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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

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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

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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.



• 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



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



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



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.



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



• 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



• 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



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



• 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



• 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



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


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



• 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



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



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



• 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



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.



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)



• 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



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



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


Grad

e of To

xicity

4 6 8 10 12 14 delayed

Single Agent anti‐PD‐1



• 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



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.



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



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



• 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


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