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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.

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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

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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

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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 (NSCLC) (squamous)

50

NSCLC (adenocarcinoma) 45

Colon cancer 45

Melanoma 40

Renal cell carcinoma 20

Keir Annu Rev Immunol (2008) Thompson PNAS (2004)

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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®)

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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)

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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/m2 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)

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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)

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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/m2 every 3 weeks • Carboplatin AUC 6 + paclitaxel 175 mg/m2 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)

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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)

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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: 1st line in combination with ipilimumab for 4

doses every 3 weeks, then monotherapy every 2 weeks

– Off-label use: 1st 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)

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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®)

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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)

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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)

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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)

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Pembrolizumab Adverse Effects

• Common:– Pruritus– Rash– Constipation– Nausea/Vomiting– Diarrhea– Muscle aches– Cough– Fatigue

• Severe:– Anemia– Pneumonitis– Infusion reaction– Hepatitis– Renal dysfunction– Erythroderma

31Merck. Keytruda package insert (2015)

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)

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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

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References

• Brahmer J, Reckamp K, Baas P, et al. N Engl J Med. 2015;373:123-135.• Garon E, Rizvi N, Hui R, et al. N Engl J Med. 2015;372:2018-2028.• Guha M. The Pharmaceutical Journal. 2014.• Keir ME, Butte MJ, Freeman GJ, et al. Annu Rev Immunol. 2008;26:677-704.• Larkin J, Chiarion-Sileni V, Gonzalez R, et al. N Engl J Med. 2015;373:23-43.• 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):257-265.• Robert C, Schachter J, Long G, et al. N Engl J Med. 2015;371:2521-2532.• 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):17174-

17179.• Wolchock, et al. Clinical Cancer Research. 2009;15:7412-7420.

Newest Oncology Agents: PD‐1 Inhibitor Clinical Information

Megan Brafford, Pharm.D., BCOP

Baptist Health Lexington

Lexington, Kentucky

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Newest Oncology Agents PD-1s Clinical Information and Patient Management

David Kwasny, Pharm.D, BCOP

Onco360® Oncology Pharmacy

Specialty Pharmacy and the Oncology Patient

Patient

Oncologist

Nurse / Navigator

Specialty Pharmacy

Payers

Surgeon

Social Worker

Pathologist

Family

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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

6 Weeks:

• Diarrhea/Colitis

8‐12 Weeks:

• Hepatotoxicity

Late Onset:

• Endocrinopathies

• Ocular toxicity

• Renal toxicity

• Pulmonary toxicity

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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‐936559

NSCLC NSCLC NSCLC NSCLC NSCLC

RCC (+ ipilimumab) Breast cancer Bladder cancer Head & Neck Melanoma

GBM Head & Neck cancer RCC RCC

RCC Melanoma

Gastric Cancer

Bladder cancer

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Thank You!

Questions?

Thank You!

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