Immunotherapy Revolutionizes Treatment of ES-SCLC
Addition of atezolizumab and durvalumab to chemotherapy is a win for patients with extensive-stage small cell lung cancer
Small cell lung cancer (SCLC) accounts for approximately 15% of all lung cancer cases, with almost all cases attributed to tobacco smoke exposure.1,2
SCLC is generally characterized by an aggressive, rapidly growing disease course with a high rate of metastasis. Although this rapid growth and proliferation translate into higher response rates to chemotherapy and radiation, patients relapse quickly with increased rates of disease progression.
Clinical staging for SCLC has historically been classified using the Veterans Administration Lung Study Group's 2-stage system to categorize patients to having either limited-stage SCLC (LS-SCLC) or extensive-stage SCLC (ES-SCLC) disease.3 This system differs from most solid tumor staging, which uses the American Joint Committee on Cancer TNM staging system. The National Comprehensive Cancer Network (NCCN) uses a combined approach for staging SCLC using the TNM staging criteria but ultimately classifies patients with SCLC as having LS-SCLC or ES-SCLC.4 Patients with ES-SCLC have a more advanced disease course. Therefore, the goal of treatment for these patients shifts from curative intent to an intent geared toward disease control and palliation.
For several decades, first-line treatment for ES-SCLC has consisted of systemic chemotherapy with a platinum agent (carboplatin or cisplatin) plus etoposide. Because of the favorable toxicity profile of carboplatin over cisplatin and comparable efficacy rates between the 2 platinum agents, carboplatin was preferred over cisplatin in ES-SCLC treatment regimens. Although response rates were reported as high as 80%, median overall survival rates for patients treated with carboplatin and etoposide were approximately 10 months.5
In recent years, immune checkpoint inhibitors have revolutionized oncology treatment with 7 checkpoint inhibitors approved by the FDA to treat various types of cancer, including melanoma, non–small cell lung cancer, renal cell carcinoma, urothelial carcinoma, and many others. By manipulating physiologic immune checkpoint pathways in place to reduce autoimmunity, cancer cells can evade recognition and targeting by cytotoxic T lymphocytes (CTLs). Immune checkpoint inhibitors target these pathways, either by inhibiting CTL antigen-4 (CTLA-4) or the interaction between PD-1 receptors and its ligands, PD-L1/L2.
Two immune checkpoint inhibitors, atezolizumab (Tecentriq; Genentech) and durvalumab (Imfinzi; AstraZeneca), were recently studied in the first-line setting for patients with ES-SCLC in combination with a platinum agent and etoposide. This addition of immunotherapy to chemotherapy represents the first change in ES-SCLC treatment since the 1990s. Both atezolizumab and durvalumab are humanized, IgG monoclonal antibodies targeting PD-L1 on the surface of tumor cells.
Atezolizumab was studied in combination with carboplatin and etoposide for first-line treatment in ES-SCLC in the phase 1/3 IMpower133 trial.6 In a 1:1 fashion, 403 patients with untreated ES-SCLC were randomized to receive treatment with carboplatin, etoposide, and atezolizumab or a matching placebo every 21 days for 4 cycles. After the initial 4-cycle induction phase of treatment, patients received maintenance therapy with atezolizumab or a placebo every 21 days until loss of clinical benefit, disease progression, or unacceptable toxicity.
After a median follow-up of 13.9 months, patients in the atezolizumab arm had a longer median overall survival (12.3 months) compared with the placebo arm (10.3 months).6 The HR was 0.70 (95% CI, 0.54-0.91; P=.007), suggesting a 30% lower risk of death with the addition of atezolizumab to standard carboplatin-etoposide therapy. In February 2021, an updated analysis was published after a median follow-up of 22.9 months, supporting the original results of the IMpower133 trial.7 The update reported a median overall survival of 12.3 months in the atezolizumab arm compared with 10.3 months in the placebo arm (HR, 0.76; 95% CI, 0.60-0.95; P=.054).
Durvalumab was the second PD-L1 inhibitor approved by the FDA based on the results of the CASPIAN trial.8 In this trial, 805 patients with untreated ES-SCLC were randomized 1:1:1 to receive treatment with a platinum agent (carboplatin or cisplatin) and etoposide; platinum-etoposide plus durvalumab; or platinum-etoposide plus durvalumab and tremelimumab, a CTLA-4 inhibitor. Initial treatment was given for 4 cycles (up to 6 cycles in the platinum-etoposide arm), followed by maintenance durvalumab every 4 weeks until disease progression or unacceptable toxicity.
The published results of the CASPIAN trial included analysis of the platinum-etoposide and platinum-etoposide-durvalumab arms.8 After a median follow-up of 25.1 months, updated results were published showing that the median overall survival was longer in the platinum-etoposide-durvalumab arm (12.9 months) compared with the platinum-etoposide arm (10.5 months).9 The HR was 0.75 (95% CI, 0.62-0.91; P=.0032), similar to the results from the IMpower133 trial.
As with other checkpoint inhibitors, treatment with both atezolizumab and durvalumab is associated with a unique immune-mediated toxicity profile, ranging from mild toxicities to potentially life-threatening toxicities. With a heterogeneous clinical presentation, immune-mediated toxicities can affect any organ system, most commonly the gastrointestinal tract, liver, skin, and thyroid gland. Immune-mediated toxicities should be identified as early as possible for close monitoring, prompt initiation or high-dose corticosteroids, and supportive care.
Based on the results of both the CASPIAN and IMpower133 trials, the addition of atezolizumab or durvalumab to platinum-etoposide therapy is considered the standard of care for patients with untreated ES-SCLC, as recommended by the NCCN guidelines. Pharmacists should recognize the role of adding atezolizumab and durvalumab to first-line treatment for ES-SCLC, along with the unique toxicities with which these patients may present.
REFERENCES
1. Rudin CM, Brambilla E, Faivre-Finn C, Sage J. Small-cell lung cancer. Nat Rev Dis Primers. 2021;7(1):3. doi:10.1038/s41572-020-00235-0
2. Pesch B, Kendzia B, Gustavsson P, et al. Cigarette smoking and lung cancer-relative risk estimates for the major histological types from a pooled analysis of case-control studies. Int J Cancer. 2012;131(5):1210-1219. doi:10.1002/ijc.27339
3. Jett JR, Schild SE, Kesler KA, Kalemkerian GP. Treatment of small cell lung cancer: diagnosis and management of lung cancer, 3rd ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest. 2013;143(suppl5):e400S-e419S. doi:10.1378/chest.12-2363
4. Recently updated guidelines. National Comprehensive Cancer Network. Accessed April 28, 2021. https://www.nccn.org/guidelines/recently-published-guidelines
5. Socinski MA, Smit EF, Lorigan P, et al. Phase III study of pemetrexed plus carboplatin compared with etoposide plus carboplatin in chemotherapy-naive patients with extensive-stage small-cell lung cancer. J Clin Oncol. 2009;27(28):4787-4792. doi:10.1200/JCO.2009.23.1548
6. Horn L, Mansfield NS, Szczesna A, et al. First-line atezolizumab plus chemotherapy in extensive-stage small-cell lung cancer. N Engl J Med. 2018;379(23):2220-2229. doi:10.1056/NEJMoa1809064
7. Liu SV, Reck M, Mansfield AS, et al. Updated overall survival and PD-L1 subgroup analysis of patients with extensive-stage small-cell lung cancer treated with atezolizumab, carboplatin, and etoposide (IMpower133). J Clin Oncol. 2021;39(6):619-630. doi:10.1200/JCO.20.01055
8. Paz-Ares L, Dvorkin ML, Chen Y, et al. Durvalumab plus platinum-etoposide versus platinum-etoposide in first-line treatment of extensive-stage small-cell lung cancer (CASPIAN): a randomised, controlled, open-label, phase 3 trial. Lancet. 2019;394(10212):1929-1939. doi:10.1016/S0140-6736(19)32222-6
9. Goldman JW, Dvorkin M, Chen Y, et al. Durvalumab, with or without tremelimumab, plus platinum-etoposide versus platinum-etoposide alone in first-line treatment of extensive-stage small-cell lung cancer (CASPIAN): updated results from a randomised, controlled, open-label, phase 3 trial. Lancet Oncol. 2021;22(1):51-65. doi:10.1016/S1470-2045(20)30539-8
ABOUT THE AUTHOR
Bryan Fitzgerald, PharmD, BCOP, is an oncology clinical pharmacy specialist at University of Rochester Medical Center in New York.
