Immunotherapy Combinations for Lung Cancers William N. William Jr. Diretor de Onco-Hematologia Hospital BP, A Beneficência Portuguesa

Outline Immune Checkpoint Inhibitors Combinations Immune Checkpoint Inhibitors and Targeted Agents Combinations

Outline Immune Checkpoint Inhibitors Combinations Immune Checkpoint Inhibitors and Targeted Agents Combinations

Rationale Pardoll Nature Reviews Cancer 2012

Rationale Resistance to immune checkpoint inhibition may involve activation of alternative checkpoint pathway Koyama et al. Nature Communications 2016

Phase I - Checkmate 012 First-line Ipilimumab / Nivolumab Phase 1 CheckMate 012 Study Design: <br />Nivolumab Plus Ipilimumab in First-line NSCLC Hellman et al. ASCO 2016

Phase I - Checkmate 012 First-line Ipilimumab / Nivolumab Nivolumab Plus Ipilimumab in First-line NSCLC:<br />Summary of Efficacy Hellman et al. ASCO 2016

Phase I - Checkmate 012 First-line Ipilimumab / Nivolumab Nivolumab Plus Ipilimumab in First-line NSCLC:<br />Efficacy Across All Tumor PD-L1 Expression Levels Hellman et al. ASCO 2016

Phase I - Checkmate 012 First-line Ipilimumab / Nivolumab Nivolumab Plus Ipilimumab in First-line NSCLC:<br />Safety Summary Hellman et al. ASCO 2016

Phase I - Checkmate 012 First-line Ipilimumab / Nivolumab Longer-term OS data Goldman et al. ASCO 2017

Durvalumab plus Tremelimumab - NSCLC Durvalumab 20 mg/kg every 4 weeks plus tremelimumab 1 mg/kg was chosen as the expansion phase dose Antonia S et al. Lancet Oncol 2016

Durvalumab plus Tremelimumab - NSCLC Antonia S et al. Lancet Oncol 2016

Durvalumab plus Tremelimumab - NSCLC January 2017: change in endpoints to assess PFS and overall survival in patients with PDL1-expressing tumours for both durvalumab monotherapy and the combination of durva + treme, as well as in ‘all comers’ for the combination of durva + treme, versus SoC chemotherapy.

Durvalumab plus Tremelimumab - NSCLC July 27, 2017 Press Release The combination of Imfinzi and tremelimumab did not meet the primary endpoint of improving PFS compared to SoC in patients whose tumours express PD-L1 on 25% or more of their cancer cells (as determined by the VENTANA PD-L1 (SP263) assay). As a secondary endpoint, although not formally tested, Imfinzi monotherapy would not have met a pre-specified threshold of PFS benefit over SoC in this disease setting. The trial will continue to assess two additional primary endpoints of overall survival (OS) for Imfinzi monotherapy and OS for the Imfinzi plus tremelimumab combination. Final OS data from both primary endpoints are expected during the first half of 2018.

<br />CheckMate 032: Nivolumab ± Ipilimumab in Advanced SCLC <br />Phase I/II CheckMate 032 Study Design Hellman et al. ASCO 2017

CheckMate 032: Nivolumab ± Ipilimumab in Advanced SCLC <br />Summary of Response per BICR – Non-Randomized Cohort Hellman et al. ASCO 2017

CheckMate 032: Nivolumab ± Ipilimumab in Advanced SCLC <br />OS – Non-Randomized Cohort Hellman et al. ASCO 2017

CheckMate 032: Nivolumab ± Ipilimumab in Advanced SCLC<br />Summary of Response per BICR Hellman et al. ASCO 2017

CheckMate 032: Nivolumab ± Ipilimumab in Advanced SCLC<br />Summary of Safety – Pooled Cohorts Hellman et al. ASCO 2017

IDO inhibitors in NSCLC ORR 39% Gangadhar et al. ASCO 2017

Outline Immune Checkpoint Inhibitors Combinations Immune Checkpoint Inhibitors and Targeted Agents Combinations

Rationale Exposure of antigens upon triggering tumor cell kill Vanneman & Dranoff Nature Reviews Cancer 2012

Rationale Targeted agents may augment the immune response Vanneman & Dranoff Nature Reviews Cancer 2012

Rationale Vanneman & Dranoff Nature Reviews Cancer 2012

Nivolumab plus Erlotinib Rizvi et al., ASCO 2014

Durvalumab plus Gefitinib Creelan et al., ASCO 2015

Durvalumab plus Gefitinib Creelan et al., ASCO 2015

Attention to Interstitial Lung Disease !!!

Angiogenesis and Immunotherapy Developed a lung cancer multiplex immunofluorescence (IF) panel to assess expression of immunotherapy targets and immune infiltrate using FFPE tissue specimens and a lung cancer immunotherapy-related gene expression signature using FFPE tissue specimens. Selected 32 FFPE cases with paired core needle biopsies and whole sections (67 samples total) for comparison with multiplex IF panels and nanostring gene expression for immunotherapy markers. Ott et al., Front Oncol, 2015

Angiogenesis and Immunotherapy Developed a lung cancer multiplex immunofluorescence (IF) panel to assess expression of immunotherapy targets and immune infiltrate using FFPE tissue specimens and a lung cancer immunotherapy-related gene expression signature using FFPE tissue specimens. Selected 32 FFPE cases with paired core needle biopsies and whole sections (67 samples total) for comparison with multiplex IF panels and nanostring gene expression for immunotherapy markers. Response rate to ramucirumab and pembrolizumab: 30% Herbst et al., ELCC, 2017

Conclusions Strong rationale for immunotherapy combos in lung câncer Nivolumab/ipilimumab response rates in NSCLCs are promising in both PD-L1 positive and negative tumors, but early OS data may not suggest na advantage of the combo over nivolumab alone Nivolumab/ipilimumab OS data in SCLC very encouraging Pembrolizumab/epacadostat activity promising in NSCLC Pembrolizuab/ramucirumab activity promising Caution with off study use of EGFR inhibitor and other combos