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 16th, 2018 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: NCT02528357 (GSK), NCT03334617 (AZ) • Member of Data Safety and Monitoring Board: NCT02423863 (Oncovir) • Scientific Advisory Boards : Merck Serono, eTheRNA, Lytix pharma, Kyowa Kirin Pharma, , 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) Paradigm Shift in Cancer Therapy

Historical Paradigm: New Paradigm: Targeting Tumor Cells Targeting Immune Cells

Lymphocyte

Tumor Cell Know your Immune Checkpoint Antibodies

Anti-CTLA-4 Anti-PD-1 Anti-PD-L1 (BMS) (AZ) (MSD) (AZ/Medimmune) spartalizumab (Pfizer) AGEN-1884 (Novartis) (Agenus) (Roche/Genentech) (Regeneron/Sanofi) LY3300054 (Lilly) (BMS) (Incyte) FAZ053 (Novartis)

Approved Approved Approved anti-PD-1 / anti-PD-L1 immunotherapy

Hayden EC. Antibody alarm call rouses immune response to cancer. Nature. 2012 Jun 6;486(7401):16. Anti-PD-1/PD-L1 Isotypes aPD-1 aPD-L1

NIVOLUMAB PEMBROLIZUMAB ATEZOLIZUMAB DURVALUMAB

Modified Modified IgG4 IgG4 IgG1 IgG1

 NO ADCC / ADCP aPD-1/PD-L1: No Dose/Efficacy/Toxicity Correlation

KN001 Part D KN006 2 mg/kg 10 mg/kg 10 mg/kg 10 mg/kg Q3W Q3W Q3W Q2W ORR (%) 33 35 33 34 PFS (median, 5.5 4.2 4.1 5.5 mo) 6-month PFS 50 41 46 47 rate (%) 12-month OS 72 64 68 74 rate (%) aPD-1/PD-L1: No Dose/Efficacy/Toxicity Correlation

Robert C, et al. Pembrolizumab versus Ipilimumab in Advanced Ribas A, et al. Pembrolizumab versus investigator-choice . chemotherapy for ipilimumab-refractory melanoma (KEYNOTE-002): N Engl J Med. 2015;372:2521–32. a randomised, controlled, phase 2 trial. Lancet Oncol. 2015; Conclusion 1:

Anti-PD-1/PD-L1 = pure antagonistic (« checkpoints blockers ») (avelumab?) Isotypes des anti-PD-1/PD-L1 aPD-1 aPD-L1

NIVOLUMAB PEMBROLIZUMAB ATEZOLIZUMAB DURVALUMAB AVELUMAB

Modified Modified IgG4 IgG4 IgG1 IgG1 IgG1

NO ADCC / ADCP ADCC / ADCP Infusion Related Reactions ≈3% IRR≈18% Dose/PD-1 saturation

0,3mg/kg 1 mg/kg

10 mg/kg 3mg/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, 3167–3175. 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, 3167–3175. Pembrolizumab, Anti-PD-1, MSD

2nd line NSCLC: 2 mg/kg Q3W

1st line NSCLC: 200mg Q3W flat dose Conclusion 2:

We are probably overdosing patients with anti-PD(L)1 antibodies DO WE CARE ? Anti-CTLA-4 in vitro based rationale: antagonistic 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.

Blocking CTLA4: with same affinity but different isotypes Anti-CTLA-4 in vivo based rationale: depleting CTLA-4 is highly expressed on intra-tumoral Tregs

Selby, M. J. et al. Anti-CTLA-4 Simpson, T. R. et al. Fc- Antibodies of IgG2a Isotype dependent depletion of tumor- Marabelle, A. et al. Depleting Bulliard, Y. et al. Activating Fc γ Enhance Antitumor Activity infiltrating regulatory T cells tumor-specific Tregs at a receptors contribute to the through Reduction of co-defines the efficacy of anti- single site eradicates antitumor activities of Intratumoral Regulatory T Cells. CTLA-4 therapy against disseminated tumors. J. Clin. immunoregulatory receptor- Cancer Immunol. Res. 1, 32–42 melanoma. J. Exp. Med. 210, Invest. Jun 3; 123, 2447– targeting antibodies. J. Exp. (2013). 1695–710 (2013). 2463 (2013). Med. 210, 1685–93 (2013). 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, 32–42 (2013).

Anti-CTLA-4 depletes Tumor-Specific Intratumoral Tregs FOXP3 CD4

Simpson, T. R. et al. Fc-dependent depletion of Marabelle, A. et al. Depleting tumor-specific tumor-infiltrating regulatory T cells co-defines the Tregs at a single site eradicates disseminated efficacy of anti-CTLA-4 therapy against melanoma. tumors. JCI. Jun 3; 123, 2447–2463 (2013). J. Exp. Med. 210, 1695–710 (2013). Anti-CTLA-4 Treg depletion depends on FcgR

Simpson, T. R. et al. Fc-dependent depletion of tumor- infiltrating regulatory T cells co-defines the efficacy of anti- Bulliard, Y. et al. Activating Fc γ receptors contribute to CTLA-4 therapy against melanoma. J. Exp. Med. 210, 1695– the antitumor activities of immunoregulatory receptor- 710 (2013). targeting antibodies. J. Exp. Med. 210, 1685–93 (2013). Anti-CTLA4 in Humans

RITUXIMAB TRASTUZUMAB CETUXIMAB DARATUMUMAB IPILIMUMAB

IgG1 IgG1 IgG1 IgG1 IgG1

CD20 HER2 EGFR CD38 CTLA4 X X X X 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 antibody- dependent cellular cytotoxicity but, in contrast to IgG1, only by cells of myeloid lineage. J Immunol. 2010;184:512–20. 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, 2689–2697 http://dx.doi.org/10.1016/j.ejca.2015.08.012 IPEX syndrome: Human model of FOXP3 KO

COLITIS

AUTOIMMUNE ENDOCRINOPATHY HEPATITIS

SKIN

Marabelle A, et al. Arch Pediatr. 2008 Jan;15(1):55-63 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, 14987–92 (2008). 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;112:6140–5. Conclusion 2:

Anti-CTLA-4 = not checkpoint blockers but Treg depleters

Which Dose of a-CTLA-4 in Combo with a-PD-1 for bladder ?

Median reduction in target lesion, % Median reduction in target lesion, %

NIVO 1 + IPI 3 –27.8% a NIVO 3 + IPI 1 0% 100 100

75 75

50 50

25 25

0 0

–25 –25

–50 –50

Best Best Change From Baseline (%) –75 –75

–100 –100 PatientsPatients Patients aIndicates changes truncated to 100% Symbols in red indicate responders Dashed lines indicate RECIST 1.1 response Sharma P et al. SITC 2016 12 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 Impact #1: Find the right dose to overcome resistance to immunotherapy

O’Neil B, et al. Pembrolizumab in CRC. ESMO 2015 Impact #2: immune related adverse events

Bompaire et al Invest New drugs 2012 Impact #3: Address the Financial Toxicity

ipilimumab

Nature. 2013 May 30;497(7451) Immunotherapy's cancer remit widens. Ledford H. Corollary Question: Duration of Treatment ?

« Treat until unacceptable toxicity or disease progression » 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 16th, 2018