(UPDATE) Pembrolizumab (Keytruda) in NSCLC

Until recently, pembrolizumab had been the only immune checkpoint inhibitor approved for the first-line treatment of patients with advanced non–small cell lung cancer (NSCLC) and levels of programmed cell death ligand 1 (PD-L1) expression 50% or greater in tumor cells.^1,2 [For a perspective on the evolution of pembrolizumab in the treatment of patients with advanced NSCLC, as well as commentary on its clinical use by Ramaswamy Govindan, MD (Washington University School of Medicine, St Louis) and Joanne Riemer, RN, BSN (Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Medicine, Baltimore), see Original Spotlight.]  In December 2018, the combination of atezolizumab plus chemotherapy and bevacizumab was also approved in the first line, irrespective of PD-L1 expression, for patients with nonsquamous metastatic NSCLC and no EGFR or ALK genomic tumor aberrations.^1,2

Moreover, the U.S. Food and Drug Administration (FDA) has now approved pembrolizumab in combination with chemotherapy (paclitaxel or nab-paclitaxel plus carboplatin) in the first-line treatment of patients with squamous cell carcinoma.^3,4 Additionally, pembrolizumab plus pemetrexed and platinum chemotherapy is also indicated in the first line for metastatic nonsquamous disease if no EGFR or ALK genomic tumor aberrations are present, and pembrolizumab plus paclitaxel (or nab-paclitaxel) is an off-label use listed in the NCCN Guidelines.⁵ [Editor’s Note: At the end of this update, see Commentary by David S. Ettinger, MD, JNCCN 360 Site Editor, about the use of pembrolizumab in 2019.] In addition to indications for treatment in NSCLC, melanoma, head and neck squamous cell carcinoma, classical Hodgkin lymphoma, urothelial carcinoma, and microsatellite instability–high cancer, pembrolizumab is now also indicated in the treatment of primary mediastinal large B-cell lymphoma, gastric carcinoma, cervical cancer, hepatocellular carcinoma, small cell lung cancer, and Merkel cell carcinoma.⁶

Clinical Trial Updates

In October 2018, on the basis of results from KEYNOTE-407 (CinicalTrials.gov identifier NCT02775435), the FDA approved the use of pembrolizumab with carboplatin and either paclitaxel or nab-paclitaxel as first-line treatment of metastatic squamous NSCLC. The regimen improved overall survival, response rates, and duration of response compared with chemotherapy alone, irrespective of PD-L1 status.^3,4

Pembrolizumab is recommended as first-line monotherapy for patients with a PD-L1 tumor proportion score (TPS) of ≥ 50% based on the KEYNOTE-024 trial (NCT02220894).⁷ Patients receiving pembrolizumab monotherapy showed an overall survival benefit with fewer adverse events when compared with chemotherapy. A recent updated analysis continues to show the benefit of first-line pembrolizumab monotherapy versus chemotherapy in patients with metastatic NSCLC and PD-L1 levels of ≥ 50%.⁸ Preliminary data from the KEYNOTE-042 trial suggest that even patients with lower PD-L1 expression, provided it is ≥ 1%, may benefit from first-line pembrolizumab compared with chemotherapy. ^9,10

Results from the KEYNOTE-189 trial (NCT02578680) led to the full FDA approval of pemetrexed plus platinum chemotherapy (eg, carboplatin) for the first-line treatment of patients with metastatic nonsquamous NSCLC and no EGFR or ALK genomic tumor aberrations.¹¹ Accelerated approval was initially granted on the basis of findings from KEYNOTE-021, Cohort G1 (NCT02039674).^12,13

Pembrolizumab monotherapy is recommended as a second-line therapy option in certain patients with metastatic NSCLC based on the KEYNOTE‑010 trial,¹⁴ which was discussed in the original Spotlight. However, second-line pembrolizumab monotherapy is not routinely recommended in patients who experience disease progression on first-line immune checkpoint inhibitors. PD-1/PD-L1 inhibitors are contraindicated in patients with active or previously documented autoimmune disease and/or those who are currently using immunosuppressive agents or those with an oncogene that would predict lack of benefit.

Focus on Managing Immune-Related Toxicities

Early in 2018, guidelines on managing immunotherapy-related toxicities were released by both NCCN¹⁵ and ASCO.¹⁶ The NCCN Guidelines have been updated.¹⁷ These guidelines are intended to “increase awareness, outline strategies, and offer guidance on the recommended management of immune-related adverse events in patients treated with immune checkpoint inhibitors.”¹⁶ In addition, the NCCN Clinical Practice Guidelines in Oncology: Management of Immunotherapy-Related Toxicities includes a section on Principles of Immunotherapy Rechallenge.¹⁷

Furthermore, oncologists and advanced practice providers have observed immune-related adverse events occurring long after discontinuation of immunotherapy. Thus, providers should continue to follow patients treated with immune checkpoint inhibitors for long-term symptoms. Recent data suggest that immune-related adverse events may be related to improved outcomes in patients receiving immune checkpoint inhibitors.¹⁸

In 2017, experts at Johns Hopkins developed a pilot program centered on the multidisciplinary care of patients treated with immune checkpoint inhibitors. They gathered a team of oncologists and multiple medical specialists, including pulmonologists, gastroenterologists, rheumatologists, endocrinologists, dermatologists, cardiologists, and others, to assist providers in the evaluation and treatment of patients who may have immune-related toxicities. This pilot program represents an ongoing network to improve communication, centralize discussions, and assist in obtaining timely consultations.  

References

1. U.S. Department of Health and Human Services. U.S. Food & Drug Administration. FDA approves atezolizumab with chemotherapy and bevacizumab for first-line treatment of metastatic non-squamous NSCLC. Available at https://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm627874.htm. Accessed March 14, 2019.
2. Socinski MA, Jotte RM, Cappuzzo F, et al. Atezolizumab for first-line treatment of metastatic nonsquamous NSCLC. N Engl J Med 2018;378:2288–2301.
3. Paz-Ares L, Luft A, Vicente D, et al. Pembrolizumab plus chemotherapy for squamous non-small cell lung cancer. N Engl J Med 2018;379:2040–2051.
4. U.S. Department of Health and Human Services. U.S. Food & Drug Administration. FDA approves pembrolizumab in combination with chemotherapy for first-line treatment of metastatic squamous NSCLC. Available at https://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm624659.htm. Accessed March 10, 2019.
5. Ettinger DS, Wood DE, Aisner DL, et al. NCCN Clinical Practice Guidelines in Oncology: Non-Small Cell Lung Cancer. Version 3.2019. Accessed April 8, 2019. To view the most recent version of these guidelines, visit NCCN.org.
6. Merck & Co. Keytruda (pembrolizumab). Full prescribing information. Available at https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/125514s040lbl.pdf. Accessed March 10, 2019.
7. Reck M, Rodríguez-Abreu D, Robinson AG, et al. Pembrolizumab versus chemotherapy for PD-L1-positive non-small-cell lung cancer. N Engl J Med 2016;375:1823–1833.
8. Reck M, Rodríguez-Abreu D, Robinson AG, et al. Updated analysis of KEYNOTE-024: Pembrolizumab versus platinum-based chemotherapy for advanced non-small-cell lung cancer with PD-L1 tumor proportion score of 50% or greater. J Clin Oncol 2019;37:537–546.
9. Pai-Scherf L, Blumenthal GM, Li H, et al. FDA approval summary: Pembrolizumab for treatment of metastatic non-small cell lung cancer: First-line therapy and beyond. Oncologist 2017;22:1392–1399.
10. Lopes G, Wu Y-L, Kudaba I, et al. Pembrolizumab versus platinum-based chemotherapy as first-line therapy for advanced/metastatic NSCLC with a PD-L1 tumor proportion score (TPS) ≥ 1%: Open-label, phase 3 KEYNOTE-042 study. J Clin Oncol 2018;36(suppl 18): LBA4.
11. Gandhi L, Rodríguez-Abreu D, Gadgeel S, et al. Pembrolizumab plus chemotherapy in metastatic non-small-cell lung cancer. N Engl J Med 2018;378:2078–2092.
12. Langer CJ, Gadgeel SM, Borghaei H, et al. Carboplatin and pemetrexed with or without pembrolizumab for advanced, non-squamous non-small-cell lung cancer: A randomised, phase 2 cohort of the open-label KEYNOTE-021 study. Lancet Oncol 2016;17:1497–1508.
13. U.S. Department of Health and Human Services. U.S. Food & Drug Administration. FDA grants regular approval for pembrolizumab in combination with chemotherapy for first-line treatment of metastatic nonsquamous NSCLC. Available at https://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm617471.htm. Accessed March 10, 2019.
14. Herbst RS, Baas P, Kim DW, et al. Pembrolizumab versus docetaxel for previously treated, PD L1 positive, advanced non small cell lung cancer (KEYNOTE 010): A randomised controlled trial. Lancet 2016;387:1540–1550.
15. Thompson JA, Schneider BJ, Brahmer J, et al. NCCN Clinical Practice Guidelines in Oncology: Management of Immunotherapy-Related Toxicities (Immune Checkpoint Inhibitor-Related Toxicities). Version 1.2018. To view the most recent version of these guidelines, visit NCCN.org.
16. Brahmer JR, Lacchetti C, Schneider BJ, et al. Management of immune-related adverse events in patients treated with immune checkpoint inhibitor therapy: American Society of Clinical Oncology Clinical Practice Guideline. J Clin Oncol 2018;36:1714–1768.
17. Thompson JA, Schneider BJ, Brahmer J, et al. NCCN Clinical Practice Guidelines in Oncology: Management of Immunotherapy-Related Toxicities (Immune Checkpoint Inhibitor-Related Toxicities). Version 1.2019. Accessed April 8, 2019. To view the most recent version of these guidelines, visit NCCN.org.
18. Cortellini A, Chiari R, Ricciuti B, et al. Correlations between the immune-related adverse events spectrum and efficacy of anti-PD1 immunotherapy in NSCLC patients. Clin Lung Cancer 2019; in press.

Commentary by NSCLC Site Editor for JNCCN 360

David S. Ettinger, MD

Alex Grass Professor in Oncology; Professor of Oncology, The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore

According to the results from the KEYNOTE series of trials and subsequent FDA approvals, pembrolizumab may be considered with (or without) chemotherapy in the first line, irrespective of histology (ie, adenocarcinoma or squamous), depending on the level of PD-L1 expression. [Editor’s Note: The NCCN Guidelines for Non-Small Cell Lung Cancer recommend pembrolizumab monotherapy for those with PD-L1 ≥ 50% without genetic alterations; combination therapy with pembrolizumab/chemotherapy may be considered regardless of PD-L1 levels for those without genetic alterations.]¹

The question of single-agent pembrolizumab versus a combination regimen (pemetrexed plus carboplatin for nonsquamous tumors, taxane plus carboplatin for squamous tumors) “boils down to clinical judgment,” Dr. Ettinger told JNCCN 360.

An asymptomatic or mildly symptomatic individual “may be offered monotherapy with an expectation of benefit but a lower risk of toxicity,” Dr. Ettinger said. In contrast, a symptomatic patient who requires a rapid response “may be treated with a combination regimen appropriate for his or her tumor histology. The potential for prompt relief of symptoms serves to balance the higher incidence of adverse effects associated with combination regimens,” he concluded.

Disclosures

Dr. Ettinger has received clinical research support/data safety monitoring board support from Golden Biotechnology; and has served on a scientific advisory board or as a consultant or expert witness for AbbVie, BeyondSpring Pharmaceuticals, Boehringer Ingelheim GmbH, Bristol-Myers Squibb Company, Eli Lilly and Company, Genentech, Inc., and Guardant Health, Inc.

Reference

1. Ettinger DS, Wood DE, Aisner DL, et al. NCCN Clinical Practice Guidelines in Oncology: Non-Small Cell Lung Cancer. Version 3.2019. Accessed April 8, 2019. To view the most recent version of these guidelines, visit NCCN.org.