Provided by ASHP Supported by independent educational grants from Bristol-Myers Squibb and Merck Ask the Experts: The Evolution of Immune Checkpoint Inhibitors to Treat Lung Cancer and Melanoma Presented as a Live Webinar Wednesday, March 25, 2020 1:00 – 2:00 p.m. On-demand Activity Recording of live webinar Available after May 13, 2020 ACCREDITATION The American Society of Health-System Pharmacists is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education. • ACPE #: 0204-0000-20-412-L01-P • 1.0 hr, application-based The American Society of Health System Pharmacists is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. The American Society of Health-System Pharmacists designates this live activity for a maximum of 1.0 AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity. CE Processing Participants will process CPE credit online at http://elearning.ashp.org/my-activities. CPE credit will be reported directly to CPE Monitor. Per ACPE, CPE credit must be claimed no later than 60 days from the date of the live activity or completion of a home-study activity. Faculty Christine M. Walko, Pharm.D., BCOP, FCCP, Activity Chair Associate Member, Department of Individualized Cancer Management Moffitt Cancer Center Tampa, Florida Shetal Patel, M.D., Ph.D. Assistant Professor of Medicine Division of Hematology/Oncology UNC School of Medicine Chapel Hill, North Carolina View faculty bios at www.ashpadvantage.com/immunotherapy WEBINAR INFORMATION Visit www.ashpadvantage.com/immunotherapy to find • Webinar registration link • Group viewing information and technical requirements
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Provided by ASHP Supported by independent educational grants from Bristol-Myers Squibb and Merck
Ask the Experts: The Evolution of Immune Checkpoint Inhibitors to Treat Lung Cancer and Melanoma
Presented as a Live Webinar Wednesday, March 25, 2020 1:00 – 2:00 p.m.
On-demand Activity Recording of live webinar Available after May 13, 2020
ACCREDITATION The American Society of Health-System Pharmacists is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education.
The American Society of Health System Pharmacists is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.
The American Society of Health-System Pharmacists designates this live activity for a maximum of 1.0 AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.
CE Processing Participants will process CPE credit online at http://elearning.ashp.org/my-activities. CPE credit will be reported directly to CPE Monitor. Per ACPE, CPE credit must be claimed no later than 60 days from the date of the live activity or completion of a home-study activity.
Faculty Christine M. Walko, Pharm.D., BCOP, FCCP, Activity Chair Associate Member, Department of Individualized Cancer Management Moffitt Cancer Center Tampa, Florida
Shetal Patel, M.D., Ph.D. Assistant Professor of Medicine Division of Hematology/Oncology UNC School of Medicine Chapel Hill, North Carolina
View faculty bios at www.ashpadvantage.com/immunotherapy
WEBINAR INFORMATION Visit www.ashpadvantage.com/immunotherapy to find
• Webinar registration link• Group viewing information and technical
Planners, presenters, reviewers, ASHP staff, and others with an opportunity to control CE content are required to disclose relevant financial relationships with ACCME-defined commercial interests. All actual conflicts of interest have been resolved prior to the continuing education activity taking place. ASHP will disclose financial relationship information prior to the beginning of the activity.
A relevant financial relationship is a defined as a financial relationship between an individual (or spouse/partner) in control of content and a commercial interest, in any amount, in the past 12 months, and products and/or services of the commercial interest (with which they have the financial relationship) are related to the continuing education activity.
An ACCME-defined commercial interest is any entity producing, marketing re-selling, or distributing healthcare goods or services consumed by, or used on, patients. The ACCME does not consider providers of clinical serve directly to patients to be commercial interests—unless the provider of clinical service is owned, or controlled by, an ACCME-defined commercial interest.
Ask the Experts: The Evolution of Immune Checkpoint Inhibitors to Treat Lung Cancer and Melanoma
Ask the Experts: The Evolution of Immune Checkpoint
Inhibitors to Treat Lung Cancer and Melanoma
Provided by ASHP Supported by independent educational grants from Bristol‐Myers Squibb and Merck
Christine M. Walko, Pharm.D., BCOP, FCCP, Activity ChairAssociate Member, Individualized Cancer Management
H. Lee Moffitt Cancer CenterTampa, Florida
Shetal A. Patel, M.D., Ph.D.Assistant Professor of Medicine: Thoracic and Head/Neck Oncology
UNC Lineberger Comprehensive Cancer CenterUniversity of North Carolina Hospitals
Chapel Hill, North Carolina
Disclosure of Relevant Financial Relationships
Christine M. Walko: Consultant for Jackson Genetic LaboratoriesShetal A. Patel: AstraZeneca, Principle Investigator
All other planners, presenters, reviewers, ASHP staff, and others with an opportunity to control content report no financial relationships relevant to this activity.
Ask the Experts: The Evolution of Immune Checkpoint Inhibitors to Treat Lung Cancer and Melanoma
If you participated in our previous immune checkpoint inhibitor activity, what changes have you made in your practice since then? (Select all that apply)
a. Discuss with patients the place in therapy of immune checkpoint inhibitors to treat melanoma and lung cancer.
b. Discuss with other practitioners the place in therapy and mechanism of action of immune checkpoint inhibitors.
c. Collaborate with clinicians in my practice to select companion diagnostic tests and review patient characteristics when selecting immune checkpoint inhibitors to treat patients.
d. Develop a plan to recognize and manage immune related adverse events associated with immune checkpoint inhibitor use.
e. Educate patients and/or their caregivers on the potential adverse effects of immune checkpoint inhibitor use.
Evolution of Immunotherapy:Transforming Cancer Therapy
Christine M. Walko, Pharm.D., BCOP, FCCPAssociate Member, Individualized Cancer Management
Ask the Experts: The Evolution of Immune Checkpoint Inhibitors to Treat Lung Cancer and Melanoma
• RR is a 54‐year‐old male who had a localized melanoma lesion removed from his upper back 15 years ago. He did not receive any adjuvant therapy at the time
• Recently, he presented with shortness of breath and was found on CT to have numerous bilateral lung lesions.– Biopsy confirmed metastatic melanoma, BRAF V600 negative by
next generation sequencing• He is otherwise healthy and runs around 5 miles several times
per week• He is started on therapy with nivolumab and ipilimumab.
Patient Case #1
Which of the following toxicities is RR most likely to experience first?
a. Gastrointestinal toxicityb. Endocrine toxicity c. Pulmonary toxicityd. Hepatic toxicity
• Estimated 24‐month progression free survival (PFS):– In patients with a complete response: 85.4%– In patients with a partial response: 82.3%
• Pembrolizumab was dosed at 0.005 to 10 mg/kg in clinical trials with no MTD determined– 2 mg/kg every 3 weeks chosen for KEYNOTE‐001 registration trial– Similar exposure was seen for this dose and 200 mg flat dosing every 3 weeks
Robert C et al. Lancet Oncol. 2019; 20:1239‐51.Sheng J et al. J Clin Pharmacol. 2017; 57(Suppl 10):S26‐S42.
Pembrolizumab Updates
HR = 0.73, p=0.00049
Responses are durable!
Larkin J et al. N Engl J Med. 2015; 373:23‐34.
Phase III Nivolumab +/‐ Ipilimumab
N = 945Previously untreated
patients with unresectable stage III
or IV melanoma
R A N D OMIZ A TIO N
Nivolumab 1 mg/kg plus ipilimumab 3 mg/kg every 3 weeks x 4 followed by nivolumab 3 mg/kg every 2 weeks (cycle 3 and beyond)
Nivolumab 3 mg/kg every 2 weeks with placebo
Ipilimumab 3 mg/kg every 3 weeks x 4 doses with placebo
1:1:1
• Median OS:– Nivolumab alone: 37.6 months– Ipilimumab alone: 19.9 months– Nivolumab and Ipilimumab: Not yet reached
Ask the Experts: The Evolution of Immune Checkpoint Inhibitors to Treat Lung Cancer and Melanoma
• 5‐year follow‐up median OS:– Nivolumab alone: 36.9 months– Ipilimumab alone: 19.9 months– Nivolumab and Ipilimumab: Still not reached! (> 60 months)
• OS and PFS in patients who discontinued ipilimumab and nivolumab due to treatment‐related toxicity were similar to patients who did not discontinue therapy
• Flat dosing approvals
Larkin J et al. N Engl J Med. 2019; 381:1535‐46, Sheng J et al. J Clin Pharmacol. 2017; 57(Suppl 10):S26‐S42.Waterhouse D et al. Cancer Chemother Pharmacol. 2018; 81:679‐86.
Nivolumab Updates
3 mg/kg over 60 min every 2 weeks
240 mg flat dose over 60 min every 2 weeks
480 mg flat dose over 30 min every 4 weeks
3/6/2018: supplemental Biologics License Application (sBLA) approved by FDA for flat dose over 30 minutes every 4 weeks based on analysis using model‐based
exposure‐response
Larkin J et al. N Engl J Med. 2015; 373:23‐34.
Phase III Nivolumab +/‐ Ipilimumab Toxicity
Toxicity (%) Nivolumab IpilimumabNivolumab and Ipilimumab
All grade Grade 3 and 4 All grade Grade 3 and 4 All grade Grade 3 and
Ask the Experts: The Evolution of Immune Checkpoint Inhibitors to Treat Lung Cancer and Melanoma
• Since immune checkpoint inhibitors were first approved in melanoma, data in melanoma provide the longest follow‐up beyond 5 years at this time– Ongoing prospective trials are aimed at answering this question– Current recommendations are based on expert opinions and interpreted based on the long‐term
data from the original anti‐PD‐1 trials in advanced melanoma
• For patients with advanced melanoma who achieve a CR, discontinuation of anti‐PD‐1 therapy may be considered:– After 6‐12 months of treatment – Confirmed complete response– Ongoing re‐staging every 3‐4 months– Re‐treatment can be considered for relapse
• Ongoing trials to determine optimal management of patients with partial response or stable disease (NCT02743819)
Khushalani NI. J Clin Oncol. 2018; 36(17):1649‐53.
How long to treat patients?
• RR is a 54‐year‐old male who had a localized melanoma lesion removed from his upper back 15 years ago. He did not receive any adjuvant therapy at the time
• Recently, he presented with shortness of breath and was found on CT scanning to have numerous bilateral lung lesions– Biopsy confirmed metastatic melanoma, BRAF V600 negative by
next generation sequencing• He is otherwise healthy and runs around 5 miles several times
per week• He is started on therapy with nivolumab and ipilimumab
Ask the Experts: The Evolution of Immune Checkpoint Inhibitors to Treat Lung Cancer and Melanoma
• JA is a 63‐year‐old male, former 50 pack‐year smoker who is diagnosed with stage IV lung cancer after presenting with back and hip pain
• A staging PET scan demonstrates a right lung mass with lymph node and bone metastases
• Biopsy of the primary tumor reveals a poorly differentiated squamous non‐small cell lung cancer (NSCLC)
• A brain MRI is negative• His PD‐L1 tumor proportion score (TPS) is 60% and tumor mutation
burden (TMB) is 20 Muts/Mb• He presents to medical oncology for initial treatment discussion
Patient Case #2
Ribas A. N Engl J Med. 2012; 366:2517‐9.
PD‐1/PD‐L1 Blockade
• Pembrolizumab, nivolumab and cemiplimab‐rwlc: block interaction of PD‐1 with ligands• Atezolizumab, durvalumab, avelumab: block PD‐L1 interaction with PD‐1 on T cells• Mechanism guides biomarker selection• PD‐1/PD‐L1 blockade reinvigorates T‐cell function
TCR = T cell receptor GrzB = granzyme BMHC = major histocompatibility complex
Ask the Experts: The Evolution of Immune Checkpoint Inhibitors to Treat Lung Cancer and Melanoma
Potential Biomarkers for Response to Immune Checkpoint Inhibitors
• PD‐L1 expression by immunohistochemistry• Microsatellite instability• Numerous investigational factors being tested in trials:
– Tumor mutational burden (TMB) – blood and tissue– T‐cell‐inflamed gene expression profile– HLA genotype and class I diversity– Gut microbiome– Mutations in JAK2, 2‐microglobulin, STK11/KEAP1, and the ‐catenin pathway
Havel JJ et al. Nat Rev Clin Oncol. 2019; 19(3):133‐50.
PD‐L1 ExpressionBenefits
• Immunohistochemistry (IHC) is readily available, can be performed quickly, and correlates with response to PD‐1/PD‐L1 inhibitors in multiple tumor types
• Response rates vary by tumor type• PD‐L1 expression can be used to
prioritize treatment options
Challenges
• PD‐L1 expression can vary over time and between tumor sites in a given patient
• Different tests may produce different results because antibodies have different affinities and specificities
• Specimen processing techniques may decrease sensitivity
• Unclear threshold values across tests, malignancies, and PD‐1/PD‐L1 agents
Topalian SL et al. Nat Rev Cancer. 2016; 16:275‐87.
Ask the Experts: The Evolution of Immune Checkpoint Inhibitors to Treat Lung Cancer and Melanoma
• Adding immune checkpoint blockade to anti‐VEGF therapy• IMpower 150 study of patients with nonsquamous NSCLC• Preliminary activity in patients with EGFR mutations, liver metastases
Chemotherapy and Immunotherapy Combinations (continued)
Socinski M et al. N Engl J Med. 2018; 378:2288‐301.Reck M et al. Lancet Respir Med. 2019; 7(5):387‐401.
Ask the Experts: The Evolution of Immune Checkpoint Inhibitors to Treat Lung Cancer and Melanoma
Practice changes to consider:
• Discuss with patients the place in therapy of immune checkpoint inhibitors to treat melanoma and lung cancer.
• Discuss with other practitioners the place in therapy and mechanism of action of immune checkpoint inhibitors.
• Collaborate with clinicians in my practice to select companion diagnostic tests
• Consider patient characteristics when selecting immune checkpoint inhibitors to treat patients.
• Develop a plan to recognize and manage immune related adverse events associated with immune checkpoint inhibitor use.
• Educate patients and/or their caregivers on the potential adverse effects of immune checkpoint inhibitor use.
Key Takeaways• Key Takeaway #1
– Improved understanding of how the immune system can be used for cancer therapy has greatly shifted the risk:benefit ratio in a favorable direction for management of numerous types of cancer, including melanoma and lung cancer
• Key Takeaway #2– Long‐term safety and efficacy data for immune checkpoint inhibitor use in
melanoma and lung cancer supports sustained clinical benefits, especially in patients with a complete response
• Key Takeaway #3– Although some biomarkers, such as PD‐L1 expression and MSI, are closely
associated with response to immune checkpoint inhibitors in selected solid tumors, better predictors of response are needed and probably will reflect various cancer‐and drug‐specific factors
Ask the Experts: The Evolution of Immune Checkpoint Inhibitors to Treat Lung Cancer and Melanoma
• Martins F, Sofiya L, Sykiotis GP et al. Adverse effects of immune‐checkpoint inhibitors: epidemiology, management and surveillance. Nat Rev Clin Oncol. 2019; 16(9):563‐80.
• Khushalani NI. Duration of anti‐programmed death‐1 therapy in advanced melanoma: how much of a good thing is enough? J Clin Oncol. 2018; 36(17):1649‐53.
• Havel JJ, Chowell D, Chan TA. The evolving landscape of biomarkers for checkpoint inhibitor immunotherapy. Nat Rev Cancer. 2019; 19(3):133‐50.