Small-cell lung cancer: on the road to improved efficacy and tolerability
Lurbinectedin, a selective inhibitor of oncogenic transcription, has been approved at a dose of 3.2 mg/m2 Q3W for the treatment of patients with small-cell lung cancer (SCLC) showing disease progression on or after platinum-based chemotherapy in the US. The randomized, phase III ATLANTIS trial tested the combination of lurbinectedin 2 mg/m2 and doxorubicin 40 mg/m2 Q3W for a maximum of 10 cycles followed by lurbinectedin 3.2 mg/m2 Q3W in 307 patients with relapsed SCLC after one prior chemotherapy line. Patients in the control arm (n = 306) received either topotecan or cyclophosphamide/doxorubicin/vincristine (CAV) Q3W. Enrollment required a chemotherapy-free interval (CTFI) after first-line treatment of ≥ 30 days. Primary prophylaxis with G-CSF was mandatory in the whole study population. In both arms, approximately one third of patients each had a CTFI of < 90, 90-179, and ≥ 180 days. CNS involvement was present in 15.0 % and 16.0 %, respectively.
ATLANTIS did not meet its primary endpoint, as the overall survival (OS) curves for the two regimens were superimposable, with median OS of 8.6 and 7.6 months for lurbinectedin/doxorubicin and topotecan or CAV, respectively (HR, 0.967; p = 0.7032) . None of the subgroups according to the stratification factors (i. e., CTFI, ECOG PS, baseline brain involvement, prior immunotherapy) derived significant benefit from lurbinectedin/doxorubicin compared to topotecan or CAV. Median progression-free survival was significantly improved in the experimental arm (HR, 0.831; p = 0.0437). Here, patients with a CTFI of ≥ 180 days and those after prior PD-(L)1 inhibitor treatment were more likely to benefit from the lurbinectedin combination, whereas those with a short CTFI interval of < 90 days and CNS metastases appeared to fare better with the comparator regimens. Overall response rates were similar across the arms (31.6 % vs. 29.7 %), although responses lasted longer in the lurbinectedin-treated group (median duration of response, 5.7 vs. 3.8 months; HR, 0.581; p = 0.0012).
Significantly lower cytopenia rates
As the safety analysis demonstrated, higher-grade adverse events (AEs) and fatalities due to AEs occurred less frequently with lurbinectedin/doxorubicin, which also applied to dose reductions, dose delays, and treatment discontinuations (Table). These differences were mainly based on significantly lower rates of grade ≥ 3 cytopenias in the experimental arm. Anemia occurred in 14.5 % vs. 31.1 % (p < 0.0001), neutropenia in 37.0 % vs. 69.2 % (p < 0.0001), febrile neutropenia in 4.0 % vs. 8.3 % (p = 0.0377), and thrombocytopenia in 13.9 % vs. 31.1 % (p < 0.0001).
With respect to non-hematological toxicity, no major differences were observed. Overall, these results support the clinical benefit of lurbinectedin for patients with SCLC who are being treated in the second line. Also, ATLANTIS confirmed CFTI as the most important prognostic factor in the second-line setting. New combinations of lurbinectedin with other cytotoxic agents such as irinotecan as well as immune checkpoint inhibitors are being explored.
CASPIAN trial: 3-year OS
The global, randomized, open-label, three-arm, phase III CASPIAN trial was conducted to assess the first-line administration of the PD-L1 inhibitor durvalumab with or without the anti-CTLA-4 antibody tremelimumab in addition to platinum-etoposide (EP) in patients with extensive-stage (ES) SCLC. In both experimental arms, the combinations were administered Q3W for 4 cycles and were followed by durvalumab maintenance Q4W until progression. The control arm received EP alone Q3W for up to 6 cycles followed by optional prophylactic cranial irradiation.
Durvalumab plus EP, as compared to EP, has been shown to significantly improve OS (HR, 0.73; p = 0.0047) . This benefit was sustained after more than 2 years of median follow-up, while the combination of durvalumab plus tremelimumab and EP gave rise to a numerical OS improvement over EP, although this did not fulfill the requirements of statistical significance . At ESMO 2021, Paz-Ares et al. reported a planned exploratory analysis of OS after a median follow-up of more than 3 years . Progression-free survival and objective response data had not been collected since the previous data cutoff. Similarly, in terms of safety, only serious AEs including death were analyzed. Among phase III trials of EP with a PD-(L)1 inhibitor in the setting of ES-SCLC, this updated OS analysis shows the longest median follow-up reported to date.
Tripling of the survivor rate
Durvalumab plus EP demonstrated a sustained OS benefit over EP. Median OS was 12.9 vs. 10.5 months, which translated into a 29 % mortality reduction (HR, 0.71; p = 0.0003; Figure). At 36 months, the proportion of survivors was 3 times higher in the experimental arm than in the control arm (17.6 % vs. 5.8 %). The addition of the checkpoint inhibitor to chemotherapy induced OS benefits of similar magnitude in all subgroups.
Also, patients who received the durvalumab-tremelimumab combination plus EP experienced a sustained numerical OS advantage compared to EP alone, with a 19 % mortality reduction. The 36-month OS rates amounted to 15.3 % vs. 5.8 %. Most patients in the experimental arms remained on durvalumab treatment at data cutoff. Exposure to tremelimumab and chemotherapy had not changed compared to the previous analysis .
Likewise, the safety profile was consistent with the known profile of this treatment. Serious AEs occurred in similar percentages across the durvalumab plus EP and EP arms (32.5 % and 36.5 %, respectively), while this rate was higher for durvalumab plus tremelimumab and EP (47.4 %), as previously reported . Regarding treatment-related AEs leading to death, the rates were 2.3 %, 4.5 % and 0.8 % for durvalumab plus EP, durvalumab plus tremelimumab and EP, and EP alone, respectively. The authors concluded that these data further establish durvalumab plus EP as standard of care for the first-line treatment of patients with ES-SCLC.
Figure: Overall survival update after 3 years for durvalumab plus EP vs. EP alone in the CASPIAN trial
- Paz-Ares L et al., Lurbinectedin/doxorubicin versus CAV or topotecan in relapsed SCLC patients: phase III randomized ATLANTIS trial. WCLC 2021, PL02.03
- Paz-Ares L 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
- Goldman JW 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
- Paz-Ares L et al., Durvalumab ± tremelimumab + platinum-etoposide in first-line extensive-stage SCLC: 3-year overall survival update from the phase 3 CASPIAN study. ESMO 2021, LBA61
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