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

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

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

4. Rationale
Pardoll Nature Reviews Cancer 2012

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

6. 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

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

8. 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

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

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

11. 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

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

13. 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.

14. 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.

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

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

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

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

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

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

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

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

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

24. Rationale
Vanneman & Dranoff Nature Reviews Cancer 2012

25. Nivolumab plus Erlotinib
Rizvi et al., ASCO 2014

26. Durvalumab plus Gefitinib
Creelan et al., ASCO 2015

27. Durvalumab plus Gefitinib
Creelan et al., ASCO 2015

28. Attention to Interstitial Lung Disease !!!

29. 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

30. 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

31. 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