Durvalumab ± tremelimumab + platinum-etoposide in first-line extensive-stage SCLC (ES-SCLC): Updated results from the phase III CASPIAN study.

Abstract

9002 Background: CASPIAN is an open-label, Phase 3 study of durvalumab (D) ± tremelimumab (T) + etoposide and either cisplatin or carboplatin (EP) for pts with 1L ES-SCLC. At the planned interim analysis (data cutoff Mar 11, 2019; 63% maturity), D + EP demonstrated a statistically significant improvement in OS compared with EP alone (HR 0.73 [95% CI 0.59–0.91]; p=0.0047). Here we present a planned updated analysis of OS for D + EP vs EP and the first results for D + T + EP vs EP. Methods: Treatment-naïve pts with ES-SCLC (WHO PS 0/1) were randomized 1:1:1 to D 1500 mg + EP q3w, D 1500 mg + T 75 mg + EP q3w, or EP q3w. In the IO arms, pts received 4 cycles of EP + D ± T, followed by maintenance D 1500 mg q4w until disease progression. Pts received one additional dose of T 75 mg post EP in the D + T + EP arm. In the EP arm, pts received up to 6 cycles of EP and optional PCI (investigator’s discretion). The two primary endpoints were OS for D + EP vs EP and for D + T + EP vs EP. Results: 268, 268 and 269 pts were randomized to D + EP, D + T + EP and EP, respectively; baseline characteristics were generally well balanced across arms. As of Jan 27, 2020, the median follow-up was 25.1 mo, 82% maturity. D + EP continued to demonstrate improvement in OS vs EP, with a HR of 0.75 (95% CI 0.62–0.91; nominal p=0.0032); median OS 12.9 vs 10.5 mo, respectively. 22.2% of pts were alive at 2 y with D + EP vs 14.4% of pts with EP. D + T + EP numerically improved OS vs EP, however this did not reach statistical significance per the prespecified statistical plan: HR 0.82 (95% CI 0.68–1.00; p=0.0451 [p≤0.0418 required for stat sig]); the median OS was 10.4 mo and 23.4% of pts were alive at 2 y. Secondary endpoints of PFS and ORR remained improved with D + EP vs EP and will be presented. Confirmed investigator-assessed ORR was similar for D + T + EP vs EP (58.4% vs 58.0%). Median PFS was similar for D + T + EP vs EP (4.9 mo vs 5.4 mo), but the 12-mo PFS rate was numerically higher (16.9% vs 5.3%); PFS HR 0.84 (95% CI 0.70–1.01). In the D + EP, D + T + EP and EP arms, respectively, incidences of all-cause AEs of Grade 3/4 were 62.3%, 70.3% and 62.8%; AEs leading to discontinuation 10.2%, 21.4% and 9.4%; and AEs leading to death 4.9%, 10.2% and 5.6%. Conclusions: The addition of durvalumab to EP continued to demonstrate improvement in OS compared with a robust control arm, further supporting this regimen as a new standard of care for 1L ES-SCLC offering the flexibility of platinum choice. No additional benefit was observed when T was combined with D + EP in this pt population. Safety findings in all arms remained consistent with the known safety profiles of all agents. Clinical trial information: NCT03043872.

Prolonging Survival: The Role of Immune Checkpoint Inhibitors in the Treatment of Extensive-Stage Small Cell Lung Cancer

“…Global health status (measured by the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core‐30) also favored durvalumab plus chemotherapy compared with chemotherapy alone (HR, 0.81; 95% CI, 0.63─1.05) [51]. At a longer median follow‐up of 25.1 months the OS benefit was maintained (12.9 vs. 10.5 months; HR, 0.75; 95% CI, 0.62─0.91; p = .0032), and both PFS and ORR remained comparable [52]. The addition of tremelimumab to durvalumab and chemotherapy failed to significantly improve survival compared with chemotherapy alone (10.4 vs. 10.5 months; HR, 0.82; 95% CI, 0.68─1.00; p = .045) with similar PFS and ORR seen in each arm.…”

“…Significant improvements in OS and/or quality of life shown in a phase III trial using these agents as first‐line therapy for ES‐SCLC would represent a new optimal treatment. Studies assessing ipilimumab or tremelimumab used with chemotherapy or in combination with a PD‐1/PD‐L1 inhibitor either as first‐line therapy or as first‐line maintenance therapy did not show improved survival [39, 43, 52], nor did the use of nivolumab alone as first‐line maintenance (not formally tested as per protocol) [44]. However, three studies combining PD‐1/PD‐L1 inhibitors with chemotherapy first‐line, IMpower 133, CASPIAN, and KEYNOTE‐604, showed more promise [37, 40, 48].…”

“…Patient populations were comparable in terms of age, Eastern Cooperative Oncology Group (ECOG) performance status (PS), and extent of central nervous system (CNS) metastases for IMpower 133 and CASPIAN [37, 40], whereas patients in KEYNOTE‐604 had a slightly higher proportion of patients with PS 1 and CNS metastases [48]. Although ICI survival benefits emerged between 6 and 7 months with curves remaining separate at a median follow‐up of approximately 20 months in all trials [48, 50, 52], the survival benefit reached statistical significance for IMpower 133 and CASPIAN [50, 52] and was narrowly missed for KEYNOTE‐604 ( p = .016, OS superiority threshold p = .0128) [48]. ICI plus chemotherapy combinations improved HRQoL in IMpower 133 [49] and CASPIAN [51], although HRQoL data were not available for KEYNOTE‐604 [48].…”

“…ICI plus chemotherapy combinations improved HRQoL in IMpower 133 [49] and CASPIAN [51], although HRQoL data were not available for KEYNOTE‐604 [48]. Although caution should be exercised when considering cross‐trial comparisons, OS differences might be explained by a greater proportion of patients with poor prognosis enrolled in KEYNOTE‐604 as evidenced by the lower median OS for the control arm of this trial compared with IMpower 133 and CASPIAN (9.7 vs. 10.3 and 10.5 months, respectively) [48, 50, 52]. Another possibility could be that PD‐1 inhibitors are less effective at mediating immune responses compared with PD‐L1 inhibitors in SCLC, although this is unlikely given the improved survival demonstrated with the addition of nivolumab to chemotherapy in the phase II ECOG‐ACRIN 5161 study [55].…”

“…PD‐L1 inhibitors were combined with first‐line chemotherapy in IMpower 133 [37], CASPIAN [40], and KEYNOTE‐604 [48]. The addition of PD‐1/PD‐L1 inhibitors to platinum‐based chemotherapy generally resulted in comparable rates of grade 3/4 TRAEs for the combinations relative to controls (Table 2) [48, 50, 52]. However, rates of discontinuation due to AEs were higher for the ICI arm relative to chemotherapy in both IMpower 133 and KEYNOTE‐604 [48, 50] and were comparable in CASPIAN [52].…”