Are patients overdosed with the present recommendations?...N Engl J Med. 2015;372:2521–32. Ribas...
Transcript of Are patients overdosed with the present recommendations?...N Engl J Med. 2015;372:2521–32. Ribas...
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Are patients overdosed
with the present
recommendations?
Aurélien Marabelle, MD, PhD
Clinical Director, Cancer Immunotherapy Pgm
Drug Development Dpt
INSERM 1015
ESMO Advanced CourseFeb 16th, 2018
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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, 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)
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Paradigm Shift in Cancer Therapy
Tumor Cell
Historical Paradigm:Targeting Tumor Cells
Lymphocyte
New Paradigm:Targeting Immune Cells
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Anti-PD-1
Approved
Anti-CTLA-4
Approved
Know your Immune Checkpoint Antibodies
Anti-PD-L1
Approved
Nivolumab (BMS)Pembrolizumab (MSD)
spartalizumab(Novartis)
cemiplimab(Regeneron/Sanofi)
camrelizumab (Incyte)
Durvalumab(AZ/Medimmune)Avelumab (Pfizer)
Atezolizumab(Roche/Genentech)
LY3300054 (Lilly)FAZ053 (Novartis)
Tremelimumab(AZ)
AGEN-1884 (Agenus)
Ipilimumab(BMS)
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Hayden EC. Antibody alarm call rouses immune response to cancer. Nature. 2012 Jun6;486(7401):16.
anti-PD-1 / anti-PD-L1 immunotherapy
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NIVOLUMAB
IgG4
PEMBROLIZUMAB ATEZOLIZUMAB DURVALUMAB
aPD-1 aPD-L1
Modified IgG1IgG4
Modified IgG1
Anti-PD-1/PD-L1 Isotypes
NO ADCC / ADCP
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KN001 Part D KN006
2 mg/kg Q3W
10 mg/kg Q3W
10 mg/kg Q3W
10 mg/kg Q2W
ORR (%) 33 35 33 34
PFS (median, mo)
5.5 4.2 4.1 5.5
6-month PFS rate (%)
50 41 46 47
12-month OS rate (%)
72 64 68 74
aPD-1/PD-L1: No Dose/Efficacy/Toxicity Correlation
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aPD-1/PD-L1: No Dose/Efficacy/Toxicity Correlation
Robert C, et al. Pembrolizumab versus Ipilimumab in Advanced Melanoma.
N Engl J Med. 2015;372:2521–32.
Ribas A, et al. Pembrolizumab versus investigator-choicechemotherapy for ipilimumab-refractory melanoma (KEYNOTE-002):
a randomised, controlled, phase 2 trial. Lancet Oncol. 2015;
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Conclusion 1:
Anti-PD-1/PD-L1 = pure antagonistic(« checkpoints blockers »)
(avelumab?)
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NIVOLUMAB
IgG4
PEMBROLIZUMAB ATEZOLIZUMAB DURVALUMAB AVELUMAB
aPD-1 aPD-L1
Modified IgG1IgG4
Modified IgG1
IgG1
Isotypes des anti-PD-1/PD-L1
NO ADCC / ADCPInfusion Related Reactions ≈3%
ADCC / ADCPIRR≈18%
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Dose/PD-1 saturation
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-programmeddeath-1 (MDX-1106) in refractory solid tumors: safety, clinical activity, pharmacodynamics, and immunologic correlates. J. Clin. Oncol. 28, 3167–3175.
0,3mg/kg
3mg/kg
1 mg/kg
10 mg/kg
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Long-term PD-1 occupancy analysis in patients receiving nivolumab at 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-programmeddeath-1 (MDX-1106) in refractory solid tumors: safety, clinical activity, pharmacodynamics, and immunologic correlates. J. Clin. Oncol. 28, 3167–3175.
One dose 3 doses Multiple doses
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Pembrolizumab, Anti-PD-1, MSD
2nd line NSCLC: 2 mg/kg Q3W
1st line NSCLC: 200mg Q3W
flat dose
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Conclusion 2:
We are probably overdosing patients with anti-PD(L)1 antibodies
DO WE CARE ?
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Anti-CTLA-4 in vitro based rationale:antagonistic
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Anti-CTLA-4 THERAPY
Hodi et al. Abstract #3008 ASCO 2008
Screening Week 12 Week 14 Week 72
Schadendorf D, J Clin Oncol 2015.
Anti-CTLA4
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Blocking CTLA4:with same affinity but different isotypes
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Anti-CTLA-4 in vivo based rationale:depleting
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CTLA-4 is highly expressed on intra-tumoral Tregs
Bulliard, Y. et al. Activating Fc γ receptors contribute to the antitumor activities of immunoregulatory receptor-targeting antibodies. J. Exp. Med. 210, 1685–93 (2013).
Selby, M. J. et al. Anti-CTLA-4 Antibodies of IgG2a IsotypeEnhance Antitumor Activity through Reduction of Intratumoral Regulatory T Cells. Cancer Immunol. Res. 1, 32–42 (2013).
Simpson, T. R. et al. Fc-dependent depletion of tumor-infiltrating regulatory T cellsco-defines the efficacy of anti-CTLA-4 therapy againstmelanoma. J. Exp. Med. 210,1695–710 (2013).
Marabelle, A. et al. Depleting tumor-specific Tregs at a single site eradicates disseminated tumors. J. Clin. Invest. Jun 3; 123, 2447–2463 (2013).
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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).
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Anti-CTLA-4 depletes Tumor-Specific Intratumoral Tregs
Marabelle, A. et al. Depleting tumor-specificTregs at a single site eradicates disseminatedtumors. JCI. Jun 3; 123, 2447–2463 (2013).
Simpson, T. R. et al. Fc-dependent depletion oftumor-infiltrating regulatory T cells co-defines theefficacy of anti-CTLA-4 therapy against melanoma.J. Exp. Med. 210, 1695–710 (2013).
FOX
P3
CD4
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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, 1695–710 (2013).
Bulliard, Y. et al. Activating Fc γ receptors contribute to the antitumor activities of immunoregulatory receptor-targeting antibodies. J. Exp. Med. 210, 1685–93 (2013).
Anti-CTLA-4 Treg depletion depends on FcgR
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Anti-CTLA4 in Humans
CD20
RITUXIMAB
IgG1
HER2
TRASTUZUMAB
IgG1
EGFR
CETUXIMAB
IgG1
CTLA4
IPILIMUMAB
IgG1
X X XCD38
DARATUMUMAB
IgG1
X
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NK cells Monocytes
IgG1IgG1
IgG2
IgG2
IgG2 mAbs can do ADCC/ADCP(via Myeloid Cells)
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.
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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
Tremelimumab: same overall survival as ipilimumab
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IPEX syndrome: Human model of FOXP3 KO
Marabelle A, et al. Arch Pediatr. 2008 Jan;15(1):55-63
COLITIS
HEPATITIS
SKIN
AUTOIMMUNE ENDOCRINOPATHY
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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
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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 bynonclassical monocytes in melanoma patients. PNAS. 2015;112:6140–5.
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Conclusion 2:
Anti-CTLA-4 =
not checkpoint blockers but Treg depleters
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Which Dose of a-CTLA-4 in Combo with a-PD-1 for bladder ?
12
Median reduction in target lesion, %
NIVO 1 + IPI 3 –27.8%
Median reduction in target lesion, %
NIVO 3 + IPI 1 0%
aIndicates changes truncated to 100%
Symbols in red indicate responders
Dashed lines indicate RECIST 1.1 response
Patients
100
75
50
–25
0
–50
–75
–100
25
a
100
75
50
–25
0
–50
–75
–100
25
Patients
Best
Change F
rom
Baselin
e (
%)
Patients
Sharma P et al. SITC 2016
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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
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Impact #1: Find the right dose to overcome resistance to immunotherapy
O’Neil B, et al. Pembrolizumab in CRC. ESMO 2015
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Bompaire et al Invest New drugs 2012
Impact #2: immune related adverse events
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Impact #3: Address the Financial Toxicity
Nature. 2013 May 30;497(7451)Immunotherapy's cancer remit widens. Ledford H.
ipilimumab
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Corollary Question: Duration of Treatment ?
« Treat until unacceptable toxicityor disease progression »
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Are patients overdosed
with the present
recommendations?
Aurélien Marabelle, MD, PhD
Clinical Director, Cancer Immunotherapy Pgm
Drug Development Dpt
INSERM 1015
ESMO Advanced CourseFeb 16th, 2018