Targeted Therapies for Uncommon Mutations in NSCLC;

Novel Agents for SCLC

Thomas E Stinchcombe, MDThoracic Oncology Program

Duke University Medical CenterDurham, North Carolina

Disclosures

Consulting Agreements

Boehringer Ingelheim Pharmaceuticals Inc, Celgene Corporation, Lilly

Contracted Research

Bristol-Myers Squibb Company, EMD SeronoInc, Genentech BioOncology

Antitumor activity and safety of crizotinib in patients with advanced MET exon 14-altered non-small cell lung cancer

Drilon AE et al. Proc ASCO 2016;Abstract 108.

Response to Crizotinib

Drilon AE et al. Proc ASCO 2016;Abstract 108.

ORR 44%

Adverse events consistent with known safety profile of crizotinib.

MET exon 14 encodes a juxtamembrane domain involved in receptor degradation, and the introns adjacent to exon 14 are removed during normal splicing mechanisms. MET mutations disrupt the splice sites adjacent to exon 14, leading to increased MET receptor recycling to the tumor cell surface and impaired degradation. MET exon 14 alterations are found on 3% to 4% of non-squamous NSCLC and approximately 20% to 30% of sarcomatoidlung cancers. Of the patients with MET exon 14 mutations, approximately 20% had a high level of MET copy gain. MET exon 14 mutation and MET copy number amplification should be thought of as distinct molecular alterations that have been observed in patients with disease progression after an EGFR tyrosine kinase inhibitor (TKI).

Editorial

Crizotinib is an ATP competitive TKI, and the activity of crizotinib was investigated in a cohort of patients with MET exon 14 mutations as part of an ongoing Phase I trial. In the 18 response-evaluable patients, the objective response rate is 44% (95% CI, 22%-69%) and the median progression-free survival could not be calculated. These results are very promising, and crizotinib should be considered a treatment option for patients who have exhausted standard therapies and have a known MET exon 14 mutation. Patients who do not have a known molecular alteration, especially patients with sarcomatoidlung cancer, should undergo testing for MET exon 14 deletions.

Editorial (continued)

Lancet Oncol 2016;17(7):984-93.

Response to dabrafenib and trametinib in BRAFV600E-mutant NSCLC

Planchard D et al. Lancet Oncol 2016;17(7):984-93.

ORR 63.2%

BRAF V600E mutations are present in approximately 2% of non-small cell lung cancer (NSCLC) cases. This mutation occurs at a higher rate among patients with a history of tobacco use compared to EGFR mutations and ALK rearrangements. Two Phase II trials were performed in patients with metastatic NSCLC with a confirmed BRAF V600E mutation: dabrafenib, a BRAF inhibitor, alone and with trametinib, a MEK inhibitor. Approximately a third of patients enrolled in the 2 trials were never smokers. With single agent dabrafenib the investigator-assessed overall response rate was 33% (95% CI, 23% to 45%), and the median progression-free survival was 5.5 months (95% CI, 3.4 to 7.3).

Editorial

With the combination the investigator-assessed response rate was 63.2% (95% CI, 49.3% to 75.6%) and the median progression-free survival was 9.7 months (95% CI, 6.9 to 19.6). Given the numerically superior response rate and progression-free survival, the combination therapy will be the preferred therapy. The most common Grade 3-4 adverse events observed with the combination were neutropenia (9%), hyponatremia (7%), and anemia (5%). The combination of dabrafenib and trametinib has significant clinical activity, and testing for BRAF mutations should be performed on patients with adenocarcinoma. Single agent and combination therapy should not be used in patients with non-V600E BRAF mutations.

Editorial (continued)

Phase II Study of Cabozantinibfor Patients with Advanced RET-Rearranged Lung Cancers

Drilon AE et al. Proc ASCO 2015;Abstract 8007.

Response to Cabozantinib

Drilon AE et al. Proc ASCO 2015;Abstract 8007.

PR = partial response; SD = stable disease; ORR = overall response rate

Confirmed PRSD

Best response % (n)PR 44% (7/16)

ConfirmedUnconfirmed

38% (6/16)6% (1/16)

SD 56% (9/16)ORR 38%

ORR12wks 36%(5 PRs of 14 evaluable at 12 wks)

RET rearrangements occur when the tyrosine kinase domain is fused to a partner. The most common fusion partner is KIF5B, but other fusion partners include CCDC6, NCOA4, TRIM33 and KIAA1468. The frequency of this rearrangement is approximately 1% to 2%, but the rate may be higher in never or light smokers with adenocarcinoma or in patients who have been tested for and lack commonly identified oncogenic alterations. A single arm Phase II trial investigated cabozantinib 60 mg daily, which is approved for treatment of metastatic medullary thyroid cancers. This study used a 2-stage design, and in the first stage 16 patients were enrolled.

Editorial

The median age was 59 years (range 38 to 80), 12 patients were never-smokers and 3 patients had a light smoking history (<15 pack years), and all patients had adenocarcinoma. The objective response rate was 38% (95% CI, 15%-65%), median duration of response was 8 months (range 5 to 26) and the median progression-free survival was 7 months (95% CI, 5 to not available). The Grade 3 adverse events observed were fatigue, mucositis, palmar-plantar erythrodysesthesia, hypertension, retroperitoneal hemorrhage, increased liver tests, lipase increase, hypophosphatemia, and thrombocytopenia. Eight patients needed a dose reduction to 40 mg daily, and 2 patients needed a second dose reduction to 20 mg daily. Patients who underwent a dose reduction appeared to derive benefit.

Editorial (continued)

This trial demonstrated the activity of cabozantinib in patients with RET rearranged NSCLC but raised concerns about the optimal dose and tolerability. Other agents are being investigated in RET rearranged NSCLC, including vandetanib and sunitinib. Because of the small number of patients and limited efficacy data available, it is unclear if the fusion partner influences the activity of the agent. My practice is to test for RET rearrangements in patients with adenocarcinoma if our standard next-generation sequencing mutation panel, ALK FISH, and ROS1 FISH testing do not reveal an oncogenic alteration.

Editorial (continued)

Clin Cancer Res 2016;22(13):3281-5.

Comprehensive Genomic Profiling (CGP) Identifies EGFR Exon 19 Deletions Not Identified by Prior Molecular Testing

• 400 NSCLC cases with EGFR exon 19 deletions identified by well-validated, hybrid capture-based CGP– Requested by treating physicians in the course of

making therapy decisions• 71 cases had previous nonhybrid capture-based testing

results available with exon del 19 in the classic range (743-754aa)– 12/71 (17%) were negative by prior testing

• 6 cases had previous nonhybrid capture-based testing results available with exon del in C-helix (753-761aa)– 5/6 (83%) were negative by prior testing

Schrock AB et al. Clin Cancer Res 2016;22(13):3281-5.

Govindan R et al. Clin Cancer Res 2015;21(24):5439-44.

Genotyping for EGFR, ALK

Govindan R et al. Clin Cancer Res 2015;21(24):5439-44.

Eligibility (N = 6000-8000)• Stage IB-IIIA nonsquamous NSCLC, resected +/- adjuvant Rx

ALCHEMIST Schema

EGFR wt / ALK wt

Nivo vs observation

EGFR mut+ / ALK+

Comprehensive genomic analyses of tumors from relapsed pts

A081105EGFR mutant

Erlotinib vs placebo

E4512ALK rearranged

Crizotinib vs placebo

S1400: Master Lung-1 — Squamous Lung Cancer Second-Line Therapy

www.lung-map.org; www.clinicaltrials.gov; Accessed September 2016 (NCT02154490).

Taselisib Palbociclib AZD4547 Nivolumab+ Ipilimumab

vsNivolumab

Durvalumabvs

Docetaxel

Common Biomarker Profiling

S1400BPI3K

S1400CCCGA

S1400DFGFR

S1400ICheckpoint

Naive

Biomarker-DrivenSub-studies

NonmatchSub-studies

Lung-MAP (S1400): Prevalence of Targeted Genomic Alterations in Squamous Cell Lung Cancer

Overlap

Biomarker Total FGFR CDK PIK3CA

FGFR 16.8% 14.3% 2.3% 0.2%

CDK 18% — 13.9% 1.8%

PIK3CA 9.1% — — 7.1%

Papadimitrakopoulou V et al. Proc ASCO 2016;Abstract 9088.

Treatment with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors and anaplastic lymphoma (ALK) tyrosine kinase inhibitors have revolutionized the care of patients with metastatic non-small cell lung cancer (NSCLC) with the appropriate molecular alterations. There are hopes that adjuvant treatment with targeted therapy in patients with completely resected NSCLC harboring the appropriate mutation will lead to better long-term survival rates. A retrospective subset analysis of a Phase III trial of erlotinib for resected NSCLC in patients with EGFR mutant NSCLC revealed an improvement in disease-free survival but not overall survival. The difference in disease-free survival was not statistically significant due to the hierarchical testing procedure used in the study design.

Editorial

The National Cancer Institute (NCI) National Clinical Trials Network is investigating targeted therapy in the adjuvant setting. The first part of the trial is genomic screening of patients, and patients will undergo testing for EGFR mutations and ALK rearrangements as part of the trial. Samples will undergo whole exome or genome analysis by the NCI. Patients are assigned to the study based on EGFR mutation and ALK rearrangement status. Patients with EGFR mutation are assigned to 2 years of erlotinib or placebo, and patients with an ALK rearrangement are assigned to 2 years of crizotinib or placebo. The primary endpoint is overall survival. Recently a third arm for patients who do not harbor an EGFR or ALK alteration was added, and patients will be assigned to 1 year of nivolumab or observation.

Editorial (continued)

The addition of the last arm has the potential to facilitate enrollment since the majority of patients with NSCLC do not have an EGFR mutation or ALK rearrangement. Patients are required to have resected Stage IB (≥4 cm) to IIIA NSCLC and can still receive adjuvant chemotherapy. Adjuvant trials are inherently difficult to enroll and complete, and they require long follow-up. This trial is a high priority since it will prospectively investigate the role of targeted therapies and immunotherapy as adjuvant therapy.

Editorial (continued)

Nab-Paclitaxel + carboplatin (nab-P/C) in advanced non-small cell lung cancer (NSCLC): Outcomes in elderly patients (pts) with squamous (SCC) histology

Gridelli C et al. Proc ELCC 2016;Abstract 216PD.

Efficacy of nab-P/C versus P/C

ORR nab-P/C P/C p-value

≥60 y (n = 106, 110) 45% 25% 0.001

≥65 y (n = 67, 70) 46% 26% 0.012

≥70 y (n = 35, 30) 46% 20% 0.029

Median overall survival

≥60 y (n = 106, 110) 11.8 mo 9.5 mo 0.027

≥65 y (n = 67, 70) 13.9 mo 9.4 mo 0.019

≥70 y (n = 35, 30) 16.9 mo 8.6 mo 0.018

Gridelli C et al. Proc ELCC 2016;Abstract 216PD.

A Phase III trial compared carboplatin every 3 weeks and weekly nab-paclitaxel to carboplatin and standard formulation paclitaxel every 3 weeks and revealed a statistically significant higher response rate in the intent-to-treat patient population and in the squamous histology subset. This post-hoc analysis investigated the clinical outcomes of patients with squamous histology stratified by age. Of the 1,052 patients enrolled, 450 had squamous histology, and 65 patients with squamous histology were age ≥70 years. In the cohort of patients age ≥70 years with squamous histology, the objective response rate was higher with carboplatin and nab-paclitaxel compared to carboplatin and paclitaxel (46% vs 20%; p = 0.029) and the overall survival was longer (hazard ratio [HR] of 0.50, p = 0.018; median 16.9 vs 8.6 months, respectively).

Editorial

The difference in objective response rate remains statistically significant with age cut-offs of ≥65 years (n = 137) and ≥60 years (n = 226). The difference in overall survival remains statistically significant with the age cut-offs of ≥65 years (HR of 0.62, p = 0.019; median 13.9 and 9.4 months, respectively) and 60 years (HR of 0.70, p = 0.027; median 11.8 and 9.5 months, respectively). The small size and the post-hoc nature of the analysis limit the interpretation of the results since imbalances in prognostic factors and subsequent therapies may have impacted the survival results. Carboplatin and weekly nab-paclitaxel is a treatment option for elderly patients with squamous histology.

Editorial (continued)

Safety and efficacy of single-agent rovalpituzumab tesirine (SC16LD6.5), a delta-like protein 3 (DLL3)-targeted antibody-drug conjugate (ADC) in recurrent or refractory small cell lung cancer (SCLC)

Rudin CM et al. Proc ASCO 2016;Abstract LBA8505.

Rudin CM et al. Proc ASCO 2016;Abstract LBA8505.

Efficacy of Rovalpituzumab Tesirine

ORR Second line Third lineAll patients (n = 32, 28) 13% 25%DLL3 ≥50% (n = 14, 12) 29% 50%

Median OS: All pts 4.6 mo; DLL3 ≥50% 5.8 mo

Best Response by DLL3 Expression

Rovalpituzumab Tesirine: Select Adverse Events

n = 74 All grade Grade ≥3Pleural effusion 31% 8%

Peripheral edema 27% 3%

Hypoalbuminemia 18% 0%Thrombocytopenia 16% 11%Rash 16% 3%

Rudin CM et al. Proc ASCO 2016;Abstract LBA8505.

Improvements in the treatment of small cell lung cancer (SCLC) have lagged behind improvements in the treatment of NSCLC due to the lack of identified biomarkers and novel agents. Rovalpituzumab tesirine(Rova-T) is an antibody-drug conjugate that targets the delta-like protein 3 (DLL-3), a protein that is expressed on SCLC and large cell neuroendocrine cancer but not on normal tissue. This agent was investigated in a Phase I trial, and the recommended dose for Phase II trials was 0.3 mg/kg every 6 weeks for 2 treatments. Of the 74 patients enrolled, 39 (53%) had received 1 prior line of therapy and 35 (47%) had received 2 prior lines of therapy, 39 (53%) were considered platinum-sensitive and 23 (31%) were considered platinum-resistant; 7 (9%) had progressive disease on first-line therapy.

Editorial

Of the patients tested, 88% had DLL-3 expression in ≥1% of tumor cells, and 67% had DLL-3 expression in ≥50% of tumor cells. The central review objective response rate for all patients was 16%, and for patients with DLL-3 expression ≥50% it was 31%. The response rates for patients with DLL-3 ≥50% by central review in the second-(n = 14) and third-line (n = 12) settings were 29% and 50%, respectively. In the cohort of patients with DLL-3 expression ≥50% the median overall survival and 1-year overall survival rate were 5.8 months and 32%, respectively. The common Grade 3 or higher adverse events were thrombocytopenia (12%), serosal effusions (11%), and skin reaction (8%). Serosal effusions included pleural or pericardial effusions, ascites, or “capillary leak syndrome.”

Editorial (continued)

This trial demonstrated significant activity of Rova-T in patients with DLL-3 expression ≥50%. An ongoing single arm Phase II trial is investigating this agent in the third-line setting, and most likely this agent will be developed further in earlier treatment settings and as part of combination therapy.

Editorial (continued)