Mastering the Latest Developments in Immunotherapy: Renal Cell Carcinoma and Other Solid Tumors David F. McDermott, MD Director, Biologic Therapy Program Beth Israel Deaconess Medical Center Leader, Kidney Cancer Program Dana-Farber Harvard Cancer Center Boston, Massachusetts This activity is supported by an educational grant from Bristol-Myers Squibb.

About These Slides Users are encouraged to use these slides in their own noncommercial presentations, but we ask that content and attribution not be changed. Users are asked to honor this intent These slides may not be published or posted online without permission from Clinical Care Options (email permissions@clinicaloptions.com) Disclaimer The materials published on the Clinical Care Options Web site reflect the views of the authors of the CCO material, not those of Clinical Care Options, LLC, the CME providers, or the companies providing educational grants. The materials may discuss uses and dosages for therapeutic products that have not been approved by the United States Food and Drug Administration. A qualified healthcare professional should be consulted before using any therapeutic product discussed. Readers should verify all information and data before treating patients or using any therapies described in these materials.

Faculty Program Director: Louis M. Weiner, MD Professor and Director, Lombardi Comprehensive Cancer Center Francis L. and Charlotte Gragnani Chair, Department of Oncology Georgetown University School of Medicine Washington, DC David F. McDermott, MD Director, Biologic Therapy Program Beth Israel Deaconess Medical Center Leader, Kidney Cancer Program Dana-Farber Harvard Cancer Center Boston, Massachusetts Antoni Ribas, MD, PhD Professor Department of Medicine and Hematology- Oncology University of California, Los Angeles Los Angeles, California Naiyer Rizvi, MD Associate Attending Physician Memorial Sloan-Kettering Cancer Center Associate Professor of Medicine Weill Cornell Medical College New York, New York This slide lists the faculty who were involved in the production of these slides.

Faculty Disclosures David F. McDermott, MD, has disclosed that he has served as a consultant for Bristol-Myers Squibb, Genentech, and Merck. Antoni Ribas, MD, PhD, has disclosed that he has served as a consultant for Amgen, Daiichi-Sankyo, GlaxoSmithKline, Genentech, Merck, and Novartis and has ownership interest in Kite Pharma and Flexus Biosciences. Naiyer Rizvi, MD, has disclosed that he has served as a consultant for Bristol-Myers Squib, MedImmune, Merck, and Roche. Louis M. Weiner, MD, has disclosed that he has served as a consultant for AbbVie and has ownership interest in Celldex, Jounce, Merrimack, and Targeted Diagnostics. This slide lists the disclosure information of the faculty and staff involved in the development of these slides.

Development of Immunotherapy in RCC Prior to the success of targeted therapy in RCC, immunotherapy was often used in RCC[1] Low dose IFN-α showed modest impact on survival High dose IL-2 can show durable responses in select patients with advanced RCC Metastatic RCC remains a logical solid tumor for assessment of novel immunotherapy approaches 1. McDermott DF, et al. Cancer. 2009;115:2298-2305.

Phase I Nivolumab Multidose Regimen Eligibility: advanced melanoma, NSCLC, RCC, CRC, or CRPC with PD after 1-5 systemic therapies Rapid PD or clinical deterioration Off study 8-wk treatment cycle Unacceptable toxicity Follow-up q8w x 6 (48 wks) Day 1* 15* 29* 43* 57 CR, complete response; CRC, colorectal cancer; CRPC, castrate-resistant prostate cancer; IV, intravenous; NSCLC, non-small cell carcinoma; PD, progressive disease; PR, partial response; RCC, renal cell carcinoma; q2w, every 2 weeks; SD, stable disease. CR/PR/SD or PD but clinically stable Treat to confirmed CR, worsening PD, unacceptable toxicity, or 12 cycles (96 wks) *Dose administered IV q2w. Scans done at baseline and following each 8-wk treatment cycle. Drake CG, et al. ASCO 2013. Abstract 4514.

Nivolumab: Outcomes in Patients With Metastatic RCC Dose, mg/kg Objective Response Rate, % (n/N) Median DoR, Wks (Range) SD Rate, % (n/N)  24 Wks  48 Wks All doses 29.4 (10/34) 56.1 (36.6-126.7+) 26.5 (9/34) 5.9 (2/34) 1 27.8 (5/18) (40.1-76.1+) 22.2 (4/18) 5.6 (1/18) 10 31.3 (5/16) 6.3 (1/16) CI, confidence interval; NE, not estimable; NR, not reached; PFS, progression-free survival; OS, overall survival; RCC, renal cell carcinoma. Drake CG, et al. ASCO 2013. Abstract 4514.

Median OS for Patients With mRCC Treated With Nivolumab 100 Died/Treated 15/34 Median, Mos (95% CI) > 22 (13.60 - NE) 80 1-yr OS: 70% 60 OS (%) 2-yr OS: 50% 40 20 CI, confidence interval; mRCC, metastatic renal cell carcinoma; NE, not estimable; OS, overall survival. 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51 Mos Since Treatment Initiation Pts at Risk, n 34 33 28 28 23 19 14 12 8 8 8 8 8 5 2 Drake CG, et al. ASCO 2013. Abstract 4514.

Objective Responses in Patients With mRCC Receiving Nivolumab Therapy Duration of response Response following discontinuation of therapy Time to response Ongoing response mRCC, metastatic renal cell carcinoma. 24 48 72 96 120 144 168 Wks Drake CG, et al. ASCO 2013. Abstract 4514.

Change in Target Lesions From Baseline After Nivolumab Therapy Patients with mRCC treated with nivolumab 1 or 10 mg/kg Change in Target Lesions From Baseline, % 100 80 60 40 20 -20 -40 -60 -80 -100 144% 10 30 50 70 90 110 120 130 140 150 160 Weeks Since Treatment Initiation 1 mg/kg nivolumab 10 mg/kg nivolumab First occurrence of new lesion Patients with NSCLC treated with nivolumab 3 mg/kg Change in Target Lesions From Baseline, % 100 80 60 40 20 -20 -40 -60 -80 -100 10 30 50 70 90 110 120 130 140 150 Non-squamous, 3 mg/kg Squamous, 3 mg/kg First occurrence of new lesion Weeks Since Treatment Initiation mRCC, metastatic renal cell carcinoma; NSCLC, non-small cell carcinoma. Hodi FS, et al. 12th International Congress on Targeted Anticancer Therapies. Abstract O2.3.

Change in Target Lesions From Baseline After Nivolumab Therapy Unconventional “immune-related” responses in patients with NSCLC, Melanoma, and mRCC 100 80 NSCLC Melanoma 60 RCC 40 First occurrence of new lesion 20 % Change From Baseline in Target Tumor Lesion -20 mRCC, metastatic renal cell carcinoma; NSCLC, non-small cell carcinoma. -40 -60 -80 -100 10 20 30 40 50 60 70 80 90 100 110 120 130 140 150 160 Wks Since Treatment Initiation Hodi FS, et al. 12th International Congress on Targeted Anticancer Therapies. Abstract O2.3.

Nivolumab Phase II Dose-Ranging Study Pts with clear-cell mRCC (≥1 VEGF TKI; ≤ 3 previous systemic therapies) Randomized to receive nivolumab 0.3, 2, or 10 mg/kg IV every 3 wks Outcome Nivolumab Dose 0.3 mg/kg (n = 60) 2 mg/kg (n = 54) 10 mg/kg ORR, % 20 22 Median PFS, mos 2.7 4.0 4.2 Median OS, mos 18.2 25.5 24.7 Tx-related AEs, % 75 67 78 Grade 3/4 AEs,* % 5 17 13 AE, adverse events; RCC, renal cell carcinoma; Tx, treatment. *No grade 3 or 4 pneumonitis reported. Motzer RJ, et al. ASCO 2014. Abstract 5009.

Tx-Related AEs in ≥ 10% of Pts With mRCC AEs in ≥ 10% of Pts With mRCC in Any Arm, % Nivolumab 0.3 mg/kg (n = 59) Nivolumab 3 mg/kg (n = 54) Nivolumab 10 mg/kg Any Grade Grade 3/4 Any AE 75 5 67 17 78 13 Fatigue 24 22 35 Nausea 10 2 Pruritus 9 11 Rash 7 Diarrhea 3 15 Decreased appetite 4 Dry mouth 6 Dry skin Hypersensitivity Arthralgia mRCC, metastatic renal cell carcinoma. Motzer RJ, et al. ASCO 2014. Abstract 5009.

Select Tx-Related AEs in Pts With mRCC Treated With Nivolumab Nivolumab 0.3 mg/kg (n = 59) Nivolumab 3 mg/kg (n = 54) Nivolumab 10 mg/kg Any Grade Grade 3/4 Grade 3/4 Skin 22 4 28 Gastrointestinal 5 11 2 15 Endocrine Hepatic 3 7 6 Pulmonary Infusion Reaction 19 Renal mRCC, metastatic renal cell carcinoma. No grade 3/4 pneumonitis reported Motzer RJ, et al. ASCO 2014. Abstract 5009.

Phase III Study of Nivolumab vs Everolimus in Pts With mRCC A randomized, open-label phase III trial Primary endpoint: OS Secondary endpoints: PFS, ORR, DoR, OS in PD-L1 subgroup, safety Nivolumab 3 mg/kg IV every 2 wks Advanced or metastatic clear-cell RCC after previous antiangiogenic tx; ≤ 3 previous tx and progression ≤ 6 mos prior to enrollment; Karnofsky PS ≥ 70 Treat until: Progression Unacceptable toxicity Withdrawal of consent Everolimus 10 mg/day PO DoR, duration of response; ORR, overall response rate; OS, overall survival; PD-L, programmed death ligand; PFS, progression-free survival; RCC, renal cell carcinoma. ClinicalTrials.gov NCT01668784.

Nivolumab: Pulmonary AEs No grade 3/4 pneumonitis occurred in pts with mRCC in phase I and phase II trials[1,2] In the phase I trial, 4 pts (1%) in total population had grade 3/4 pneumonitis, of which 3 cases were fatal[2] 2 pts with NSCLC; 1 pt with colorectal cancer No new fatalities since follow-up reported in 2012 AEs, adverse events; NSCLC, non-small cell carcinoma; RCC, renal cell carcinoma. 1. Motzer RJ, et al. ASCO 2014. Abstract 5009. 2. Drake CG, et al. ASCO 2013. Abstract 4514.

Pneumonitis Associated With PD-1 Pathway Blockade Treatment algorithms for early detection and management implemented (dose delay/discontinuation, immunosuppression)[1] Clinical Trial Tumor Histology Any Grade % (n/N) Grade 3/4 % (n/N) Nivolumab monotherapy[2] Multiple 3 (9/296) 1 (3/296)* Nivolumab + ipilimumab[3] Concurrent treatment Sequential treatment (ipi → nivo) Melanoma 6 (3/53) 3 (1/33) 2 (1/53) 0 (0/33) Nivolumab ± peptide vaccine[4] 3 (3/90) 2 (2/90) Nivolumab ± peptide vaccine adjuvant[5] 0 (0/153) Nivolumab + chemotherapy[6] NSCLC 14 (8/56) 7 (4/56) All nivolumab trials total All Tumors 4 (27/691) 2 (11/691) Anti-PD-L1 (BMS-963559) monotherapy[7] 1 (3/284) 0 (0/284) CRC, colorectal cancer; NSCLC, non-small cell carcinoma; PD, programmed death. *3 pts with grade 3/4 pneumonitis died (1 CRC, 2 NSCLC). Data analysis in February /March 2013. Hodi FS, et al. 12th International Congress on Targeted Anticancer Therapies. Abstract O2.3. Topalian SL, et al. N Engl J Med. 2012;366:2443-2454. 3. Wolchok JD, et al. J Clin Oncol. 2013;31(18 suppl):abstr 9012. 4. Weber JS, et al. J Clin Oncol. 2013;31(18 suppl):abstr 9011. 5. Gibney GT, et al. J Clin Oncol. 2013;31(18 suppl):abstr 9056. 6. Rizvi NA, et al. J Clin Oncol. 2013;31(18 suppl):abstr 8072. 7. Topalian SL, et al. J Clin Oncol. 2013;31(18 suppl):abstr 3002.

Targeting PD-L1: MPDL3280A Phase Ia Efficacy Summary in RCC RECIST 1.1 ORR, % SD of ≥ 24 Wks, % 24-Wk PFS, % Overall population (N = 140) 21 16 45 RCC* (n = 47) 13 32 53 Clear cell (n = 40) 35 57 Nonclear cell (n = 6) 17 20 ORR, overall response rate; PFS, progression-free survival; RCC, renal cell carcinoma. *1 patient with unknown histology. Includes sarcomatoid and papillary RCC. All patients first dosed prior to August 1, 2012; data cutoff February 1, 2013. ORR includes unconfirmed PR/CR and confirmed PR/CR. Cho DC, et al. ASCO 2013. Abstract 4505.

MPDL3280A Phase Ia: Tumor Burden Over Time in Patients With RCC 100 3 mg/kg (n = 2) 10 mg/kg (n = 12) 15 mg/kg (n = 18) 20 mg/kg (n = 13) 50 Change in Sum of Longest Diameters (SLD) From Baseline (%) -50 RCC, renal cell carcinoma. New lesions -100 Discontinued study 21 42 63 84 105 126 147 168 189 210 231 252 273 294 315 336 357 378 399 420 441 Days on Study Patients first dosed at 3-20 mg/kg prior to August 1, 2012, with at least 1 postbaseline evaluable tumor assessment; data cutoff February 1, 2013. Cho DC, et al. ASCO 2013. Abstract 4505.

MPDL3280A Phase Ia Grade 3/4 AEs in Patients With RCC No grade 3-5 pneumonitis observed No grade 3/4 immune-related* AEs observed Treatment-related* grade 3-4 AEs in 7 patients (13%) Most Common Grade 3/4 AEs, Regardless of Attribution All Dose Cohorts, n (%) (N = 55) All grade 3/4 28 (51%) Hyperglycemia 3 (6%) Dyspnea Fatigue 2 (4%) Hypophosphatemia Hypoxia RCC, renal cell carcinoma. Data cutoff February 1, 2013, grade 3/4 AEs occurring in ≥ 2 patients. *Investigator assessed. Cho DC, et al. ASCO 2013. Abstract 4505.

Immune Checkpoint Inhibitors in Other Solid Tumors

MPDL3280A: Patients With Other Solid Tumors Tumor Type Dose, mg/kg Patients, n Best Response (Investigator Assessed) Time on Study for Responders (Mos) PR SD PD CRC 20 4 1 2 10.4+ GC -- 9.8 Sarcoma 3 NA SCCHN Breast 10, 20 Pancreato-duodenal Pancreatic 10 Ovarian CRC, colorectal cancer; GC, gastric cancer; PD, progressive disease; PR, partial response; SCCHN, squamous cell carcinoma of the head and neck; SD, stable disease. Data cutoff February 1, 2013; only includes patients first dosed at 3-20 mg/kg prior to August 1, 2012. Best response includes unconfirmed and confirmed PR/CR. Tabernero J, et al. ASCO 2013. Abstract 3622. Reprinted with permission.

Activity of Immune Checkpoint Inhibitors in Colon Cancer Phase I trial of nivolumab showed no major responses in CRC (cumulative RR: 0 of 17 pts)[1] Phase I trial of MPDL3280A: 4 pts with CRC[2] 1 pt achieved PR 1 pt achieved SD Baseline Week 18 (after C6) CRC, colorectal cancer; RR, relative response. 1. Topalian SL, et al. N Engl J Med. 2012;366:2443-2454. 2. Tabernero J, et al. ASCO 2013. Abstract 3622. Reprinted with permission.

Activity of Immune Checkpoint Inhibitors in Prostate Cancer After promising initial data, anti–CTLA-4 ipilimumab did not significantly prolong OS in phase III trial in advanced CRPC[1] Phase III trial in patients with less advanced disease ongoing Phase I trial of nivolumab showed no major responses in CRPC (cumulative RR: 0 of 17 patients)[2] CRPC, castration-resistant prostate cancer; OS, overall survival; RR, relative response. 1. Gerritsen W, et al. ECC 2013. Abstract 2850. 2. Topalian SL, et al. N Engl J Med. 2012;366:2443-2454.

Activity of MPDL3280A in Bladder Cancer Phase I study of pts with PD-L1+ metastatic urothelial bladder cancer (n = 30) 71% received ≥ 2 previous therapies 97% received previous platinum-based chemotherapy Tx-related AEs occurring in ≥ 2 pts included decreased appetite, fatigue, nausea, pyrexia, asthenia, chills, and lethargy Tx-related grade 3 AEs: 4% of pts No immune-related AEs, no tx-related grade 4/5 AEs In PD-L1+ pts, ORR: 43% (1 CR) PD-L, programmed death ligand. Powles T, et al. ASCO 2014. Abstract 5011.

Response to MPDL3280A in a Patient With Metastatic HNSCC of the Tongue 78-yr-old-female with PD-L1+ HNSCC who has received multiple lines of therapy, including chemotherapy combinations and cetuximab Baseline Wk 2 Wk 3 Wk 6 Tabernero J, et al. ASCO 2013. Abstract 3622. Reprinted with permission.

Ongoing Trials With Immune Checkpoint Inhibitors

Clinical Development of Immune Checkpoint Inhibitors in Solid Tumors Target Antibody Molecule Development Stage PD-1 Nivolumab (BMS-936558) Fully human IgG4 Phase III multiple tumors (NSCLC, melanoma, RCC, HNSCC) CT-011 Humanized IgG1 Phase II multiple tumors (pancreatic, CRC, HCC, breast, RCC, prostate) Pembrolizumab (MK-3475) Humanized IgG4 Phase III melanoma Phase I/II multiple tumors (RCC, breast, NSCLC) PD-L1 MedI-4736 Engineered human IgG1 Phase III NSCLC MPDL-3280A Phase II multiple tumors (bladder, RCC) BMS-936559 Phase I CRC, colorectal cancer; HCC, hepatocellular carcinoma; HNCC, head and neck squamous cell carcinoma; NSCLC, non-small cell carcinoma; PD, programmed death; PD-L, programmed death ligand; RCC, renal cell carcinoma.

Clinical Development of Immune Checkpoint Inhibitors in Solid Tumors Target Antibody Molecule Development Stage CTLA-4 Ipilimumab Humanized IgG1 Phase III prostate cancer Phase II multiple tumors (cervical, ovarian, gastric, pancreatic, HNSCC) Tremelimumab Fully human IgG2 Phase I and II multiple tumors (malignant mesothelioma, NSCLC, RCC, melanoma) IDO INCB024360 Small-molecule inhibitor Phase II multiple tumors (ovarian, melanoma) NLG919 Phase I B7-H3 MGA271 Humanized IgG1kappa LAG-3 BMS-986016 --- HNCC, head and neck squamous cell carcinoma.

Conclusions Immune checkpoint inhibitors have shown durable responses and a favorable safety profile for patients with previously treated mRCC Treatment of patients with immune checkpoint inhibitors can be different than with conventional therapies, including Identifying unconventional responses to immune checkpoint inhibitors (eg, pseudo-progression) Understanding and managing immune-related adverse events Preliminary data are promising in some other solid tumors, including bladder cancer and HNSCC, but additional follow-up is needed

Go Online for More CCO Coverage of Cancer Immunotherapy! Expert Analysis of key ASCO 2014 abstracts Downloadable slidesets with up to date data Local live events on immunotherapy with expert faculty presenters clinicaloptions.com/oncology