Newest Oncology Agents: PD 1 Inhibitors Clinical Information and Patient Management

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1 Newest Oncology Agents: PD 1 Inhibitors Clinical Information and Patient Management Stacey Jassey Megan Brafford David Kwasny This CE activity was originally presented live at the 2015 NASP Annual Meeting & Expo in National Harbor, MD. Anyone that claimed CE credit for the live session should not claim credit for this enduring activity Thank you. 1

2 Newest Oncology Agents: PD 1 Inhibitor Clinical Information Megan Brafford, Pharm.D., BCOP Baptist Health Lexington Lexington, Kentucky Objectives Discuss the current clinical data and utilization results of PD-1s Discuss dosing, safety and efficacy data available for PD-1s 2

3 Immunotherapy Activate immune system to target tumors Developmental hurdles Lack of reliable biomarker Antigenic similarity of tumor cells and normal cells Immunosuppressive nature of tumor environment PD-1 Inhibitor Mechanism of Action Acts on programmed death-1 (PD-1) pathway Binds to the PD-1 receptor and blocks interaction with programmed death ligand 1 (PD-L1) and programmed death ligand 2 (PD-L2) Releases PD-1 pathway-mediated inhibition of immune response Blocks body s immune system from attacking cancerous cells 3

4 PD-1 Inhibitor Mechanism of Action Guha Pharmaceutical Journal (2014) PD-1 Tumor Prevalence Tumor Type Estimated PD 1 Prevalence (%) Non small cell lung cancer 50 (NSCLC) (squamous) NSCLC (adenocarcinoma) 45 Colon cancer 45 Melanoma 40 Renal cell carcinoma 20 Keir Annu Rev Immunol (2008) Thompson PNAS (2004) 4

5 Immune-Related Response Criteria (irrc) Developed to adequately assess tumor response to immunotherapy Tumor flare or pseudoprogression can occur Anti-tumor response may take longer First evaluation scan at 12 weeks Subsequent scans every 8 weeks O Regan AJR (2011) Wolchock Clinical Cancer Research (2009) Nivolumab (Opdivo ) 5

6 CheckMate 063 Phase 2, single-arm, international trial Advanced, refractory squamous NSCLC (n = 117) 2 or more prior treatments Nivolumab 3 mg/kg every 2 weeks Primary end point: confirmed objective response rate (ORR) Rizvi Lancet Oncology (2015) CheckMate 063 Results Confirmed ORR: 14.5% Stable disease: 26% Median time to response: 3.3 months Median duration of response: NR (not reached) Grade 3 4 adverse events: 17% Rizvi Lancet Oncology (2015) 6

7 CheckMate 017 Phase 3, randomized, open-label, international trial Advanced squamous NSCLC (n = 272) Failed platinum-based doublet chemotherapy (PT-DC) Nivolumab 3 mg/kg every 2 weeks (n = 135) Docetaxel 75 mg/m 2 every 3 weeks (n = 137) Primary end point: OS (overall survival) Spigel DR J Clin Oncol (2015) CheckMate 017 Results Median OS: Nivolumab: 9.2 months Docetaxel: 6.0 months ORR: Nivolumab: 20% Docetaxel: 9% Risk of death: Decreased by 41% with nivolumab Grade 3 4 adverse effects: Nivolumab: 7% Docetaxel: 55% Spigel DR J Clin Oncol (2015) 7

8 CheckMate 057 Phase 3, open-label, international, randomized trial Advanced or metastatic non-squamous NSCLC (n = 582) Failed PT-DC and tyrosine kinase inhibitor, if eligible Nivolumab 3 mg/kg IV every 2 weeks (n = 292) Docetaxel 75 mg/m2 IV every 3 weeks (n = 290) Primary endpoint: OS Paz Ares J Clin Oncol (2015) CheckMate 057 Results OS: Nivolumab: 12.2 months Docetaxel: 9.4 months ORR: Nivolumab: 19.2% Docetaxel: 12.4% Grade 3-4 adverse effects: Nivolumab: 10.5% Docetaxel: 53.7% PD-L1 expression associated with benefit from nivolumab Paz Ares J Clin Oncol (2015) 8

9 CheckMate 037 Phase 3, randomized, controlled, open-label, international trial Unresectable or metastatic melanoma (n = 167) Failed ipilimumab and a BRAF inhibitor, if BRAF V600 mutation positive Nivolumab 3mg/kg every 2 weeks (n=120) Investigator s choice of chemotherapy (ICC) (n=47) Dacarbazine 1000 mg/m 2 every 3 weeks Carboplatin AUC 6 + paclitaxel 175 mg/m 2 every 3 weeks Primary end point: ORR Weber JS Lancet Oncology (2015) CheckMate 037 Results Confirmed ORR: Nivolumab: 31.7% ICC: 10.6% Grade 3 4 adverse events: Nivolumab: 5% ICC: 9% Weber JS Lancet Oncology (2015) 9

10 CheckMate 067 Phase 3, randomized, double-blind trial Unresectable or metastatic melanoma (n = 945) Untreated patients Nivolumab 3 mg/kg every 2 weeks (n = 315) Nivolumab 1 mg/kg every 3 weeks for 4 cycles followed by 3 mg/kg every 2 weeks + ipilimumab 3 mg/kg every 3 weeks for 4 cycles (n = 315) Ipilimumab 3 mg/kg every 3 weeks for 4 cycles (n = 315) Primary end point: PFS (progression-free survival) Larkin N Engl J Med (2015) CheckMate 067 Results PFS: Nivolumab: 6.9 months Nivolumab + ipilimumab: 11.5 months Ipilimumab: 2.9 months ORR: Nivolumab: 43.7% Nivolumab + ipilimumab: 57.6% Ipilimumab: 19.0% Grade 3 4 adverse effects: Nivolumab: 16.3% Nivolumab + ipilimumab: 55.0% Ipilimumab: 27.3% Larkin N Engl J Med (2015) 10

11 Nivolumab Indications Advanced or metastatic, squamous NSCLC with progression on, or after PT-DC Off-label use: non-squamous NSCLC Unresectable or metastatic melanoma with progression following ipilimumab and if BRAF V600 mutation positive, a BRAF inhibitor Off-label use: 1 st line in combination with ipilimumab for 4 doses every 3 weeks, then monotherapy every 2 weeks Off-label use: 1 st line for patients without a BRAF mutation Dose: 3 mg/kg IV infusion over 1 hour every 2 weeks BMS. Opdivo package insert (2015) Nivolumab Adverse Effects Common: Pruritus Rash Electrolyte abnormalities Constipation Appetite suppression Nausea/Vomiting Cough Musculoskeletal pain Fatigue Severe: Colitis (diarrhea) Hepatitis Hypo/hyper-thyroidism Renal dysfunction Dyspnea Pneumonitis BMS. Opdivo package insert (2015) 11

12 Nivolumab Monitoring Reduction in tumor growth Liver function tests Serum creatinine Thyroid function tests S/S pneumonitis S/S colitis BMS. Opdivo package insert (2015) Pembrolizumab (Keytruda ) 12

13 KEYNOTE-001 Phase I trial Advance or metastatic NSCLC (n = 495) Previously treated and treatment naïve Pembrolizumab 2 mg/kg every 3 weeks (n = 165) Pembrolizumab 10 mg/kg every 3 weeks (n = 165) Pembrolizumab 10 mg/kg every 2 weeks (n = 165) Garon E N Engl J Med (2015) KEYNOTE-001 Results ORR: 19.4% High PD-L1 expressing patients: 45.2% Median duration of response: 12.5 months PFS: 3.7 months OS: 12 months Garon E N Engl J Med (2015) 13

14 KEYNOTE-006 Phase 3, randomized, controlled trial Advanced, unresectable or metastatic melanoma (n = 834) No more than 1 prior therapy Pembrolizumab 10 mg/kg every 3 weeks (n = 278) Pembrolizumab 10 mg/kg every 2 weeks (n = 278) Ipilimumab 3 mg/kg every 3 weeks for 4 cycles (n = 278) Primary end points: PFS and OS Robert C N Engl J Med (2015) KEYNOTE-006 Results OS (12 month): Pembrolizumab every 3 weeks: 74.1% Pembrolizumab every 2 weeks: 68.4% Ipilimumab: 58.2% PFS: Pembrolizumab every 3 weeks: 47.3% Pembrolizumab every 2 weeks: 46.4% Ipilimumab: 26.5% Robert C N Engl J Med (2015) 14

15 KEYNOTE-006 Results ORR: Pembrolizumab every 3 weeks: 32.9% Pembrolizumab every 2 weeks: 33.7% Ipilimumab: 11.9% Grade 3 4 adverse effects: Pembrolizumab every 3 weeks: 13.3% Pembrolizumab every 2 weeks: 10.1% Ipilimumab: 19.9% Robert C N Engl J Med (2015) Pembrolizumab Indication Unresectable or metastatic malignant melanoma Following ipilimumab and, if BRAF V600 mutation positive, a BRAF inhibitor Dose: 2 mg/kg IV infusion over 30 minutes every 3 weeks Merck. Keytruda package insert (2015) 15

16 Pembrolizumab Adverse Effects Common: Pruritus Rash Constipation Nausea/Vomiting Diarrhea Muscle aches Cough Fatigue Severe: Anemia Pneumonitis Infusion reaction Hepatitis Renal dysfunction Erythroderma Merck. Keytruda package insert (2015) 31 Pembrolizumab Monitoring Reduction in tumor growth Hypoglycemia Liver function tests Serum creatinine Thyroid function tests S/S pneumonitis S/S colitis S/S hypophysitis Merck. Keytruda package insert (2015) 16

17 Where Do We Go From Here? Need to determine long-term benefit of PD-1 inhibitors Define how immune system is best able to attack the tumor Personalize therapy Excellent response rates in niche patient population Key Takeaways Validation of long term responses are needed to understand the full benefit and optimal role of these new treatments in therapy PD-1 inhibitors are one mechanism of harnessing immune system to target cancer Further development in other malignancies Additional options under way in clinical trials 17

18 References Brahmer J, Reckamp K, Baas P, et al. N Engl J Med. 2015;373: Garon E, Rizvi N, Hui R, et al. N Engl J Med. 2015;372: Guha M. The Pharmaceutical Journal Keir ME, Butte MJ, Freeman GJ, et al. Annu Rev Immunol. 2008;26: Larkin J, Chiarion-Sileni V, Gonzalez R, et al. N Engl J Med. 2015;373: O Regan K, Jagannathan J, Ramaiya N, et al. AJR. 2011;1997:W241-W246. Paz-Ares L, Hom L, Borghaei H, et al. J Clin Oncol. 2015; 22(abst LBA109). Rizvi N, Mazieres J, Planchard D, et al. Lancet Oncology. 2015;16(3): Robert C, Schachter J, Long G, et al. N Engl J Med. 2015;371: Spigel D, Reckamp K, Rizvi N, et al. J Clin Oncol. 2015;33(abst 8009). Thompson RH, Gillett MD, Cheville JC, et al. PNAS. 2004;101(49): Wolchock, et al. Clinical Cancer Research. 2009;15: Newest Oncology Agents: PD 1 Inhibitor Clinical Information Megan Brafford, Pharm.D., BCOP Baptist Health Lexington Lexington, Kentucky 18

19 Newest Oncology Agents PD-1s Clinical Information and Patient Management David Kwasny, Pharm.D, BCOP Onco360 Oncology Pharmacy Specialty Pharmacy and the Oncology Patient Oncologist Family Nurse / Navigator Pathologist Patient Specialty Pharmacy Social Worker Payers Surgeon 19

20 Value Added at Every Encounter Pre-Treatment Benefit and PA assistance Establish communication with patient and prescriber SPOC, dedicated nursing line, 24h availability, etc. Clinical review of orders Dose, frequency, duration, Appropriateness? Provide information / help establish expectations During Treatment Ensure medication available when needed Assist in proper administration Provide instruction for compounding, filtration, monitoring, etc. Be proactive irae Timeline 4 Weeks: Rash/Mucosal Irritation 8 12 Weeks: Hepatotoxicity 6 Weeks: Diarrhea/Colitis Late Onset: Endocrinopathies Ocular toxicity Renal toxicity Pulmonary toxicity 20

21 Intervention Provide conduit for prompt identification of moderate or severe iraes Prompt initiation of immunosuppression leads to favorable outcomes Withhold treatment Initiate corticosteroids Do not resume until toxicity returns to grade 1 or less Infliximab Frequent communication between patient and ALL members of the clinical team is crucial. What s Next? Remain optimistic, yet realistic Not yet ready for prime time in all disease states Nivolumab Pembrolizumab MPDL3280A (Roche) MEDI4736 (AstraZeneca/Lilly) BMS NSCLC NSCLC NSCLC NSCLC NSCLC RCC (+ ipilimumab) Breast cancer Bladder cancer Head & Neck Melanoma GBM Head & Neck cancer RCC RCC RCC Gastric Cancer Bladder cancer Melanoma 21

22 Thank You! Questions? Thank You! To receive CE credit Return to the CE activity page, click the Post-Test/Evaluation link and sign in to the CE Center Complete the Post-Test and Evaluation A score of > 70% is required to receive credit Your credit will be processed and uploaded to CPE Monitor Click Here To return to CE activity page 22