The FDA on March 27, 2020, approved durvalumab for the first-line treatment of adult patients with locally advanced, unresectable, and extensive-stage small cell lung cancer (ES-SCLC) when used in combination with standard-of-care chemotherapy, including etoposide plus carboplatin or cisplatin. Approval was made in response to pivotal findings from the phase III CASPIAN trial, an open-label trial that examined the safety and efficacy of durvalumab with or without tremelimumab plus standard-of-care chemotherapy in treatment-naive patients with ES-SCLC (Lancet 2019;394(10212):1929-1939).
Approximately 200,000 new cases of lung cancer are reported in the United States each year, and nearly 150,000 annual deaths are attributed to this disease (Clin Cancer Res 2015;21(10):2213-20). Smoking is the primary cause of SCLC, but as tobacco use continues to decline in the United States, so have new cases of SCLC (Oncologist 2010;15(2):187-95). Those with SCLC, however, often present with extensive-stage disease, which is usually incurable. Combination chemotherapy can be helpful in patients with this aggressive form of lung cancer, but response rates are relatively low and treatment is sometimes associated with a relatively short survival.
And while systemic chemotherapy is the mainstay for patients with extensive-stage disease, progression can sometimes occur soon after an initial response. Patients with ES-SCLC, a rapidly growing lung cancer, can often relapse after initial chemotherapy, with only around 2-3 percent of patients surviving up to 1 year following diagnosis (Cancer Manag Res 2019;11:10767-10775). While this highlights the importance of discovering new novel approaches to improve outcomes in these patients, effective therapies have been somewhat challenging to identify, partly because of the aggressive nature of the disease.
"Once cancer progression occurs, it becomes very difficult to treat and patients don't live very long," noted CASPIAN investigator Yuanbin Chen, MD, PhD, of the Cancer & Hematology Centers of Western Michigan and Michigan State University. "[Our findings suggest that] adding durvalumab to initial chemotherapy followed by maintenance increases the chance for these patients to live longer."
Approval for Aggressive Lung Cancer
Prior to the FDA's new approval of durvalumab, the drug was also indicated for locally advanced or metastatic urothelial carcinoma in patients with disease progression during or after platinum-containing chemotherapy or in patients with disease progression within 12 months of neoadjuvant or adjuvant platinum-containing chemotherapy. Approval for this indication was announced May 2017 following findings from a single-arm trial.
In the CASPIAN trial, an international team of researchers at 209 sites across 23 countries randomized adult patients with untreated ES-SCLC to intravenously administered durvalumab plus platinum-etoposide (n=268) or platinum-etoposide alone (n=269). Another group of patients was randomized to durvalumab plus tremelimumab and platinum-etoposide, but findings from this group were not reported in the interim analysis. Overall survival (OS) comprised the primary endpoint in the intention-to-treat population.
A significant improvement in OS was observed with durvalumab plus platinum-etoposide versus platinum-etoposide alone (hazard ratio [HR], 0.73; 95% CI, 0.59-0.91; p=0.0047). The median OS was also longer in the durvalumab plus platinum-etoposide group versus the platinum-etoposide group (13.0 months [95% CI, 11.5-14.8] vs. 10.3 months [95% CI, 9.3-11.2], respectively). Approximately 34 percent (95% CI, 26.9-41.0) of patients in the durvalumab plus platinum-etoposide arm was alive at 18 months, compared with 25 percent (95% CI, 18.4-31.6) of patients randomized to platinum-etoposide alone.
Across both groups, the CASPIAN investigators observed a similar proportion of any-cause grade 3 or 4 adverse events (62% in both). Adverse events that led to death were reported in 5 percent of patients in the durvalumab plus platinum-etoposide group versus 6 percent of patients in the platinum-etoposide arm.
According to Chen, durvalumab demonstrated a similar efficacy profile as other anti-PDL1 first-line therapies, particularly in terms of OS, progression-free survival, response rate, and duration of response. Additionally, durvalumab demonstrated a similar safety profile comparable to other anti-PDL1 drugs, including in regard to immune-mediated adverse events. The CASPIAN trial reported no other unexpected safety concerns associated with durvalumab.
Future Directions for Durvalumab
Durvalumab is the only immunotherapy to demonstrate a significant survival benefit and improved response rate when combined with chemotherapy for patients with ES-SCLC. The CASPIAN findings are particularly promising, added Chen, as the design of the trial incorporated real-word practice habits, such as the use of chemotherapy backbone with either cisplatin or carboplatin and the inclusion of patients with untreated brain metastasis.
"Based on our findings, I think this regimen will fit in real-world practice very well," he commented.
Currently, testing is being completed for durvalumab after concurrent chemoradiation therapy in patients with limited-stage SCLC (Clin Lung Cancer 2020;21(2):e84-e88; ClinicalTrials.gov: NCT03703297). Data from this phase III ADRIATIC trial are anticipated sometime in 2021.
Brandon May is a contributing writer.