Immunotherapy drugs work by boosting the immune system so that a person’s own immune system works smarter to identify and destroy any cancer cells. The immune system has various types of breaks or safeguards called checkpoints to prevent it from attacking healthy cells. Some types of cancer cells know how to activate these checkpoints to remain undetected. Immune checkpoint inhibitors work by turning off checkpoints to allow the immune system to fully attack cancer cells.
Among various immunotherapy drug classes, immune checkpoint inhibitors have shown most activity thus far against solid tumors, including lung cancer.1 Of the 7 FDA-approved immune checkpoint inhibitors, 4 (atezolizumab, durvalumab, nivolumab, pembrolizumab) are indicated for the treatment of lung cancer.2 We first saw checkpoint inhibitors in 2015, with nivolumab as the first approved immunotherapy drug for lung cancer. It was approved for squamous cell non–small cell lung cancer (NSCLC).3 Advances in immunotherapy for lung cancer have continued.
This paper highlights the recent approvals in immunotherapy options for patients with lung cancer. In 2018, the FDA approved 1 new immunotherapy drug for lung cancer, and 2 other immunotherapy drugs received additional indications in lung cancers.4
For NSCLC, Durvalumab Was Newly Approved, and Pembrolizumab Was Approved for an Additional Indication
In February 2018, durvalumab was newly approved for patients with stage III NSCLC whose cancer cannot be removed by surgery and whose cancer did not progress after at least 2 cycles of platinum chemotherapy and radiation therapy.5 The interim analysis of the PACIFIC trial using durvalumab monotherapy led to this approval. Progression-free survival (PFS) was the major efficacy measurement in this clinical trial. PFS was significant in this study at almost 17 months for patients receiving durvalumab compared with about 5.5 months for those receiving placebo. Recently updated results show increased overall survival (OS) with the addition of durvalumab.6
This monoclonal antibody blocks a molecule called PD-L1 found on T cells. PD-L1 prevents the immune system from attacking normal body cells, so by blocking PD-L1 we remove the breaks, allowing T cells to find and destroy cancer cells.7
Pembrolizumab was initially approved by the FDA in 2015 for the treatment of patients with metastatic NSCLC whose tumors express PD-L1 and whose tumors progressed on platinum-based chemotherapy.
Pembrolizumab approvals in lung cancer include:
- In 2016, first-line monotherapy for metastatic NSCLC whose tumor expresses ≥50% PD-L1 expression;
- In 2017, first-line combination therapy with pembrolizumab, carboplatin, and pemetrexed in metastatic nonsquamous NSCLC2;
- In August 2018, pembrolizumab received FDA approval to be given in combination with pemetrexed and platinum as first-line treatment for patients with metastatic nonsquamous NSCLC without EGFR or ALK genomic tumor aberrations. This approval was based on the results from the Keynote-189 study. The primary end points of this study were OS and PFS. Study results showed that at 12 months, estimated OS was almost 70% for patients who received pembrolizumab combination therapy compared with almost 50% for patients who received placebo with combination therapy. Median PFS was almost 9 months for patients who received pembrolizumab combination therapy compared with almost 5 months for patients who received placebo with combination therapy8;
- On October 30, 2018, first-line combination therapy with pembrolizumab, carboplatin, paclitaxel, or nab- paclitaxel for metastatic squamous NSCLC was approved. This most recent approval was based on the Keynote-407 study, which randomized patients with metastatic squamous cell lung cancer to chemotherapy ± pembrolizumab. Median survival was 15.9 months with the addition of pembrolizumab compared with 11.3 months with chemotherapy alone.9
Pembrolizumab works by targeting PD-1. PD-1 is a protein found on immune system T cells. The job of the PD-1 protein is to prevent these T cells from attacking normal cells in the body. By blocking PD-1, pembrolizumab allows the immune system to attack the cancer cells to shrink tumors or slow their growth.10 Thus far, it does not appear that there is a major difference in efficacy or toxicity between PD-1 inhibitors (pembrolizumab, nivolumab) and PD-L1 inhibitors (atezolizumab, durvalumab).
For Small Cell Lung Cancer (SCLC), 1 Immunotherapy Drug Was Approved in 2018 to Date
In August 2018, nivolumab received another approval in lung cancer: an accelerated approval for third-line treatment of metastatic SCLC. It is now approved for patients with metastatic SCLC whose cancer worsened after platinum-based chemotherapy and 1 or more other lines of therapy.11 This is the first immune checkpoint inhibitor to receive FDA approval for metastatic SCLC.
This approval was based on positive results from the CheckMate-032 study using nivolumab with or without ipilimumab for patients with metastatic solid tumors. One subgroup was the metastatic SCLC in whom platinum-based therapy and at least 1 other prior line of therapy failed, regardless of tumor PD-L1 status. Overall response rate (ORR) and duration of response according to RECIST v1.1 were the major efficacy end points for this study. With nivolumab monotherapy, the ORR was 12%. Of the 13 patients who responded, more than 75% were stable for ≥6 months, more than 60% were stable for ≥12 months, and almost 40% were stable for ≥18 months. In this study, the PD-L1 tumor status did not predict response.12
Similar to pembrolizumab, nivolumab also targets PD-1. Prior to 2018, nivolumab was indicated for metastatic NSCLC whose tumors progressed on platinum-based chemotherapy.
The Future of Immunotherapy in Lung cancer
Atezolizumab is another PD-L1 immunotherapy, initially approved by the FDA in 2016 for the treatment of patients with metastatic NSCLC whose cancer progressed during or after platinum chemotherapy. Results from the IMpower133 trial using atezolizumab combined with carboplatin and etoposide in untreated, extensive-disease SCLC showed a survival benefit compared with chemotherapy alone, with a median survival of 12.3 months versus 10.3 months.13
The FDA is currently reviewing data from the IMpower150 study, which randomized metastatic nonsquamous NSCLC patients to avastin/carboplatin/taxol ± atezolizumab in the first-line setting. This study showed median survival of 19.2 months compared with 14.7 months in favor of the atezolizumab arm.14
The FDA is also reviewing data from Checkmate 227, which randomized metastatic NSCLC patients to the nivolumab/ipilimumab combination versus conventional chemotherapy and whose tumors had >10 tumor mutation burden/megabase pair. In this subset of cancer patients, the immunotherapy combination produced a median survival of 23 months compared with 16 months with chemotherapy.15
Immune checkpoint inhibitors have become an integral part of lung cancer treatments. They have shown meaningful survival benefits with or without conventional chemotherapy. Future directions will include utilizing immunotherapy in earlier-stage cancer settings to increase cure rates, improving efficacy of immunotherapy with the goal of producing durable remission, and ultimately cure in patients with advanced-stage lung cancer.
Lavinia Dobrea, RN, MS, OCN: No disclosures. Timothy E. Byun, MD: On speakers’ bureau for Bristol-Myers Squibb and Merck. Consultant for Abbvie.
1. Marin-Acevedo JA, Soyano AE, Dholaria B, et al. Cancer immunotherapy beyond immune checkpoint inhibitors. J Hematol Oncol. 2018;11:8.
2. US Food and Drug Administration. Hematology/Oncology (Cancer) Approvals & Safety Notifications. www.fda.gov/Drugs/InformationOn Drugs/ApprovedDrugs/ucm279174.htm. 2018.
3. De Lartigue J. Nivolumab: first immunotherapy approved for lung cancer. The Journal of Community and Supportive Oncology. www.mdedge.com/sites/default/files/issues/articles/JCSO_sep_314_Abraham.pdf. 2015.
4. National Cancer institute. Drugs Approved for Lung Cancer. www.cancer.gov/about-cancer/treatment/drugs/lung. 2018.
5. US Food and Drug Administration. FDA approves durvalumab after chemoradiation for unresectable stage III NSCLC. www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm597248.htm. 2018.
6. Antonia SJ, Villegas A, Daniel D, et al, for the PACIFIC Investigators. Overall survival with durvalumab after chemoradiotherapy in stage III NSCLC. N Engl J Med. www.nejm.org/doi/pdf/10.1056/NEJMoa1809697. 2018.
7. Faiena I, Cummings AL, Crosetti AM, et al. Durvalumab: an investigational anti-PD-L1 monoclonal antibody for the treatment of urothelial carcinoma. Drug Des Devel Ther. 2018;12:209-215.
8. 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.
9. Paz-Ares L, Luft A, Vicente D, et al, for the KEYNOTE-407 Investigators. Pembrolizumab plus chemotherapy for squamous non–small-cell lung cancer. www.nejm.org/doi/full/10.1056/NEJMoa1810865. 2018.
10. Prescribers’ Digital Reference. Pembrolizumab - Drug Summary. www.pdr.net/drug-summary/Keytruda-pembrolizumab-3600.8263. 2018.
11. US Food and Drug Administration. FDA grants nivolumab accelerated approval for third-line treatment of metastatic small cell lung cancer. www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm617370.htm. 2018.
12. The ASCO Post. IASLC 2017: CheckMate-032: Nivolumab Alone or With Ipilimumab in Recurrent SCLC With High Tumor Mutation Burden. www.ascopost.com/News/58147. 2018.
13. Horn L, Mansfield AS, Szczęsna A, et al. First-line atezolizumab plus chemotherapy in extensive-stage small-cell lung cancer. N Engl J Med. www.nejm.org/doi/full/10.1056/NEJMoa1809064. 2018.
14. Socinski MA, Jotte RM, Cappuzzo F, et al, for the IMpower150 Study Group. Atezolizumab for first-line treatment of metastatic nonsquamous NSCLC. N Engl J Med. 2018;378:2288-2301.
15. Hellmann MD, Ciuleanu T, Pluzanski A, et al. Nivolumab plus ipilimumab in lung cancer with a high tumor mutational burden. N Engl J Med. 2018;378:2093-2104.