Are patients overdosed with the present recommendations?

Transcription

1 Are patients overdosed with the present recommendations? Aurélien Marabelle, MD, PhD Clinical Director, Cancer Immunotherapy Pgm Drug Development Dpt INSERM 1015 ESMO Advanced Course Feb 16 th, 2018

2 DISCLOSURES Over the last 3 years : Principal Investigator of Clinical Trials from the following companies: Roche/Genentech, BMS, Merck (MSD), Pfizer, Lytix pharma, Eisai, Astra Zeneca/Medimmune, Chugai Member of Clinical Trial Scientific Committee: NCT (GSK), NCT (AZ) Member of Data Safety and Monitoring Board: NCT (Oncovir) Scientific Advisory Boards : Merck Serono, etherna, Lytix pharma, Kyowa Kirin Pharma, Novartis, BMS, Symphogen, Genmab, Amgen, Biothera, Nektar, GSK, Oncosec, Pfizer, Seattle Genetics, Astra Zeneca/Medimmune, Servier Teaching/Speaker activities: Roche/Genentech, BMS, Merck (MSD), Merck Serono, Astra Zeneca/Medimmune, Amgen, Sanofi Scientific & Medical Consulting : Roche, Pierre Fabre, Onxeo, EISAI, Bayer, Genticel, Rigontec, Daichii Sankyo, Imaxio, Sanofi, BioNTech, Medimmune Co-founder: Pegascy SAS Patent holder: anti-cd81 (Stanford University)

3 Paradigm Shift in Cancer Therapy Historical Paradigm: Targeting Tumor Cells New Paradigm: Targeting Immune Cells Lymphocyte Tumor Cell

4 Know your Immune Checkpoint Antibodies Anti-CTLA-4 Tremelimumab (AZ) AGEN-1884 (Agenus) Ipilimumab (BMS) Approved Anti-PD-1 Nivolumab (BMS) Pembrolizumab (MSD) spartalizumab (Novartis) cemiplimab (Regeneron/Sanofi) camrelizumab (Incyte) Approved Anti-PD-L1 Durvalumab (AZ/Medimmune) Avelumab (Pfizer) Atezolizumab (Roche/Genentech) LY (Lilly) FAZ053 (Novartis) Approved

5 anti-pd-1 / anti-pd-l1 immunotherapy Hayden EC. Antibody alarm call rouses immune response to cancer. Nature Jun 6;486(7401):16.

6 Anti-PD-1/PD-L1 Isotypes apd-1 apd-l1 NIVOLUMAB PEMBROLIZUMAB ATEZOLIZUMAB DURVALUMAB IgG4 IgG4 Modified IgG1 Modified IgG1 NO ADCC / ADCP

7 apd-1/pd-l1: No Dose/Efficacy/Toxicity Correlation KN001 Part D KN006 2 mg/kg Q3W 10 mg/kg Q3W 10 mg/kg Q3W 10 mg/kg Q2W ORR (%) PFS (median, mo) month PFS rate (%) month OS rate (%)

8 apd-1/pd-l1: No Dose/Efficacy/Toxicity Correlation Robert C, et al. Pembrolizumab versus Ipilimumab in Advanced Melanoma. N Engl J Med. 2015;372: Ribas A, et al. Pembrolizumab versus investigator-choice chemotherapy for ipilimumab-refractory melanoma (KEYNOTE-002): a randomised, controlled, phase 2 trial. Lancet Oncol. 2015;

9 Conclusion 1: Anti-PD-1/PD-L1 = pure antagonistic («checkpoints blockers») (avelumab?)

10 Isotypes des anti-pd-1/pd-l1 apd-1 apd-l1 NIVOLUMAB PEMBROLIZUMAB ATEZOLIZUMAB DURVALUMAB AVELUMAB IgG4 IgG4 Modified IgG1 Modified IgG1 IgG1 NO ADCC / ADCP Infusion Related Reactions 3% ADCC / ADCP IRR 18%

11 Dose/PD-1 saturation 0,3mg/kg 1 mg/kg 3mg/kg 10 mg/kg Brahmer, J.R., Drake, C.G., Wollner, I., Powderly, J.D., Picus, J., Sharfman, W.H., Stankevich, E., Pons, A., Salay, T.M., McMiller, T.L., et al. (2010). Phase I study of single-agent anti-programmed death-1 (MDX-1106) in refractory solid tumors: safety, clinical activity, pharmacodynamics, and immunologic correlates. J. Clin. Oncol. 28,

12 Long-term PD-1 occupancy analysis in patients receiving nivolumab at 10 mg/kg One dose 3 doses Multiple doses Brahmer, J.R., Drake, C.G., Wollner, I., Powderly, J.D., Picus, J., Sharfman, W.H., Stankevich, E., Pons, A., Salay, T.M., McMiller, T.L., et al. (2010). Phase I study of single-agent anti-programmed death-1 (MDX-1106) in refractory solid tumors: safety, clinical activity, pharmacodynamics, and immunologic correlates. J. Clin. Oncol. 28,

13 Pembrolizumab, Anti-PD-1, MSD 2 nd line NSCLC: 2 mg/kg Q3W 1st line NSCLC: 200mg Q3W flat dose

14 Conclusion 2: We are probably overdosing patients with anti-pd(l)1 antibodies DO WE CARE?

15 Anti-CTLA-4 in vitro based rationale: antagonistic

16 Anti-CTLA-4 THERAPY Screening Week 12 Week 14 Week 72 Hodi et al. Abstract #3008 ASCO 2008 Anti-CTLA4 Schadendorf D, J Clin Oncol 2015.

17

18 Blocking CTLA4: with same affinity but different isotypes

19 Anti-CTLA-4 in vivo based rationale: depleting

20 CTLA-4 is highly expressed on intra-tumoral Tregs Selby, M. J. et al. Anti-CTLA-4 Antibodies of IgG2a Isotype Enhance Antitumor Activity through Reduction of Intratumoral Regulatory T Cells. Cancer Immunol. Res. 1, (2013). Simpson, T. R. et al. Fcdependent depletion of tumorinfiltrating regulatory T cells co-defines the efficacy of anti- CTLA-4 therapy against melanoma. J. Exp. Med. 210, (2013). Marabelle, A. et al. Depleting tumor-specific Tregs at a single site eradicates disseminated tumors. J. Clin. Invest. Jun 3; 123, (2013). Bulliard, Y. et al. Activating Fc γ receptors contribute to the antitumor activities of immunoregulatory receptortargeting antibodies. J. Exp. Med. 210, (2013).

21 Anti-CTLA-4 depletes intra-tumoral Tregs Selby, M. J. et al. Anti-CTLA-4 Antibodies of IgG2a Isotype Enhance Antitumor Activity through Reduction of Intratumoral Regulatory T Cells. Cancer Immunol. Res. 1, (2013).

22 FOXP3 Anti-CTLA-4 depletes Tumor-Specific Intratumoral Tregs CD4 Simpson, T. R. et al. Fc-dependent depletion of tumor-infiltrating regulatory T cells co-defines the efficacy of anti-ctla-4 therapy against melanoma. J. Exp. Med. 210, (2013). Marabelle, A. et al. Depleting tumor-specific Tregs at a single site eradicates disseminated tumors. JCI. Jun 3; 123, (2013).

23 Anti-CTLA-4 Treg depletion depends on FcgR Simpson, T. R. et al. Fc-dependent depletion of tumorinfiltrating regulatory T cells co-defines the efficacy of anti- CTLA-4 therapy against melanoma. J. Exp. Med. 210, (2013). Bulliard, Y. et al. Activating Fc γ receptors contribute to the antitumor activities of immunoregulatory receptortargeting antibodies. J. Exp. Med. 210, (2013).

24 Anti-CTLA4 in Humans RITUXIMAB TRASTUZUMAB CETUXIMAB DARATUMUMAB IPILIMUMAB IgG1 IgG1 IgG1 IgG1 IgG1 CD20 HER2 X X EGFR CD38 X X CTLA4

25 IgG2 mabs can do ADCC/ADCP (via Myeloid Cells) NK cells Monocytes IgG2 IgG1 IgG1 IgG2 Schneider-Merck T, et al. Human IgG2 antibodies against epidermal growth factor receptor effectively trigger antibodydependent cellular cytotoxicity but, in contrast to IgG1, only by cells of myeloid lineage. J Immunol. 2010;184:

26 Tremelimumab: same overall survival as ipilimumab Zeynep Eroglu, Dae Won Kim, Xiaoyan Wang, Luis H. Camacho, Bartosz Chmielowski, Elizabeth Seja, Arturo Villanueva, Kathleen Ruchalski, John A. Glaspy, Kevin B. Kim, Wen-Jen Hwu, Antoni Ribas Long term survival with cytotoxic T lymphocyte-associated antigen 4 blockade using tremelimumab European Journal of Cancer, Volume 51, Issue 17, 2015,

27 IPEX syndrome: Human model of FOXP3 KO COLITIS AUTOIMMUNE ENDOCRINOPATHY HEPATITIS SKIN Marabelle A, et al. Arch Pediatr Jan;15(1):55-63

28 Ipilimumab Depletes Tregs in vivo Liakou, C. I. et al. CTLA-4 blockade increases IFNgamma-producing CD4+ICOShi cells to shift the ratio of effector to regulatory T cells in cancer patients. Proc. Natl. Acad. Sci. U. S. A. 105, (2008).

29 Ipilimumab Depletes Tregs in vivo (although it needs ADCC prone macrophages) Romano E, et al. Ipilimumab-dependent cell-mediated cytotoxicity of regulatory T cells ex vivo by nonclassical monocytes in melanoma patients. PNAS. 2015;112:

30 Conclusion 2: Anti-CTLA-4 = not checkpoint blockers but Treg depleters

31

32 Best Change From Baseline (%) Which Dose of a-ctla-4 in Combo with a-pd-1 for bladder? Median reduction in target lesion, % Median reduction in target lesion, % 100 NIVO 1 + IPI % 100 a NIVO 3 + IPI 1 0% Patients a Indicates changes truncated to 100% Symbols in red indicate responders Dashed lines indicate RECIST 1.1 response Patients Sharma P et al. SITC

33 Which dose for anti-ctla-4?? Melanoma: ipilimumab 3mg/kg Q3W x4 + nivo 1mg/kg Q3W x4 followed by nivolumab 3m/kg Q2W RCC: ipilimumab 1mg/kg x4 Q3W nivolumab 3mg/kg Q3W followed by nivolumab 3m/kg Q2W NSCLC: ipilimumab 1mg/kg Q6W nivolumab 3m/kg Q2W

34 O Neil B, et al. Pembrolizumab in CRC. ESMO 2015 Impact #1: Find the right dose to overcome resistance to immunotherapy

35 Impact #2: immune related adverse events Bompaire et al Invest New drugs 2012

36 Impact #3: Address the Financial Toxicity ipilimumab Nature May 30;497(7451) Immunotherapy's cancer remit widens. Ledford H.

37 Corollary Question: Duration of Treatment? «Treat until unacceptable toxicity or disease progression»

38 Are patients overdosed with the present recommendations? Aurélien Marabelle, MD, PhD Clinical Director, Cancer Immunotherapy Pgm Drug Development Dpt INSERM 1015 ESMO Advanced Course Feb 16 th, 2018