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
ASHP Financial Relationship Disclosure Statement
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.
Copyright © 2020 American Society of Health-System Pharmacists, Inc. All rights reserved. 2
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.
Copyright © 2020 American Society of Health-System Pharmacists, Inc. All rights reserved. 3
Ask the Experts: The Evolution of Immune Checkpoint Inhibitors to Treat Lung Cancer and Melanoma
• Define the pathophysiology of immunotherapy and the evolution of immune checkpoint inhibition.
• Analyze recent immune checkpoint inhibitor survival and toxicity data and apply to the therapy management of patients with melanoma and lung cancer.
• Identify established and emerging biomarkers to optimize selection of immune checkpoint regimens for patients with melanoma and lung cancer.
• Describe interprofessional education strategies for patients and caregivers on the safety and monitoring of immune checkpoint inhibitors.
Learning Objectives
On average how many cancer patients being treated with immunotherapies for lung cancer or melanoma do you provide care to each month?
a. None‐I am not directly involved in patient care
b. 1‐10 patients/monthc. 11‐30 patients/monthd. 31‐50 patients/monthe. More than 50 patients/month
Copyright © 2020 American Society of Health-System Pharmacists, Inc. All rights reserved. 4
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
H. Lee Moffitt Cancer Center
Tampa, Florida
Copyright © 2020 American Society of Health-System Pharmacists, Inc. All rights reserved. 5
Ask the Experts: The Evolution of Immune Checkpoint Inhibitors to Treat Lung Cancer and Melanoma
Progression of Immunotherapy
1970s 1980s 1990s 2000s 2010s
1976Spontaneous regressions in melanoma believed to be secondary to immune component
1986Interferon‐approved for cancer immunotherapy
1992Interleukin‐2 approved for cancer immunotherapy
2011Ipilimumab approved for advanced melanoma
2014Pembrolizumab and nivolumab both approved for advanced melanoma
2015Nivolumab approved for second line advanced NSCLC
2017Nivolumab approved as adjuvant therapy for melanoma
Non‐small cell lung cancer (NSCLC)https://www.fda.gov/drugs
1891: Coley ToxinsWilliam B. Coley injects streptococcus into a patient with incurable cancer
Ann Surg. 1891;14(3):199‐220
2015Nivolumab/Ipilimumab combination approved for advanced melanoma
High dose (HD) IL‐2 Therapy: Durable Responses
• HD IL‐2 produces durable responses in 6% to 10% of patients with advanced melanoma or renal cell carcinoma (RCC)
• Few relapses in patients responding for over 2.5 years (therefore, can be considered cured)• FDA approval in 1992 (RCC) and 1997 (melanoma)
Atkins MB et al. J Clin Oncol. 1999; 17:2105‐16. McDermott DF et al. Expert Opin Biol Ther. 2004; 4:455‐68.
Metastatic Melanoma (N = 270) Metastatic RCC (N = 255)
1.0
0.8
0.6
0.4
0.2
0.0
Probab
ility of Continuing Response
0 10 20 30 40 50 60 70 80 90 100 110 120 130Duration of Response (Months)
CR (n = 17)PR (n = 26)CR + PR (n = 43)
1.0
0.8
0.6
0.4
0.2
0.0
Probab
ility of Continuing Response
0 10 20 30 40 50 60 70 80 90 100 110 120 130
Duration of Response (Months)
CRPR All
140 150 160 170 180
CR=complete response; PR=partial response
Copyright © 2020 American Society of Health-System Pharmacists, Inc. All rights reserved. 6
Ask the Experts: The Evolution of Immune Checkpoint Inhibitors to Treat Lung Cancer and Melanoma
Nivolumab Phase I Trial Design
• Cohorts of 3‐6 patients enrolled in each cohort– 0.1, 0.3, 1.0, 3.0, and 10 mg/kg
• Expansion groups enrolled after no maximum tolerated dose (MTD) was found
Topalian S et al. N Engl J Med. 2012; 366:2443‐54.
N=296 patientsMelanoma (n = 104) Non‐small cell lung cancer (NSCLC)(n = 122)
Renal cell carcinoma (n = 34) Prostate cancer (n = 17) Colorectal cancer (n = 19)
All patients had an ECOG performance status of <2 and measurable disease
Phase 1 dose escalation of anti‐PD‐1 inhibitor
0.1 to 10 mg/kg IV every 2 weeks for up to 12 cycles or until disease progression or complete response where therapy could
continue
Tumor samples analyzed for PD‐L1 expression using immunohistochemistry (IHC)
BMS‐936558
ECOG=Eastern Cooperative Oncology Group
Summary of Results
• Antitumor activity was seen at all dose levels• Objective response rate (complete or partial)
– 28% in melanoma– 27% in renal cell carcinoma– 18% in NSCLC
• 65% of the responses were durable for 1 year or more in patients with >1 year follow up
• IHC staining for PD‐1L predicted response rate– 0 of 17 responses in PD‐1L negative tumors– 9 of 25 responses in PD‐1L positive tumors
Topalian S et al. N Engl J Med. 2012; 366:2443‐54.
Copyright © 2020 American Society of Health-System Pharmacists, Inc. All rights reserved. 7
Ask the Experts: The Evolution of Immune Checkpoint Inhibitors to Treat Lung Cancer and Melanoma
Currently Approved Immune Checkpoint Inhibitors
Drug Target Initial Approval DateNumber of Approvals for
Different Cancers
Ipilimumab CTLA‐4 3/2011 4
Nivolumab PD‐1 12/2014 9
Pembrolizumab PD‐1 9/2014 15
Cemiplimab‐rwlc PD‐1 9/2018 1
Atezolizumab PD‐L1 5/2016 4
Avelumab PD‐L1 3/2017 3
Durvalumab PD‐L1 5/2017 2
www.fda.gov accessed 03/2020
Metastatic Melanoma:Lessons learned and future questions
Christine M. Walko, Pharm.D., BCOP, FCCPAssociate Member, Individualized Cancer Management
H. Lee Moffitt Cancer Center
Tampa, Florida
Copyright © 2020 American Society of Health-System Pharmacists, Inc. All rights reserved. 8
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
Copyright © 2020 American Society of Health-System Pharmacists, Inc. All rights reserved. 9
Ask the Experts: The Evolution of Immune Checkpoint Inhibitors to Treat Lung Cancer and Melanoma
• RR is a 54‐year‐old male with relapsed, metastatic melanoma who was treated with ipilimumab and nivolumab followed by nivolumab x 2 years
• He achieved a complete response and has been without evidence of disease for the past 18 months
Patient Case #1
How long should RR continue to receive nivolumab since he has achieved a complete response?
a. He should continue therapy until he develops toxicity or relapse
b. He can consider discontinuing therapy with close monitoringc. He should only discontinue therapy if he developed early
grade 3 toxicityd. He should continue therapy for the standard duration of 5
years followed by close monitoring
Copyright © 2020 American Society of Health-System Pharmacists, Inc. All rights reserved. 10
Ask the Experts: The Evolution of Immune Checkpoint Inhibitors to Treat Lung Cancer and Melanoma
FDA Approvals for Melanoma
• Adjuvant Therapy (after complete resection)– Nivolumab– Pembrolizumab
• Metastatic Therapy
– Nivolumab– Nivolumab + ipilimumab– Pembrolizumab
Keeping our eye on: MASTERKEY trial comparing
pembrolizumab with or without talimogene laherparepvec (TVEC)
Robert C et al. N Engl J Med. 2015; 372:2521‐32.
Phase III Pembrolizumab vs. Ipilimumab1:1:1
N = 834Unresectable stage III or IV melanoma with no more than 1 prior
treatment
R A N D OMIZ A TIO N
Pembrolizumab 10 mg/kg every 2 weeks over 30 min
Ipilimumab 3 mg/kg every 3 weeks over 90 min x 4 doses
Pembrolizumab 10 mg/kg every 3 weeks over 30 min
• Estimated 12‐month overall survival (OS):– Pembrolizumab every 2 weeks: 74.1%– Pembrolizumab every 3 weeks: 68.4%– Ipilimumab x 4 doses: 58.2% HR = 0.69, p=0.0036
HR = 0.63, p=0.0005
Copyright © 2020 American Society of Health-System Pharmacists, Inc. All rights reserved. 11
Ask the Experts: The Evolution of Immune Checkpoint Inhibitors to Treat Lung Cancer and Melanoma
• 5‐year follow‐up median OS:– Pembrolizumab: 32.7 months– Ipilimumab 15.9 months
• 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
p<0.001
p<0.001
Copyright © 2020 American Society of Health-System Pharmacists, Inc. All rights reserved. 12
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
4
Diarrhea 19.2 2.2 33.1 6.1 44.1 9.3
Fatigue 34.2 1.3 28 1 35 4.2
Rash 25.9 0.6 32.8 1.9 40.3 4.8
Increased ALT 3.8 1.3 3.9 1.6 17.6 8.3
Increased AST 3.8 1.0 3.5 0.6 15.3 6.1
Hypothyroidism 8.6 0 4.2 0 15 0.3
Colitis 1.3 0.6 11.6 8.7 11.8 7.7
Arthralgia 7.7 0 6.1 0 10.5 0.3
Dyspnea 4.5 0.3 4.2 0 10.2 0.6
Copyright © 2020 American Society of Health-System Pharmacists, Inc. All rights reserved. 13
Ask the Experts: The Evolution of Immune Checkpoint Inhibitors to Treat Lung Cancer and Melanoma
PD‐1 and PD‐L1 Toxicities
Adapted from Martins F et al. Nat Rev Clin Oncol. 2019; 16:567.
Duration of treatment (weeks)
Grad
e of To
xicity
Duration of treatment (weeks)
Grad
e of To
xicity
4 6 8 10 12 14 delayed 4 6 8 10 12 14 delayed
Skin Toxicity PneumonitisDiarrhea/Colitis
Liver Toxicity Endocrine Toxicity
Single Agent anti‐PD‐1 Anti‐PD‐1 + ipilimumab
• RR is a 54‐year‐old male with relapsed, metastatic melanoma who was treated with ipilimumab and nivolumab followed by nivolumab x 2 years.
• He achieved a complete response and has been without evidence of disease for the past 18 months.
• How long should he be treated with nivolumab?
Patient Case #1
Copyright © 2020 American Society of Health-System Pharmacists, Inc. All rights reserved. 14
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
Patient Case #1
Copyright © 2020 American Society of Health-System Pharmacists, Inc. All rights reserved. 15
Ask the Experts: The Evolution of Immune Checkpoint Inhibitors to Treat Lung Cancer and Melanoma
Which of the following toxicities is RR most likely to experience first?
a. Gastrointestinal toxicityb. Endocrine toxicity c. Pulmonary toxicityd. Hepatic toxicity
• RR is a 54‐year‐old male with relapsed, metastatic melanoma who was treated with ipilimumab and nivolumab followed by nivolumab x 2 years
• He achieved a complete response and has been without evidence of disease for the past 18 months
Patient Case #1
Copyright © 2020 American Society of Health-System Pharmacists, Inc. All rights reserved. 16
Ask the Experts: The Evolution of Immune Checkpoint Inhibitors to Treat Lung Cancer and Melanoma
How long should RR continue to receive nivolumab since he has achieved a complete response?
a. He should continue therapy until he develops toxicity or relapse
b. He can consider discontinuing therapy with close monitoring
c. He should only discontinue therapy if he developed early grade 3 toxicity
d. He should continue therapy for the standard duration of 5 years followed by close monitoring
Lung Cancer: Optimizing treatment decisions for each
individual patient
Shetal A. Patel, MD, PhDAssistant Professor of Medicine: Thoracic and Head/Neck Oncology
Copyright © 2020 American Society of Health-System Pharmacists, Inc. All rights reserved. 17
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
Copyright © 2020 American Society of Health-System Pharmacists, Inc. All rights reserved. 18
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.
Copyright © 2020 American Society of Health-System Pharmacists, Inc. All rights reserved. 19
Ask the Experts: The Evolution of Immune Checkpoint Inhibitors to Treat Lung Cancer and Melanoma
KEYNOTE‐024 TrialPembrolizumab vs. platinum doublet for first‐line NSCLC
• Squamous and non‐squamous NSCLC• PD‐L1 TPS ≥50% 22C3 assay• No sensitizing epidermal growth factor receptor (EGFR) or anaplastic lymphoma
kinase (ALK) mutations• Response rate (RR), progression‐free survival (PFS), and overall survival (OS)
improved with pembrolizumab
Reck M et al. N Engl J Med. 2016; 375(19):1823‐33.Reck M et al. J Clin Oncol. 2019; 37(7):537‐546.
Pembrolizumab Platinum doublet HR (95% CI)
RR (%) 45 28
median PFS 10.3 6.0 0.5(0.37‐0.68)
median OS 30 14.2 0.63(0.47‐0.86)
Chemotherapy and Immunotherapy Combinations
• KEYNOTE‐189 nonsquamous NSCLC• KEYNOTE‐407 squamous NSCLC• OS improved across TPS subsets for chemotherapy + pembrolizumab
Adapted from Gandhi L et al. N Engl J Med. 2018; 378:2078‐92.Gadgeel S et al. J Clin Oncol. 2020 [Epub ahead of print]
Paz‐Ares L et al. N Engl J Med. 2018; 379:2040‐51.OS = overall survivalChemotherapy = platinum doublet
StudyPembrolizumab+ chemotherapy
Placebo+ chemotherapy
HR (95% CI)
Nonsquamous(KN‐189) 22 10.7 0.56
(0.45‐0.7)
Squamous(KN‐407) 15.9 11.3 0.64
(0.49‐0.85)
Copyright © 2020 American Society of Health-System Pharmacists, Inc. All rights reserved. 20
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.
ABCP = atezolizumab + bevacizumab + carboplatin/paclitaxelBCP = bevacizumab + carboplatin/paclitaxelVEGF=Vascular endothelial growth factor
ABCP BCPHR
(95% CI)P value
Overall population 19.2 months 14.7 months 0.78
(0.64‐0.96) 0.02
Baseline Liver Metastases 13.3 months 9.4 months 0.52
(0.33‐0.82)
Sensitizing EGFRmutations NE 17.5 months 0.41
(0.23‐0.75)
• JA is a 63‐year‐old male, former 50 pack‐year smoker who is diagnosed with stage IV squamous lung cancer (bone metastases)
• Past medical history notable for mild hypertension, no history of autoimmune disorders
• He has severe pain in the back and hips, the sites of multiple bone metastases
Patient Case # 2 continued
Copyright © 2020 American Society of Health-System Pharmacists, Inc. All rights reserved. 21
Ask the Experts: The Evolution of Immune Checkpoint Inhibitors to Treat Lung Cancer and Melanoma
a) Pembrolizumab monotherapyb) Nivolumab + ipilimumabc) Pembrolizumab + chemotherapyd) Carboplatin/paclitaxel/bevacizumab + atezolizumabe) None of the above
Which of the following treatments is FDA approved for patients with a TMB > 10 muts/Mb
• Choosing a first‐line regimen:o PD‐L1 expression o Is patient symptomatic (chemotherapy + PD‐1/PD‐L1 have higher
response rates)o Contraindications to chemotherapy (e.g., neuropathy, renal
insufficiency)?o TMB ‐ unclear utility as a predictive biomarker
o Checkmate 227o KEYNOTE 189
Patient Case # 2
Copyright © 2020 American Society of Health-System Pharmacists, Inc. All rights reserved. 22
Ask the Experts: The Evolution of Immune Checkpoint Inhibitors to Treat Lung Cancer and Melanoma
o JA initiates treatment with carboplatin/paclitaxel + pembrolizumab based on KEYNOTE 407
o He develops diarrhea 1 week after the first cycle of treatment, with 3‐4 episodes per day
o No abdominal pain, hematochezia, fever, or chillso Infectious workup is negative and he is treated with
loperamide with improvement in symptoms
Patient Case # 2
o Given the timing, diarrhea was felt to be related to chemotherapy
o He is able to tolerate future cycles with 20% dose reduction for cytopenias
o Restaging scans after 2 cycles demonstrate a partial response, with improvement in pain and treatment is continued
o After 4 cycles he is continued on pembrolizumab monotherapy
Patient Case # 2
Skin ToxicityPneumonitisDiarrhea/Colitis
Liver ToxicityEndocrine Toxicity
Duration of treatment (weeks)
Grad
e of To
xicity
4 6 8 10 12 14 delayed
Single Agent anti‐PD‐1
Copyright © 2020 American Society of Health-System Pharmacists, Inc. All rights reserved. 23
Ask the Experts: The Evolution of Immune Checkpoint Inhibitors to Treat Lung Cancer and Melanoma
• Checkmate 003 (pretreated): 5‐year survival rate 15.6% • Checkmate 057/017: 4‐year survival rate 14%• KEYNOTE 001: 5‐year survival
– Untreated 23.2%– Pretreated 15.5%
Garon EB et al. J Clin Oncol. 2019; 37(28):2518‐27.Topalian SL et al. JAMA Oncol. 2019; 5(10):1411‐20.
Antonia SJ et al. Lancet Oncol. 2019; 20(10):1395‐408.
Long‐term survival
Challenges and Novel therapies
• Tumor microenvironment is complex
• Numerous positive/negative regulators, unique to each patient
• Novel treatments:– Oncolytic viruses– Immune checkpoint antibodies– Agonists– Chimeric antigen receptor (CAR)‐T cells– Tumor infiltrating lymphocyte (TIL)
therapy
Copyright © 2020 American Society of Health-System Pharmacists, Inc. All rights reserved. 24
Ask the Experts: The Evolution of Immune Checkpoint Inhibitors to Treat Lung Cancer and Melanoma
FDA‐Approved PD‐1 Antibody: Nivolumab
• Nivolumab– Melanoma (adjuvant and metastatic
settings)– Metastatic non‐small cell lung cancer
(NSCLC)– Metastatic small cell lung cancer– Advanced renal cell carcinoma (RCC)– Relapsed classical Hodgkin lymphoma– Metastatic squamous cell carcinoma of
the head and neck– Metastatic bladder cancer after platinum
therapy– MSI‐H/dMMR colorectal cancer– Advanced hepatocellular carcinoma (HCC)
• Nivolumab + ipilimumab – Melanoma (adjuvant and metastatic
settings)– Metastatic MSI‐H/dMMR colorectal
cancer (CRC)– Advanced renal cell carcinoma
(intermediate or poor risk)– Hepatocellular carcinoma (after prior
treatment with sorafenib)
MSI‐H: microsatellite instability highdMMR: deficient mismatch repair Opdivo (nivolumab) prescribing information, 2020
M
FDA‐Approved PD‐1 Antibody: Pembrolizumab
• Pembrolizumab– Melanoma (adjuvant and metastatic settings)– Metastatic NSCLC
• Also stage IIIB non‐resectable NSCLC– Metastatic small cell lung cancer (SCLC)– Metastatic squamous cell carcinoma of the head
and neck– Relapsed classical Hodgkin lymphoma– Primary mediastinal large B‐cell lymphoma– Metastatic bladder cancer after platinum therapy
or not eligible for platinum therapy– MSI‐H/dMMR solid tumors– Advanced hepatocellular carcinoma– Recurrent/metastatic gastric cancer– Recurrent/metastatic esophageal cancer– Recurrent/metastatic cervical cancer– Recurrent/locally advanced Merkel cell carcinoma
• Pembrolizumab + carboplatin + pemetrexed• Metastatic non‐squamous NSCLC
• Pembrolizumab + carboplatin + paclitaxel– Metastatic squamous NSCLC (can also use
paclitaxel protein‐bound particles [Abraxane])
• Pembrolizumab + axitinib• First‐line therapy for advanced renal cell
carcinoma
• Pembrolizumab + lenvatinib• Advanced endometrial cancer
Keytruda (pembrolizumab) prescribing information, 2020 Jan.
Copyright © 2020 American Society of Health-System Pharmacists, Inc. All rights reserved. 25
Ask the Experts: The Evolution of Immune Checkpoint Inhibitors to Treat Lung Cancer and Melanoma
FDA‐Approved PD‐L1 Antibody: Atezolizumab
• Atezolizumab– Locally advanced or metastatic bladder
cancer not eligible for platinum therapy or after progression on platinum therapy
– Metastatic NSCLC
• Atezolizumab + carboplatin + etoposide– First‐line extensive‐stage small cell lung
cancer
• Atezolizumab + carboplatin + paclitaxel + bevacizumab– First‐line metastatic non‐squamous
NSCLC, with no EGFR or ALK mutations
• Atezolizumab + paclitaxel protein‐bound particles (Abraxane)– Advanced/metastatic triple negative
breast cancer (TNBC)
Tecentriq (atezolizumab) prescribing information, 2019 Dec.
Other FDA‐Approved PD‐1 and PD‐L1 Antibodies
Prescribing information for Libtayo (cemiplimab‐rwlc), 2019 Mar; Bavencio (avelumab), 2019 May; and Imfinzi (durvalumab) 2019 Aug.
Checkpoint Inhibitor
Drug Target FDA‐Approved Indications
Cemiplimab‐rwlc PD‐1 • Metastatic cutaneous squamous cell carcinoma
Avelumab PD‐L1
• Metastatic Merkel cell carcinoma• Metastatic urothelial carcinoma after platinum‐
based therapy• In combination with axitinib for advanced RCC
Durvalumab PD‐L1
• Unresectable stage III NSCLC following platinum‐based therapy
• Metastatic urothelial carcinoma after platinum‐based therapy
Copyright © 2020 American Society of Health-System Pharmacists, Inc. All rights reserved. 26
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
Copyright © 2020 American Society of Health-System Pharmacists, Inc. All rights reserved. 27
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.
Selected Resources
Copyright © 2020 American Society of Health-System Pharmacists, Inc. All rights reserved. 28