves as an advisor for Novartis, Merck, AstraZeneca, Clovis Oncology, Chugai Pharmaceuticals, Genentech, and Eli Lilly
Expert testimony for Genentech Shareholder and Consultant to KEW Group Post-marketing Royalties for EGFR mutation
testing
Conflicts
Presenter
Presentation Notes
The link between EGFR mutations and Response Diversity of Response to EGFR-TKIs to Different Mutations Genomic Characterization has shown us a role of TITF-1 in Adenocarcinomas of Lung LKB1 Mutations in Adenocarcinoma
• EGFR mutations and ALK rearrangements • Other Oncogenic Drivers- BRAF and ROS1 • Specific Agents for T790M mediated acquired
resistance to EGFR tyrosine kinase inhibitors
Impact of Genomic Changes on the Treatment of Lung Cancer
Presenter
Presentation Notes
The link between EGFR mutations and Response Diversity of Response to EGFR-TKIs to Different Mutations Genomic Characterization has shown us a role of TITF-1 in Adenocarcinomas of Lung LKB1 Mutations in Adenocarcinoma
January 2007 October 2009
Woman with Adenocarcinoma Treated with Erlotinib
Epidermal Growth Factor Receptor Mutations
Lynch et al. 2004
Paez et al. 2004
25 of 31 Patients with Response to Gefitinib had EGFR Mutation
Pao et al. 2004
Presenter
Presentation Notes
Studies were undertaken by two groups within our same institutions, the Dana Farber Cancer Institute and Brigham and Women’s Hospital with genomic support from the Broad Institute at MIT. These were undertaken at the same time at one of the members of the Dana Farber/Harvard Cancer Center, Massachusetts General Hospital. Both groups identified mutations in the intracellular portion of the epidermal growth factor receptor in patients who had dramatic responses to gefitinib, The most common mutations in both patients from the United States and Japan include deletions of nucleotides in exon 19 that code for 5 amino near the ATP binding pocket and one amino acid in exon 21, L858R. The other mutation that is seen in the 719th amino acid. This is very consistent between groups in the US, Europe, Japan, and the rest of East Asia.
Impact of Genomic Changes on the Treatment of Lung Cancer
Key entry criteria ● Diagnosis of locally
advanced/metastatic non-squamous NSCLC; ECOG 0-2
● Positive for ALK ● No prior treatment for
advanced disease ● Brain metastases allowed
R A N D O M I Z E
N=320
Arm A: Crizotinib 250 mg BID administered on a continuous dosing schedule
Arm B: Pemetrexed/ cisplatin or pemetrexed/ carboplatin Day 1 of a 21-day cycle
N=160
N=160
Patients in Arm B who have RECIST-defined PD as determined by the independent radiology review will be
allowed to cross over to Arm A
www.clinicaltrials.gov (NCT01154140)
Primary end point: PFS
Secondary end point: ORR
Randomized phase III trial of Crizotinib vs. chemotherapy in chemotherapy naïve EML4-ALK NSCLC
Crizotinib Versus Chemotherapy for First Line ALK+ NSCLC
Solomon et al. NEJM 2014; 371:2167
Crizotinib Versus Chemotherapy for First Line ALK+ NSCLC
ALK+ Non-Small Cell Lung Cancer Rx with Ceretinib
March 2013 May 2015
•Stage IV NSCLC •Previously treated
•BRAF V600E mutant
Shaw et al. NEJM 2014 370:1189
ALK+ Non-Small Cell Lung Cancer Rx with Ceretinib
Presenter
Presentation Notes
. Panel A shows the change in tumor size after patients received ceritinib at doses of 400 to 750 mg per day. The bars indicate the largest percentage change in target lesions from baseline. The dashed line indicates a 30% reduction from baseline. Dots below individual bars indicate patients with disease progression or death at the time of data cutoff.
•Stage IV NSCLC •Previously treated
•BRAF V600E mutant
ALK+ Non-Small Cell Lung Cancer; Ceretinib
Shaw et al. NEJM 2014 370:1189
Presenter
Presentation Notes
Shown are Kaplan–Meier estimates of progression-free survival among patients with advanced, ALK-rearranged non–small-cell lung cancer (NSCLC) who received ceritinib at doses of 400 to 750 mg daily. In these 114 patients, the median progression-free survival was 7.0 months (blue). In the subgroup of 80 patients who had received crizotinib previously, the median progression-free survival was 6.9 months (orange). In the subgroup of 34 patients who had not received crizotinib previously, the median progression-free survival was not reached (green). Vertical lines on the survival curves indicate censoring of data.
• EGFR mutations and ALK rearrangements • Other Oncogenic Drivers- ROS1 and BRAF • Specific Agents for T790M mediated acquired
resistance to EGFR tyrosine kinase inhibitors
Implication of Genomic Heterogeneity in Lung Cancer
Presenter
Presentation Notes
The link between EGFR mutations and Response Diversity of Response to EGFR-TKIs to Different Mutations Genomic Characterization has shown us a role of TITF-1 in Adenocarcinomas of Lung LKB1 Mutations in Adenocarcinoma
EGFR
KRAS
BRAFHER2
PIK3CA
ALK
No known genotype
ROS1
NTRK1RETMET
Impact of Genomic Changes on the Treatment of Lung Cancer
•Stage IV NSCLC •Previously treated
•BRAF V600E mutant
ROS1+ Non-Small Cell Lung Cancer
Bergethon et al. J Clin Oncol 2012; 30:863
Presenter
Presentation Notes
A) A break-apart fluorescent in situ hybridization probe reveals separation of the 5′ ROS1 probe (green) from the 3′ ROS1 probe (red) in a non–small-cell lung cancer formalin-fixed paraffin-embedded specimen. Nuclei are stained with 4′,6-diamidino-2-phenylindole. Size bar = 10 μm. (B) Representative histologic appearance of a ROS1-rearranged tumor, stained with hematoxylin and eosin, showing a solid subtype of adenocarcinoma with highly atypical cytologic features. (C) Sanger sequencing of a reverse transcriptase polymerase chain reaction product from a tumor harboring a SLC34A2-ROS1 rearrangement. ROS1-positive patients tend to be younger (median age, 49.8 years) never-smokers with a histologic diagnosis of adenocarcinoma.7 There is also an overrepresentation of Asians (P < .001) and patients presenting with stage IV disease, with the realization that those conclusions are based on small numbers. Detailed histologic analysis of ROS1-positive NSCLCs did not reveal a clear correlation with a subtype of adenocarcinoma. The presence of signet ring cells, a common feature of ALK-rearranged NSCLCs,17 was not common in ROS1-rearranged tumors. In fact, there was a broad distribution of tumor grade; however, eight of the tumors were poorly differentiated with highly atypical infiltrating tumor cells (Fig 1B and Appendix Fig A1, online only). Kaplan-Meier survival analysis of patients with metastatic NSCLC treated at one of our institutions (MGH) reveals similar OS in patients with and without ROS1 rearrangements (median OS, 663 days in ROS1-positive patients and 607 days ROS1-negative patients; P = .42; Appendix Fig A2, online only).
•Stage IV NSCLC •Previously treated
•BRAF V600E mutant
ROS1+ Non-Small Cell Lung Cancer Rx with Crizotinib
Shaw et al. NEJM 2014 371:1963
Presenter
Presentation Notes
Panel A shows the best response of patients treated with crizotinib in the ROS1 expansion cohort. The bars indicate best percent change in the target tumor burden from baseline. Two patients died within 6 weeks after receiving the first dose of crizotinib, so the tumor response was unknown. The asterisk indicates the tumor burden in a patient who had an atypical result on fluorescence in situ hybridization (FISH) for ROS1 (an isolated 5′ green signal). Since this tumor was subsequently shown to be negative for ROS1 rearrangement on next-generation sequencing, an isolated green signal is probably not indicative of a ROS1 rearrangement. The letter A denotes a FISH-positive tumor that was negative for ROS1 rearrangement on next-generation sequencing but positive for ALK rearrangement on FISH and next-generation sequencing. The letter M denotes a FISH-positive tumor that was also positive for MET amplification on FISH (MET-to-CEP7 ratio, 5.34) Among the 50 study patients, 3 patients (6%) had a complete response, 33 patients (66%) had a partial response, and 9 patients (18%) had stable disease as their best response (Figure 1AFigure 1Tumor Responses to Crizotinib in ROS1-Rearranged Non–Small-Cell Lung Cancer., and Table S2 in the Supplementary Appendix). The overall response rate was 72% (95% confidence interval [CI], 58 to 84). The median time to the first response was 7.9 weeks (range, 4.3 to 32.0) (Figure 1B, and Table S2 in the Supplementary Appendix). At the time of data cutoff, 23 of the 36 responses (64%) were ongoing (Figure 1C). The estimated median duration of response was 17.6 months (95% CI, 14.5 to not reached [NR]) (Table S2 in the Supplementary Appendix).
•Stage IV NSCLC •Previously treated
•BRAF V600E mutant
Shaw et al. NEJM 2014 371:1963
ROS1+ Non-Small Cell Lung Cancer Rx with Crizotinib
Presenter
Presentation Notes
Shown is the Kaplan–Meier curve for estimated progression-free survival in the ROS1 cohort of patients treated with crizotinib. Progression-free survival was defined as the time from the administration of the first dose of crizotinib to objective disease progression or death from any cause. Data from 27 patients were censored; of these patients, 25 remained in follow-up for progression-free survival at the time of data cutoff. The shaded area represents the 95% Hall–Wellner confidence limits. Vertical lines on the survival curve indicate censoring of data. Among the 50 patients, the median duration of treatment was 64.5 weeks (range, 2.3 to 182.0), and 30 patients (60%) continued to receive crizotinib after the data cutoff date. Median progression-free survival was 19.2 months (95% CI, 14.4 to NR) (Figure 2Figure 2Progression-free Survival.). Data for 27 patients (54%) were censored, including data for 25 patients (50%) undergoing follow-up for progression. Median follow-up for overall survival was 16.4 months (95% CI, 13.8 to 19.8). Nine of the 50 patients (18%) had died by the time of data cutoff. The overall survival rate at 12 months was 85% (95% CI, 72 to 93); the median had not been reached.
EGFR
KRAS
BRAFHER2
PIK3CA
ALK
No known genotype
ROS1
NTRK1RETMET
2004
2015
Impact of Genomic Changes on the Treatment of Lung Cancer
• Inclusion: – Stage IV NSCLC – Measurable disease according to RECIST 1.1 – Presence of BRAF V600E mutation (based on local testing) – Prior progression on systemic chemotherapy – ECOG PS 0-2
• Exclusion: – History of cancer within the past 5 years – Previous treatment with BRAF or MEK inhibitor – Symptomatic, nonstable, or > 1 cm brain mets
Key Inclusion and Exclusion Criteria
*Planchard D, et al. Ann Oncol 2014;25(suppl 4):abstract LBA38_PR.
• EGFR mutations and ALK rearrangements • Other Oncogenic Drivers- BRAF and ROS1 • Specific Agents for T790M mediated acquired
resistance to EGFR tyrosine kinase inhibitors
Impact of Genomic Changes on the Treatment of Lung Cancer
Presenter
Presentation Notes
The link between EGFR mutations and Response Diversity of Response to EGFR-TKIs to Different Mutations Genomic Characterization has shown us a role of TITF-1 in Adenocarcinomas of Lung LKB1 Mutations in Adenocarcinoma
EGFR
KRAS
BRAFHER2
PIK3CA
ALK
No known genotype
ROS1
NTRK1RETMET
Impact of Genomic Changes on the Treatment of Lung Cancer
Sequist et al. Sci Trans Med 2011; 3: 75ra26 n=37
Genomic Heterogeneity in Acquired Resistance to EGFR-TKIs in EGFR+ Lung Cancer
Yu et al. Clin Cancer Res 2013; 19: 2240 n=155
Presenter
Presentation Notes
The 37 paired pre- and post-EGFR TKI tumor samples were analyzed for the presence of genetic alterations with our standard clinical genotyping platform, the SNaPshot assay. The pretreatment activating EGFR mutation was present in each drug-resistant specimen (Table 1 and table S1). As predicted, we observed mechanisms of TKI resistance that were previously validated in clinical specimens. Eighteen (49%) patients acquired the exon 20 EGFR mutation T790M, and two (5%) patients developed MET amplification (Fig. 1). In one case of an L858R EGFR-mutant cancer that subsequently developed MET amplification, the pretreatment specimen had marked EGFR amplification but no MET amplification (Fig. 2A). After resistance developed, MET amplification was abundant, but the EGFR amplification was lost (Fig. 2A). Given that the resistant lesion biopsied had initially responded to the TKI and harbored the same activating EGFR mutation as the treatment-naïve cancer, it seems most likely that the resistant tumor was derived from a distinct MET-amplified subpopulation of EGFR-mutant cells (that did not harbor EGFR amplification) that were selectively enriched during EGFR TKI administration, consistent with previous observations (14).
Third Generation EGFR Tyrosine Kinase Inhibitors for Lung Cancer
Erlotinib AZD9291
Cohort 1 20 mg
T790M+
Cohort 2 40 mg
Cohort 3 80 mg
Cohort 4 160 mg
T790M+
T790M-
T790M+ T790M-
T790M+ T790M-
Escalation Not preselected by T790M status
Expansion Enrollment by local
testing followed by central
laboratory confirmation (cobas® EGFR
Mutation Test) of T790M status or by central laboratory
testing alone
Cohort 5 240 mg
T790M+
1st-line EGFRm+
* Biopsy#
Rolling six design
Tablet##
1st-line EGFRm+
* Biopsy#
*Prior therapy not permissible in this cohort. #Paired biopsy cohort patients with T790M+ tumours. ##Not selected by mutation status, US only.
Woman with T790M Acquired Resistance to EGFR-TKIs Rx with AZD9291
Best Percentage Change in Target-Lesion Size when Treated with AZD9291 by T790M Status
Jänne PA et al. NEJM 2015;372:1689
Progression-free Survival According to Status with Respect to EGFR T790M.
Jänne PA et al. NEJM 2015;372:1689
• EGFR mutations and ALK rearrangements • Other Oncogenic Drivers- BRAF and ROS1 • Specific Agents for T790M mediated acquired
resistance to EGFR tyrosine kinase inhibitors
Impact of Genomic Changes on the Treatment of Lung Cancer
Presenter
Presentation Notes
The link between EGFR mutations and Response Diversity of Response to EGFR-TKIs to Different Mutations Genomic Characterization has shown us a role of TITF-1 in Adenocarcinomas of Lung LKB1 Mutations in Adenocarcinoma
