ES-SCLC: tremelimumab + durvalumab + chemotherapy misses endpoint

Addition of tremelimumab to frontline durvalumab and platinum-based chemotherapy did not demonstrate a significant improvement in overall survival in patients with extensive-stage small-cell lung cancer, missing the co-primary endpoint of the phase 3 CASPIAN study.

The addition of tremelimumab to frontline durvalumab and platinum-based chemotherapy did not demonstrate a statistically significant improvement in overall survival (OS) in patients with extensive-stage small-cell lung cancer (ES-SCLC), missing the co-primary endpoint of the phase 3 CASPIAN study.

Presented by Prof. Luis Paz-Ares (Hospital 12 de Octubre, Madrid, Spain), this was the first report of the third study arm of CASPIAN, in which investigational CTLA-4 inhibitor tremelimumab was added to PD-L1 checkpoint inhibitor durvalumab on top of standard of care chemotherapy [1].

CASPIAN randomised 805 patients to 3 treatment arms: durvalumab + tremelimumab + etoposide cisplatin/carboplatin (EP) (n=268), EP alone (n=269), or durvalumab + EP (n=268). The primary endpoint of the study was OS; secondary endpoints included progression-free survival (PFS), objective response rate (ORR), and safety and tolerability. Findings from CASPIAN reported previously for the last of the 2 treatment arms showed that, after a median follow-up of 14.2 months, the addition of the durvalumab improved the median OS to 13.0 months versus 10.3 months with EP alone (HR 0.73; 95% CI 0.59-0.91; P=0.0047) [2]. Consequently, in March 2020, the FDA approved durvalumab in combination with EP as first-line therapy for ES-SCLC.

In the current presentation, after a median follow-up of 25.1 months, the median OS was 12.9 months among patients who received durvalumab + EP compared with 10.5 months for those who received EP alone (HR 0.75; 95% CI 0.62-0.91; P=0.0032), fully supporting the initial report. Of note, the study design allowed the use of either backbone carboplatin or cisplatin; the OS data favored durvalumab no matter 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 Prof. Paz-Ares.

However, the study’s third arm testing dual checkpoint blockade with tremelimumab + durvalumab + EP did not meet the prespecified threshold for statistical significance (P≤0.0418). The median OS for this combination was 10.4 months versus 10.5 months for EP alone (HR 0.82; 95% CI 0.68-1.00; P=0.0451). The OS survival rates at 18 months were 32.0% in the durvalumab + EP arm, 30.7% in the tremelimumab + durvalumab + EP group, and 24.8% in the EP cohort; at 24 months, those rates were 22.2%, 23.4%, and 14.4%, respectively.

The median PFS was 4.9 months for the tremelimumab + durvalumab + EP arm compared with 5.4 months for the EP arm (HR 0.84; 95% CI 0.70-1.01). The confirmed ORR and median duration of response were 58.4% and 5.2 months, respectively, in the tremelimumab + durvalumab + EP group compared with 58.0% and 5.1 months for the EP arm.

Safety events were consistent with the known adverse events (AEs) associated with the medications. The rates of grade 3/4 and serious AEs were, respectively, 70.3% and 45.5% in the tremelimumab + durvalumab + EP arm, 62.3% and 32.1% in the durvalumab + 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 tremelimumab + durvalumab + EP arm, 10.2% in the durvalumab + EP group, and 9.4% in the EP cohort. Treatment-related deaths were 12 in the tremelimumab + durvalumab + EP arm, 6 in the durvalumab + EP arm, and 2 in the EP arm. In conclusion, the benefit-to-risk ratio favored treatment with durvalumab + EP, without tremelimumab, for treatment-naïve ES-SCLC.

Sources:
1. Paz-Ares LG,et al. Durvalumab ± tremelimumab + platinum-etoposide in first-line extensive-stage SCLC (ES-SCLC): Updated Results from the phase III CASPIAN study. ASCO Virtual Meeting, 29-31 May 2020, Abstract 9002.
2. Paz-Ares LG, et al. Durvalumab plus platinum-etoposide versus platinum-etoposide in first-line treatment of extensive-stage small-cell lung cancer (CASPIAN): a randomized, controlled, open-label, phase 3 trial. Lancet. 2019;394(10212):1929-1939.

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