CTLA4 Blockade in Melanoma Treatment. Antoni Ribas, M.D. Associate Professor of Medicine and Surgery University of California Los Angeles.

Transcription

1 CTLA Blockade in Melanoma Treatment Antoni Ribas, M.D. Associate Professor of Medicine and Surgery University of California Los Angeles.

2 CTLA Negatively Modulates T-Cell Activation MHC Antigen TCR Dendritic cell T cell CD8 B7 CTLA

3 Blocking Antibodies to CTLA Allow Positive Signaling from Costimulatory Molecules to T Cells MHC Antigen TCR Dendritic cell T cell B7 CD8 CTLA Leach DR, Krummel MF, Allison JP. Enhancement of antitumor immunity by CTLA- blockade. Science 996;7:7-76.

4 CTLA Antagonistic Monoclonal Antibodies in Clinical Development Antibody Name Former Name Maker Type of Antibody* Ig Subtype* Plasma Half Life* ipilimumab MDX BMS76 Medarex /BMS Fully human IgG 5 days tremelimumab CP-675,6 ticilimumab Pfizer Fully human IgG days IgG IgG IgG IgG ADCC +++ +/ Complement fixation Plasma Half Life 9 Ribas et al. J Clin Oncol 5 Korman et al. Adv Immunol 6

5 Published Full Text Manuscripts of Antitumor Activity of Anti-CTLA mab in Melanoma Ref. Antibody Combination mab Dose Ab. Dose No. Pts with Measurable Melanoma Objective Responses Hodi et al. Ipilimumab No Single 7 PNAS (MDX) mg/kg Attia et al. JCO 5 (Phan et al. PNAS ) Ipilimumab (MDX) gp peptides mg/kg qw 56 7 Maker et al. Ann Surg Onc 5 Ipilimumab (MDX) HD IL-.- mg/kg qw 6 8 Maker et al. Ipilimumab No -9 qw 6 5 J Immunother 6 (MDX) mg/kg Ribas et al. JCO 5 Tremelimumab (CP-675,6) No.-5 mg/kg Single 9 5 Reuben et al. Cancer 6 Tremelimumab (CP-675,6) No -5 mg/kg qm or qm 5 Overall: -5% RR

6 Early Clinical Development Issues What is the maximum tolerable dose? What are the optimal plasma levels? What is the right dose? What is the right schedule? What is the mechanism of action of response and resistance? Are there biomarkers for response?

7 Phase : Toxicity and Response with CP-675,6 Dose Level (mg/kg) No. Patients Evaluable for Response Response (months) Autoimmune Toxicities SD x 6 SD x SD x 5 CR x Vitiligo. 9 SD x 7 Diarrhea, Lipase PR x 5+ Vitiligo, Asthma SD x 5. 6 PR x 5+ Diarrhea, Rash CR x 5+ Panhypopituitarism CR x 5+ (removal of lesion) Hyperthyroidism Increasing the dose leads to responses and toxicities Ribas, Camacho, Gomez-Navarro et al. JCO 5, Update 7/7

8 Antibody Exposure/PD Correlation Preclinical testing: Concentration-dependent IL- release in PBMC Predicted minimal efficacious plasma concentration: - µg/ml Clinical testing: PD effects (toxicity and/or response): Doses leading to sustained plasma levels beyond µg/ml In vitro In vivo Concentration (µg/ml). 5 mg/kg mg/kg 6 mg/kg mg/kg mg/kg. 6 5 D. Hanson D. Noe. mg/kg. 6 8 Time after End of Infusion (wk)

9 Anti-CTLA Brief Clinical Summary A threshold of circulating antibody is required for biological effects, which result in: No toxicity and no response in the majority of patients. Toxicity and/or response in a minority of patients (-5%). Responses are durable, longest 6 years, with very few relapses. The key issue is to understand the MOA of response and toxicity.

10 Immune Monitoring in Peripheral Blood After analyzing,9 data points of samples obtained from peripheral blood : MHC Tetramers (79). ELISPOT (,69). Comin-Anduix et al., Clin Cancer Res 6 Flow cytometry for T cell activation marker HLA- DR and T cell memory marker CD5RO on CD and CD8 cells (66). FoxP by QPCR (56) and ICS (9). Conclusion: Non-specific markers of activation of CD+ T cells are the only biomarker of CP-675,6 administration, which provides little mechanistic insight.

11 /5 Partial Response (+ mo) Post /5 Negative Stain - HMB5 Melanoma + 7/5 CD B Cells - CD T Cells +++ CD T helper +++ CD8 CTL +++

12 Partial Response (+ mo) /5 5/5 H&E MART- CD8 CD CD CDa CDa CDa x ExpMCEOS86. FL-H FL-H R.6% 6.9 #5 gp Tetramer /5 Peripheral blood BYOPSYMC55. FL-H FL-H R.8% 5.5 CD8+ /5 Tumor biopsy x

13 Study of Intratumoral Changes after CP-675,6 89 patients dosed with CP-675,6 at UCLA, a small subset of patients underwent tumor biopsies Samples collected for: Diagnostic or therapeutic need (more likely on progressing patients) Research purposes under UCLA IRB# (more likely on responding patients) IHC staining for: Melanoma markers: S-, HMB5, MART-, tyrosinase Immune cell subset markers: CDa, CD, CD, CD8, CD Treg marker: FoxP Immune suppressive DC marker: IDO IHC scoring by Dr. Alistair Cochran: Frequency (-+) of reactive cells Distribution (diffuse or patchy) of reactive cells

14 Pre Post Partial Response (+ mo) BiopsyJCK6_TILS JCK.fcs 5.8%.7% Color AlexaFluor5/PacificBlue FITC PE PC5/7AAD (Dump Channel) ECD APC/AlexaFluor67 APC-Cy7/APC-AF75 CD8 + : %, CD + : 6.5% BiopsyJCK6_TILS JCK.fcs.%.5% BiopsyJCK6_TILS JCK.fcs Marker CD CD5RO CD7 CD9/CD56 HLA-DR CCR7 CD.%.5% S- CD8 CD S- CD8 CD BiopsyJCK6_TILS JCK.fcs.9% 6.57% CD 5.% CD.% PE-A CD+CD- CD7-7.% 6.% FITC/AlexaFluor 88-A BiopsyJCK6_TILS JCK.fcs.7% 9.85% ECD-A HLA-DR.5% PE-A 5.% CD7 ECD-A HLA-DR.%.9% FITC/AlexaFluor 88-A BiopsyJCK6_TILS JCK.fcs.%.9% APC/AlexaFluor67-A CCR7 5.7% PE-A 6.85% CD7 APC/AlexaFluor67-A CCR7 7.7% 5.% FITC/AlexaFluor 88-A CD5RO CD5RO CD5RO BiopsyJCK6_TILS JCK.fcs.%.% APC/AlexaFluor67-A CCR7 6.6% Phenotype CD8 + : HLA-DR + CD5RO +++ CD7 ++ CCR7 - (T early memory) ECD-A 6.5% HLA-DR

15 Intratumoral CD8 and CD T Cell Infiltrates Patient No. Response Timing of Biopsy (first dose/last dose) CD8 CD Change PR Pre NA Post ( mo/mo) +++ diffuse ++ diffuse PR Pre Post ( mo/ mo) ++ diffuse + diffuse ppr Pre ++ patchy + patchy Post (9 mo/ mo) ++ diffuse +++ diffuse Progression Pre +/- patchy +/- patchy Post ( mo/ mo) +/- patchy +/- patchy =

16 T cell Treg Depletion with CTLA Blocking Monoclonal Antibodies T cell B7 B7 CTLA Treg Treg depletion in peripheral blood with anti- FoxP CTLA mab: Reuben et al. Cancer 6 Anti-CTLA Anti-CTLA CTLA FoxP Treg No Treg depletion in peripheral blood with anti- CTLA mab: Maker et al. J Immunol 5 Comin-Anduix et al. isbtc 6

17 Post Patient PD: FoxP by IHC or ICS in TIL FoxP in TIL by IHC FoxP in TIL by ICS S CD CD CD5 CD5+ ByBS_GHW66.6.7% CD=CD5high CD/CD5hi CD+ CD Side Scatter FoxP+ 9.66% #67 FoxP ICS ByBS_GHW66.6 FoxP+ FoxP 9% FoxP x FoxP x

18 ppr: FoxP Pre and Post CP-675,6 Pre HMB5 CD8 FoxP FoxP Post HMB5 CD8 x x FoxP x FoxP

19 Inhibition of IDO by CTLA Blocking Monoclonal Antibodies Treg DC DC B7 IDO CTLA Anti-CTLA Anti-CTLA B7 IDO CTLA Treg Grohmann, Fallarino et al. Nat Immunol., 97 () Grohmann, Fallarino et al. Nat Immunol., 6 () Munn, Mellor et al. J Clin Invest., 8 () Munn, Mellor et al. Int Immunol. 6, 9 ()

20 ppr: IDO Pre and Post CP-675,6 Pre HMB5 CD8 IDO IDO Post HMB5 CD8 x x IDO x IDO

21 Intratumoral FoxP+ and IDO+ Cells Patient No. Resp onse Timing of Biopsy FoxP FoxP Change IDO IDO Change PR Pre ++ diffuse Post ( mo/mo) + patchy + patchy PR Pre + patchy Post ( mo/ mo) + patchy + patchy = ppr Pre + patchy + patchy Post (9 mo/ mo) ++ patchy + patchy = Progr Pre + patchy - Post ( mo/ mo) + patchy = - =

22 CTLA mab Clinical Development Leading to Pivotal Clinical Trials Early Clinical Data Pivotal Trials MDX FIH mg/kg 6/ mg/kg qw pts RR: 8% G/:% (?) () Single arm in nd line:. Ipi mg/kg qw + gp pep mg/kg qw 56 pts RR:.5% G/: 5% () Randomized in nd line:. gp pep. Ipi mg/kg qw. Ipi mg/kg qw + gp + DTIC mg/kg qw 5 pts RR: 7% G/: 8.6% mg/kg qw 7 pts RR: 5% G/: 8.5% () Randomized in st line:. DTIC. Ipi mg/kg qw + DTIC CP-675,6 FIH 5 mg/kg qw pts RR: 7% ().-5 mg/kg G/: % Single arm in nd line:. Treme 5 mg/kg qw / mg/kg qw pts RR: % G/: 7% () Weber, J et al. Proc ASCO 7 () Attia, P et al. JCO 5 () Fischkoff, SA et al. Proc ASCO 5, all 95% CI overlapping () Ribas, A et al. Proc ASCO 7, all 95% CI overlapping Randomized in st line:. DTIC. Treme 5 mg/kg qw

23 Is Dose Correlated with Response or Toxicity or Both? Anti-Self Toxicity Anti-Melanoma Response

24 Is Toxicity Correlated with Response? Attia, Rosenberg et al. JCO 5: (ipilimumab + gp peptides) Reuben, Camacho et al. Cancer 6: (CP-675,6) -II III/IV -I II/IV No Response 9 9 No Response Response 5 7 Response P =.8 Fisher exact test P =. Chi-square P =.5 Chi-square

25 Is Toxicity Correlated with Response? Attia, Rosenberg et al. JCO 5: (ipilimumab + gp peptides) Reuben, Camacho et al. Cancer 6: (CP-675,6) -II III/IV -I II/IV No Response 9 9 No Response Response 5 7 Response P =.8 Fisher exact test P =. Chi-square P =.5 Chi-square But Toxicity with no response (red) is more common than toxicity with response (green).

26 Is Toxicity Correlated with Response? Attia, Rosenberg et al. JCO 5: (ipilimumab + gp peptides) Reuben, Camacho et al. Cancer 6: (CP-675,6) -II III/IV -I II/IV No Response 9 9 No Response Response 5 7 Response P =.8 Fisher exact test P =. Chi-square P =.5 Chi-square But Response without toxicity is possible. More doses, more likely to develop toxicities, more likely to demonstrate a response.

27 Is Toxicity Correlated with Response? Attia, Rosenberg et al. JCO 5: (ipilimumab + gp peptides) Reuben, Camacho et al. Cancer 6: (CP-675,6) -II III/IV -I II/IV No Response 9 9 No Response Response 5 7 Response P =.8 Fisher exact test P =.5 Chi-square Maker, Rosenberg et al. JIT 6: (ipilimumab intra-patient dose escalation) -I III/IV No Response 8 Response P =. Fisher exact test

28 What Have We Learned Thus Far? Responses: Somewhere between 5-5% Most are durable, lasting years. Toxicity: Serious autoimmune or inflammatory toxicity in - %. Relationship between toxicity and response: Unclear. Biomarkers of antitumor activity: Peripheral blood: No good evidence. Tumors: Marked immune infiltrates in responders. Mechanism of action: Immune-mediated. Unlikely participation of Treg or IDO+ cells.

29 Phase II Registrational Clinical Trials mab Population No. Pts Primary Objective Dosing Init. Compl. Tremelimumab nd line or greater 5 Best ORR 5 mg/kg qm Dec 5 Oct 6 Ipilimumab nd line or greater 5 Best ORR mg/kg qw Feb 6 Jan 7 Ipilimumab nd line Best ORR. mg/kg qw mg/kg qw Feb 6 April 7 mg/kg qw Source: ClinicalTrials.gov.

30 Phase III Registrational Clinical Trials mab Treatments Pop. No. Pts Primary Objective Dosing Init. Compl. Ipilimumab. Ipi. gp. Ipi + gp nd line 75 Best ORR mg/kg qw Sept Ongoing Tremelimumab. DTIC or TMZ. Treme st line 6 OS 5 mg/kg qm March 6 June 7 Ipilimumab. DTIC. Ipi + DTIC st line 5 PFS mg/kg qw June 6 Ongoing Source: ClinicalTrials.gov.

31 Key Features of the Pivotal Testing Ipilimumab: Testing single agent, combination with peptides and combination with chemotherapy Testing different dosing regimens Dosing beyond the MTD (more toxicity, more responses?) Phase III: PFS Tremelimumab: Single agent testing Dosing regimen optimized to minimize toxicity Phase III: OS

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33 Acknowledgements UCLA: Begonya Comin-Anduix, PhD Bartosz Chmielowski, MD, PhD Jason Jalil, BS Lilah Morris, MD Jackie Hernandez Denise Oseguera, RN Rosalinda Rivera Elisabeth Seja Geoff Slonkier Arturo Villanueva John A. Glaspy, MD, MPH James S. Economou, MD, PhD Alistair Cochran, MD Pfizer Global Research and Development: Sas Bulanhagui, MS Meg Marshal, MD Viviana Bozon, MD Dmitri Pavlov, PhD Dennis Noe, MD Amar Sharma, MD Jesus Gomez-Navarro, MD M.D. Anderson: Luis Camacho, MD, MPH Support: Research funding from Pfizer K CA976 Jonsson Comprehensive Cancer Center Melanoma Research Foundation