CASPIAN Update Shows Ongoing Survival Benefit With Durvalumab in ES-SCLC

Luis Paz-Ares, MD, PhD

Updated findings from the phase 3 CASPIAN trial presented at the 2020 American Society of Clinical Oncology Virtual Scientific Program showed maintained overall survival (OS) benefit of durvalumab (Imfinzi) treatment in combination with platinum etoposide chemotherapy in newly diagnosed patients with extensive-stage small cell lung cancer (ES-SCLC) after more than 2 years of follow-up.¹

The findings solidify the use of the PD-L1 inhibitor in combination with etoposide plus either cisplatin or carboplatin (EP) as a new frontline standard of care for this patient population, principal investigator Luis Paz-Ares, MD, PhD, said in presenting the data.

After a median follow-up of 25.1 months, the median OS was 12.9 months (95% CI, 11.3-14.7) among patients who received durvalumab plus EP compared with 10.5 months (95% CI, 9.3-11.2) for those who received EP alone, which translated into an HR of 0.75 (95% CI, 0.62-0.91; nominal P = .0032).¹ The OS data favored the durvalumab whether carboplatin (HR, 0.79; 95% CI, 0.63-0.98) or cisplatin (HR, 0.67; 95% CI, 0.46-0.97) was used.

“Importantly, the separation among the curves seems to be observed over time and, indeed, survival at 2 years improves from 14% [of participants] in the control arm to 22% on the experimental arm. The magnitude of the benefit is very similar and very consistent across all the prespecified subgroups of patients analyzed, including those treated with cisplatin or those patients with liver or brain metastases,” said Paz-Ares, chair of the Medical Oncology Department, Hospital Universitario Doce de Octubre in Madrid, Spain.

“This is an effective first-line treatment in the extensive-stage setting, where improving outcomes has been a challenge and so few patients survive 5 years,” Paz-Ares noted in a press release from AstraZeneca, the manufacturer of durvalumab.²

In March 2020, the FDA approved durvalumab in combination with EP as first-line therapy for ES-SCLC based on interim findings from CASPIAN showing that, after a median follow-up of 14.2 months, the addition of the immunotherapy agent improved median OS to 13.0 months versus 10.3 months with EP alone (HR, 0.73; 95% CI, 0.59-0.91; P = .0047).^3,4

The approval marked another benchmark for incorporating immunotherapy directed at the PD-1/PD-L1 pathway into the treatment paradigm for small cell lung cancer; the introduction of these agents over the past 2 years has improved OS in the frontline setting after more than 3 decades of limited progress, said Paz-Ares.

Approximately two-thirds of patients diagnosed with small cell lung cancer have extensive-stage disease and, although nearly 80% of patients initially respond to EP therapy, most relapse within 6 months, according to Paz-Ares and colleagues. Historically, the median OS has been about 10 months.⁴

Although the CASPIAN findings support the durvalumab regimen, the study also tested a dual immunotherapy combination plus EP that did not meet a prespecified threshold for statistical significance (P ≤.0418). The combination of durvalumab plus tremelimumab, an investigational CTLA-4 immune checkpoint inhibitor, and EP demonstrated a median OS of 10.4 months (95% CI, 9.6-12.0) versus 10.5 months (95% CI, 9.3-11.2) for EP alone (HR, 0.82; 95% CI, 0.68-1.00; P = .0451).¹

Details of the CASPIAN Study

In CASPIAN (NCT03043872), investigators evaluated the impact of chemoimmunotherapy versus chemotherapy across 3 arms: 1) durvalumab plus tremelimumab and EP every 3 weeks for 4 cycles, followed by durvalumab every 4 weeks until progressive disease with an additional dose of tremelimumab (D+T+EP arm); 2) durvalumab plus EP every 3 weeks for 4 cycles, followed by durvalumab every 4 weeks until disease progression (D+EP arm); and 3) EP every 3 weeks for up to 6 cycles, followed by prophylactic cranial irradiation at the investigator’s discretion (EP arm).

Durvalumab was administered at 1500 mg and tremelimumab was dosed at 75 mg. In all study arms, patients received etoposide at 80 to 100 mg/m² on days 1 to 3 of each 21-day cycle, with investigator’s choice of either carboplatin area under the curve 5 to 6 mg/mL per minute or cisplatin at 75 to 80 mg/m² administered on day 1 of each cycle.^1,4

The primary end point of the study was OS; secondary end points included progression-free survival (PFS), objective response rate (ORR); and safety and tolerability. To be eligible for the study, patients had to have treatment-naïve ES-SCLC, defined as stage IV and classified as T any, N any, M1a or M1b or T 3 to 4.4 Patients with asymptomatic or treated and stable brain metastases were permitted to enroll.

Overall, 805 patients were randomized to 1 of the 3 treatment arms. The median age was 63 years in the D+T+EP (n = 268) and EP (n = 269) arms and 62 in the D+EP (n = 268) arm. The percentage of patients with brain or central nervous system metastases in the treatment arms was 14.2%, 10.4%, and 10.0% for the D+T+EP, D+EP, and EP arms, respectively. Those with liver metastases made up 43.7%, 40.3%, and 38.7% in each arm, respectively.

Chemoimmunotherapy Findings

Across all arms of the study, the use of immunotherapy demonstrated an improvement in OS rates compared with EP. The OS survival rates at 18 months were 32.0% in the D+EP arm, 30.7% in the D+T+EP group, and 24.8% in the EP cohort; at 24 months, those rates were 22.2%, 23.4%, and 14.4%, respectively.

Nevertheless, in addition to a lack of OS benefit, the D+T+EP regimen did not show significant improvement over the EP arm in several other key investigator-assessed measures per RECIST v1.1 criteria. The median PFS was 4.9 months (95% CI, 4.7-5.9) for the D+T+EP arm compared with 5.4 months (95% CI, 4.8-6.2) for the EP arm (HR, 084; 95% CI, 0.70-1.01). The confirmed ORR and median duration of response were 58.4% and 5.2 months (95% CI, 4.9-5.6), respectively, in the D+T+EP group compared with 58.0% and 5.1 months (95% CI, 4.8-5.3) for the EP arm.

In the updated analysis, the PFS for the D+EP arm versus the EP group was not formally evaluated for statistical significance. The median PFS was 5.1 months (95% CI, 4.7-6.2) with D+EP versus 5.4 months (95% CI, 4.8-6.2) for EP (HR, 0.80; 95% CI, 0.66-0.96). The ORR was 67.9% for the D+EP arm compared with 58.0% for EP (OR, 1.53; 95% CI, 1.08-2.18). The median duration of response was the same for both arms at 5.1 months.

In terms of the toxicity profile of each regimen, Paz-Ares said that safety findings remained consistent with the known adverse events (AEs) associated with the agents used in each regimen. The rates of grade 3/4 and serious AEs were, respectively, 70.3% and 45.5% in the D+T+EP arm, 62.3% and 32.1% in the D+EP arm, and 62.8% and 36.5% in the EP group. AEs leading to treatment discontinuation occurred in 21.4% of patients in the D+T+EP arm, 10.2% in the D+EP group, and 9.4% in the EP cohort. There were 12 deaths in the D+T+EP arm, 6 in the D+EP arm, and 2 in the EP arm that investigators attributed to treatment-related AEs.

José Baselga, executive vice president of Oncology R&D for AstraZeneca, echoed Paz-Ares’ conclusions about the study in the company’s press release. “After 2 years median follow-up, Imfinzi continues to show sustained and meaningful improvements in survival and prolonged treatment response for patients facing this devastating and aggressive disease,” Baselga said. “These data reinforce Imfinzi plus chemotherapy as an important new standard of care for extensive-stage small cell lung cancer patients, and this regimen offers patients convenient dosing every 4 weeks during maintenance.”²

_References

1. _{Paz-Ares L, Dvorkin M, Chen Y, et al. Durvalumab ± tremelimumab + platinum-etoposide in first-line extensive-stage SCLC (ES-SCLC): updated results from the phase III CASPIAN study. J Clin Oncol. 2020;38(suppl; abstr 9002). doi: 10.1200/JCO.2020.38.15_suppl.9002}
2. _{Imfinzi showed a sustained overall survival benefit in 1st-line extensive-stage small cell lung cancer in the phase III CASPIAN trial. News release. AstraZeneca. Published May 29,, 2020. Accessed May 29, 2020. bit.ly/3gCj6ss}
3. _{FDA approves durvalumab for extensive-stage small cell lung cancer. FDA. Published March 30, 2020. Accessed May 29, 2020. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-durvalumab-extensive-stage-small-cell-lung-cancer}
4. _{Paz-Ares L, Dvorkin M, 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}