The Really Important Questions Current Immunotherapy Trials are Not Answering

Transcription

1 The Really Important Questions Current Immunotherapy Trials are Not Answering David McDermott, MD Beth Israel Deaconess Medical Center Dana Farber/Harvard Cancer Center Harvard Medical School

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3 PD-1 Pathway Blockade Based ImmunoRx: Questions to be answered Single Agent Clinical What is the proper duration of Rx? Can treatment be stopped before 2 years? Do some patients require maintenance? How many responses are durable off Rx? What is the role of re-challenge? What endpoints predict for OS/TFS? Translational

4 Early responses Treatment-free Survival

5 PD-1 Pathway Blockade Based ImmunoRx: Questions to be answered Single Agent Clinical What is the proper duration of Rx? How many responses are durable off Rx? What is the role of re-challenge? What endpoints predict for OS/TFS? Translational

6 Overall Survival (%) PD-1 OS Curve (Melanoma): Where is the plateau? ORR (RECIST 1.0) was 32% for all treated patients; ORR 41% for the 3 mg/kg dose, which is selected for phase 3 studies 1 year OS 63% Pts at risk, n OS Rate, % (95% CI) 6 Mo (74, 88) 1 Yr (53, 71) 2 Yr (38, 57) 3 Yr (31, 51) 2 year OS 48% 3 year OS 41% Months Since Treatment Initiation This study provides the longest follow-up of any PD-1 inhibitor study median overall follow-up of 22 months (14 51); 47 patients are still alive at time of analysis

7 PD-1 Pathway Blockade Based ImmunoRx: Questions to be answered Single Agent Clinical Translational How can we improve patient selection? Why is the clinical activity less in RCC?

8 Biomarker Development Challenges Does PD-L1 expression alone reliably predict responders? NO (Multiple Investigators) Will tumor heterogeneity complicate biomarker development in RCC? YES (Callea, et al, Cancer Immunol Res, 2015) Can biomarkers guide clinical development? NOT YET But they will be essential for next gen trials

9 Opportunities to Improve Biomarkers CD8 T cells and PDL1 expression at the invasive margin 1 Clonality of T cells in the tumor 1, 5 Mutational frequency 2, 4 Neo-epitope signature 2 Inflammatory gene expression pattern 3, 5 Tumor Histology 6 1. Tumeh et al Nature 2014; 2. Snyder et al N Engl J Med 2014, 3. Petrylak et al ASCO 2015, 4. Le et al NEJM 2015, 5. Choueiri et al ASCO 2015, 6. McDermott et all JCO 2015

10 Future Directions Front-line single agent Non-clear cell RCC 1 Adjuvant 1. Choueiri et al, Ann Oncol 2014

11 PD-1 Pathway Blockade Based ImmunoRx: Questions to be answered Combination Is combination therapy necessary? In which pts? Will the costs > benefits Is sequence better than combination? Do patients require maintenance? Does combination rx salvage PD-1 failures? What endpoints predict for OS/TFS?

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13 PD-1 pathway blockade combination studies Study Treatment Setting Phase Status Patients Completi on Nivolumab NCT CheckMate-016 NCT CheckMate-214 NIV + SUN vs NIV + PAZ vs NIV + IPI first line I ongoing, not recruiting 175 Jun 2015 NIV + IPI vs SUN first line III recruiting 1070 Jan 2018 NCT NIV vs NIV + BEV vs NIV + IPI Pembrolizumab neoadjuvant II recruiting 45 Nov 2018 NCT PAZ ± PEM first line I/II recruiting 228 Oct 2018 MPDL3280A NCT MPDL3280A ± BEV first line a Ib recruiting 225 Feb 2016 NCT MPDL3280A ± BEV vs SUN first line II ongoing, not recruiting 300 Jan 2016 NCT MPDL3280A + BEV vs SUN first line III recruiting 550 Oct 2019 a Subgroup of patients with mrcc receiving first-line therapy. Available at (Accessed June 2015). BEV, bevacizumab; IPI, ipilimumab; NIV, nivolumab; PAZ, pazopanib; PEM, pembrolizumab; SUN, sunitinib.

14 Innovative Trial Design Metastatic Limited Duration Randomized Discontinuation Sequence Comparison Combination + Maintenance vs. Combination Landmark Endpoints Adjuvant

15 Sorafenib: Randomized Discontinuation Trial 25% Tumor shrinkage Continue BAY BAY week run-in -25% to +25% Tumor stabilization Continue BAY weeks Placebo* 12 weeks % SD 24 weeks >25% Tumor growth Off study Ratain et al NCI / EORTC / AACR Mtg, Boston 2003 *Placebo pts with PD may cross over to BAY

16 Sorafenib: RDT Patient status at 12-week assessment* 100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% Colorectal N = 108 Renal cell N = 50 Malignant melanoma N = 20 Other** N = 71 Randomized Responders PD/AE/Other ** * Investigator assessed ** Includes pancreas, sarcoma, thyroid, mesothelioma, and variety of other tumor types

17 Innovative Trial Design Metastatic Limited Duration e.g. 6 mo vs 12 mo Sequence Comparison Combination + Maintenance vs. Combination Landmark Endpoints Adjuvant

18 EA6134: Ipi/Nivo to D/T vs D/T to Ipi/Nivo Arm 1: PD ECOG PS LDH 1. Normal 2. Elevated R A N D O M I Z E Ipi 3/Nivo 1 mg/kg/ q 3wks x 4 +Maint Nivo Arm 2: D 150 BID / T 2 mg Qd PD D 150 BID / T 2 mg Qd Ipi 3/Nivo 1 mg/kg q 3wks x 4 +Maint Nivo ECOG and SWOG protocol Atkins, Chmielowski Accruing

19 Innovative Trial Design Metastatic Limited Duration Sequence Comparison Combination + Maintenance vs. Combination Landmark Endpoints Adjuvant Pre-Surgical Therapy Observation vs. Placebo control

20 Established Landmark Endpoints

21 Innovative Trial Design Metastatic Adjuvant Is Pre-Surgical Rx > Post-surgical Rx? Are IV Placebos feasible?

22 Rationale for Pre-Nephrectomy Anti-PD-1 Priming Harshman Cancer J 2014 Ongoing but unsuccessful anti-tumor T cell response in the tumor, tumor microenvironment, and draining lymph nodes Post-PD-1 blockade anti-tumor CD8 T cells may preferentially expand in these areas traffic to distant sites as memory cells eradicate micrometastases Nephrectomy will remove the majority of these effector cells and cytokines potentially resulting in a less potent response We know nivolumab can work when there is tumor present; no idea if it does when there is little or no antigen Woo Cancer Res 2012, C Drake personal comm.

23 Phase III Perioperative PD-1 Blockade Non-metastatic RCC: Optimizing for Success NCI GU SC Approved L Harshman - PI Primary endpoint: 13% absolute benefit in recurrence-free survival (RFS) % power to increase RFS from 55.8% 68.8% at 5 yrs Secondary endpoint OS: 5 yr OS: 78.7% to 87.3%; HR 0.77 Accrue 264 pts/year for 2.9 years with 2.1 additional years of follow-up 28

24 Rational Application of Immunotherapy for Kidney Cancer? Rational Combinations Improved Biomarkers Limited Therapy

25 Acknowledgements Patients who participated in the clinical trials and their families DF/HCC SPORE Colleagues Sabina Signoretti Toni Choueiri Cathy Wu Lauren Harshman Kathleen Mahoney Gordon Freeman Arlene Shape Mike Atkins (GLCCC) Steve Hodi Slides Chuck Drake (JHU) Hans Hammers (JHU) Bob Motzer (MSKCC) Toni Ribas (UCLA) Tom Powles (St. Barts) Mario Sznol (Yale) Lauren Harshman Toni Choueiri Mike Atkins