Updates in Immunotherapy Focus on Checkpoint Inhibitors in Oncology Christopher Campen PharmD BCOP Greenville Health System – Cancer Institute Clinical Pharmacist October 27,2016

Disclosures Advisory board for Taiho Oncology and Eisai

Objectives 1. Discuss the mechanisms and indications of immunotherapy agents. 2. Define the principles of immunotherapy toxicities and assess general management strategies for the pharmacist. 3. Describe future ongoing high-interest areas in immunotherapy treatment. 4. Discuss limitations in future use of immunotherapy agents including cost of therapy.

The Immune System and Cancer Immune system design Cancer evades immune destruction “hide” or prevent T-cell invasion Downregulates expression of surface antigens Overexpression of surface proteins designed to induce immune deactivation Changes in microenvironment around tumor Immunotherapy: using the immune system to treat cancer. http://www.cancer.gov/research/areas/treatment/immunotherapy-using-immune-system#1. Accessed 10/4/2016.

Innate vs. Adaptive Immunity Nonspecific defense mechanism First line of defense Fast WBC’s, neutrophils Adaptive Antigen-specific immune response Memory Slower B and T cells Surveillance and cancer Both innate and adaptive response involved Goals of immunotherapy

T-Cells Mellman I, et al. Nature. 2011;480:480-489.

History of Immunotherapy 1997: First mAb for cancer approved, rituximab 2011: CTLA-4 inhibitor approved for melanoma 1976: BCG vaccine for bladder cancer 2008: First cancer vaccine approved for RCC 1796: First use of immunotherapy, Jenner smallpox vaccine 1992: IL-2 approved for RCC 1863: Connection between immunotherapy and cancer recognized 2014-2015: PD-1 inhibitors approved for melanoma, squamous NSCLC 1985: Interferon approved 2010: Sipuleucel-T approved for prostate cancer 2016: PD-1 inhibitor approved for cHL PD-L1 inhibitor approved for UC Elert E. Calling Cells to Arms. Nature. 2013;504:S2-S3.

Patient Case RJ is a 58 year old male with newly diagnosed metastatic melanoma BRAF mutation negative Patient performance status good Provider recommending treatment Ipilimumab + nivolumab

Immunotherapy Modalities Checkpoint Inhibitors Immune Cell-based tx Therapeutic Antibodies Treatments Immune Modulators Vaccine Therapies

Checkpoint Pathway Target checkpoints in immune pathway Release “brakes” in immune pathway Target T cells Approved checkpoint inhibitors Cytotoxic T-Lymphocyte-associated antigen 4 (CTLA-4) Programmed Cell Death-1 (PD-1) Programmed Cell Death-1 receptor ligand (PD-L1)

Mechanisms TCR = T-Cell Receptor MHC = Major Histocompatibility Complex Dizon DS. Clinical cancer advances 2016: annual report on progress against cancer from the American Society of Clinical Oncology. 2016:1-25. .

FDA Approved Agents (PD-1/PD-L1 Inhibitors) Nivolumab Hodgkin Lymphoma Melanoma Non Small Cell Lung Cancer Renal Cell Carcinoma Pembrolizumab Non Small Cell Lung cancer Head/Neck Cancer Atezolizumab Urothelial Carcinoma

FDA Approved Agents (CTLA-4 Inhibitor) Ipilimumab Melanoma Adjuvant and metastatic

Checkpoint Inhibitors Ipilimumab Cytotoxic T Lymphocyte-Associated Antigen (CTLA-4) Ipilimumab 3 mg/kg Q3weeks x 4 doses Metastatic melanoma - Improvement in median OS 10.1 months vs. 6.4 months with gp100. Long-term survival improvements in ~25% of patients Immune toxicities – Black box warnings/REMS Led to FDA approval of first checkpoint inhibitor in 2011 Hodi FS, et al. N Engl J Med. 2010;363:711-723.

Melanoma – PD-1 blockade Ipilimumab Refractory Versus Chemotherapy ~2-fold improvement in 6-month PFS First-Line Versus Ipilimumab Nearly 2-fold improvement in 6-month PFS A/E profile Ribas A et al. Lancet Oncol 2015;908-18. Robert C et al. N Engl J Med 2015;2521-32.

Progression-Free Survival Ribas A et al. Lancet Oncol 2015;908-18.

Ipilimumab/Nivolumab Ipilimumab x 4 doses + nivolumab maintenance vs. nivolumab vs. ipilimumab – Metastatic Melanoma Phase III, ~315 patients each arm Best Overall Response Nivolumab (%) Nivo + Ipi (%) Ipilimumab (%) CR 8.9 11.5 2.2 PR 34.8 46.2 16.8 SD 10.8 13.1 21.9 PD 37.7 22.6 48.9 Larkin J, et al. N Engl J Med. 2015;371:23-34.

Progression-free Survival Larkin J, et al. N Engl J Med. 2015;371:23-34.

Combination Blockade Putting results into perspective for melanoma PFS 6 years ago versus now Significant toxicities Future directions to maintain/improve responses + mitigating toxicities Clear choice for patients? Stratification?

Patient Case RJ is a 58 year old male with newly diagnosed metastatic melanoma BRAF mutation negative Patient performance status good Provider recommending treatment Ipilimumab + nivolumab Clinical checks for pharmacists?

Non-Small Cell Lung Cancer Pembrolizumab Metastatic NSCLC Refractory to platinum agent, PD-L1+ 2700 patients screened 1475 PD-L1 positive 633 > 50% 842 1-49% ~1000 patients assigned to treatment Pembrolizumab 2 mg/kg, pembrolizumab 10 mg/kg, Docetaxel Herbst R, et al. Lancet 2016;387:1540-50.

Pembrolizumab - NSCLC Overall Survival Analysis Adverse event analysis OS 10.4 months (pembro 2 mg/kg) vs. 8.5 months (docetaxel), HR 0.71 CI 0.58-0.88 Hazard Ratio Analysis by PD-L1 PD-L1 1-49: (0.6-0.96) PD-L1 50+: 0.53 (0.40-0.70) Adverse event analysis Herbst R, et al. Lancet 2016;387:1540-50.

Non-Small Cell Lung Cancer Nivolumab Metastatic NSCLC Refractory to platinum agent, did NOT have to be PD-L1+ Nivolumab vs. docetaxel Q3w Overall survival 12.2 months vs. 9.4 months respectively Progression-free survival 2.3 mo vs. 4.2 mo respectively Borghaei, et al. N Engl J Med 2015;373:1627-39.

Overall Survival Borghaei, et al. N Engl J Med 2015;373:1627-39.

Metastatic NSCLC – First-Line Treatment PD-L1 > 50% staining No mutations in EGFR/ALK Pembrolizumab vs. investigator choice platinum combination 1653 patients eval for PD-L1, 500 > 50% TPS PD-L1 305 patients randomized Median PFS 10.3 months vs. 6 months respectively OS at 6 months 80.2% vs. 72.4% Immune related adverse events ~30% of patients Not FDA approved yet for this indication Reck M, et al. N Engl J Med 2016;epub ahead of print October 9.

Progression-free Survival Reck M, et al. N Engl J Med 2016;epub ahead of print October 9.

Managing Toxicities Unique spectrum Not all immunotherapies are equal Combination immunotherapy increases toxicity Important to intervene early Don’t be afraid to stop immunotherapy

Toxicities Dermatitis (rash) Colitis Hepatitis Pneumonitis Endocrinopathies Hypothyroidism Hypophysitis

Monitoring Thyroid Function Tests Hepatic Function Tests Serum Creatinine Rash Diarrhea Changes in lung function (SOB)

PD-1/PD-L1 Inhibitors (Nivolumab for reference) Adverse Event Any Grade (%) Grade 3/4 (%) Dermatitis 25.9 0.6 Diarrhea 19.2 2.2 AST/ALT ↑ 3.8 1 Dyspnea 4.5 0.3 Hypothyroidism 8.6 Tx Discontinuation 7.7 Larkin J, et al. N Engl J Med. 2015;371:23-34.

Ipilimumab 3 mg/kg Adverse Event Any Grade (%) Grade 3/4 (%) Dermatitis 32.8 1.9 Diarrhea 33.1 6.1 AST/ALT ↑ ~4 ~1.5 Dyspnea 4.2 Hypothyroidism Tx Discontinuation 14.8 Larkin J, et al. N Engl J Med. 2015;371:23-34.

Ipilimumab 10 mg/kg Adverse Event Any Grade (%) Grade 3/4 (%) Dermatitis 38 1 Diarrhea 39 10 AST/ALT ↑ 16 5 Dyspnea NR Hypothyroidism 9 Hypophysitis 13 6 Tx Discontinuation 52 Eggermont A et al. Lancet Oncol 2015; 16: 522–30.

Nivolumab/Ipilimumab Adverse Event Any Grade (%) Grade 3/4 (%) Dermatitis 40.3 4.8 Diarrhea 44.1 9.3 AST/ALT ↑ ~17 ~8 Dyspnea 10.2 0.6 Hypothyroidism 15 0.3 Tx Discontinuation 36 Larkin J, et al. N Engl J Med. 2015;371:23-34.

Weber J et al. J Clin Oncol 2012:2691-97.

Managing Toxicities Based on severity of the toxicity General rules for management Moderate (grade 2), hold checkpoint inhibitor and resume when grade 1 or less. Severe/life threatening (grade 3/4) non-rash, discontinue treatment. High dose steroids. Use topical treatments/supportive care when indicated Postow MA. 2015 ASCO educational book

Steroids Steroids are vital in blunting the effects of immunotherapies Dosing 1-2 mg/kg/day prednisone Effective, fast Doses often cannot be titrated off quickly Opportunistic infections – Consider PJP prophylaxis in patients on steroids > 4 weeks at doses > prednisone 20 mg/day Postow MA. 2015 ASCO educational book

Patient Case RJ is a 58 year old male with metastatic melanoma Completed 3 cycles of treatment Ipilimumab + nivolumab Wife calls clinic, RJ experiencing 8-10 stools a day for the last 5 days Patient called after 2 days, told to take loperamide Nurse asks for guidance

Patient Case RJ is a 58 year old male with metastatic melanoma Patient now hypotensive in clinic Sent to hospital for management Stool tests negative, presumed to be colitis Treatment options?

Treating A/E’s Refractory to Steroids Continue supportive care Increase steroid dose Add infliximab 5 mg/kg every 2 weeks Postow MA. 2015 ASCO educational book

Key Points Most patients respond to steroids and removal of offending immunotherapy Do not delay Taper steroids SLOW Steroids do NOT blunt the effectiveness of checkpoint inhibitors Immune A/E’s do not appear to correlate with efficacy Stopping treatment is OK!!!

Limitations Not all studies have been successful Only a small percentage of certain tumors are infiltrated by effector T-cells 50% of melanomas 20-30% renal cell carcinoma 20% of non small cell lung cancer <20% colorectal tumors (mostly MSI high)

Limitations Negative studies Nivolumab first line treatment for NSCLC Phase III, 541 patients Nivolumab 3 mg/kg Q2weeks versus chemotherapy Excluded EGFR and ALK mutations PD-L1 expression 5% cutoff (423 patients) PFS 4.2 months nivolumab vs. 5.9 months chemo (p=0.25) OS 14.4 vs 13.2 months (p = NS) http://www.medscape.com/viewarticle/867169. Accessed 10-3-2016

Limitations Negative studies Combination chemotherapy +/- ipilimumab for first line treatment of SCLC Phase III, 1,132 patients Ipilimumab 10 mg/kg Q3weeks x 4 doses Median OS 11 months with combo chemo-immunotherapy vs. 10.9 months immunotherapy alone High rates of AE’s High rates of treatment discontinuation Reck M, et al. J Clin Oncol epub ahead of print July 25,2016.

Limitations Biomarkers No perfect biomarker Responses can occur in patients with no/low PD-L1 staining Responses enriched high PD-L1 staining Biomarkers to stratify treatment may go beyond just immunologic biomarkers Molecular, genomic

Immunoscore Method to define the level of immune cell infiltration into cancer cells Density measurement CD8+ and CD3+ T Cells center/periphery ASCO 2016 presentation ~2700 colon cancer patients, stage I-III Overall survival and time to recurrence improved in immunoscore high vs. low patients Immunotherapy study implications May eventually add on to the TNM classification – TNM-I Galon J, et al. ASCO 2016. Abstract 3500.

Limitations Cost PD-1/PD-L1 x 1 year (approved doses) – approx $150,000-$180,000 Ipilimumab 3 mg/kg x 4 doses – approx $160,000 Ipilimumab/nivolumab x 1 year – approx $300,000 Ipilimumab 10 mg/kg adjuvant treatment – ~125,000 PER DOSE or ~1.8 million for the entire 3 year course http://www.ascopost.com/issues/july-10-2015/cost-of-immunotherapy-projected-to-top-1-million-per-patient-per-year/. Accessed 9-25-2016

Cost Many studies now using PD-1/PD-L1 dosing beyond FDA approved dosing Studies mostly positive, but at what cost? Impact on society – 1.6 million cancer cases each year http://www.ascopost.com/issues/july-10-2015/cost-of-immunotherapy-projected-to-top-1-million-per-patient-per-year/. Accessed 9-25-2016

Future Research Biomarkers/Immune scoring PD-1/PD-L1 blockade studies in additional cancers Multiple myeloma, GI cancers, lymphoma, breast cancer When to stop treatment Traditionally at progression Combination checkpoint inhibition Targeting activating T-Cell receptors Induction of T-cell infiltration in low immunogenic tumor types Vaccine based therapies, stimulate, ie light the fire

T-Cells Mellman I, et al. Nature. 2011;480:480-489.

Conclusion Checkpoint inhibition is just the beginning Pharmacists play a key role in management of immunotherapy Work with staff for education and development of tools to assess immunotherapy A/E’s For severe immunotherapy a/e’s – Steroids It is not a race to stop steroids