Treatment and disease characteristics. Eighty-one participants were screened, and 78 were randomized (Fig. 1). One withdrew consent and one was found ineligible, leaving 76 evaluable for efficacy. Patient and disease characteristics showed no evidence of imbalance.11 Notably, 49% of participants had received > 3 prior lines of chemotherapy and 18% had platinum-refractory disease, with no statistical differences between the arms (p = 0.82 and p = 0.14, respectively). Within the IXA arm (N = 37), 9 (24%) of patients were taxane-resistant, 10 (27%) were taxane-refractory; within the IXA + BEV arm (N = 39), 13 (33%) were taxane-resistant, 13 (33%) were taxane-refractory (p = 0.44) (Table 1). Both arms contained patients previously treated with weekly paclitaxel, either in combination with carboplatin or in the platinum-resistant setting as part of an AURELIA4 regimen: 35% (N = 13; IXA) and 26% (N = 10, IXA + BEV).[2] One additional patient in the IXA + BEV arm also received weekly nab-paclitaxel but was not included for purity of the analysis. Among all patients previously treated with weekly paclitaxel, two patients in each arm (5. % and 5.1%, respectively) had received weekly paclitaxel with bevacizumab and two patients in each arm had received weekly paclitaxel monotherapy. Of note, one patient received both weekly paclitaxel followed 16 months later by weekly paclitaxel with bevacizumab and is therefore counted towards both totals.
Primary endpoint: PFS. At the data cutoff (05/27/2023), 75 PFS events and 70 deaths had occurred among 76 participants during 94.37 person-years of observation. Median PFS was 5.5 versus 2.2 months, HR 0.31, 90%CI 0.20–0.49, p < 0.001); this is unchanged from the previous estimates.
Secondary endpoints: OS, OR rate (ORR), safety. Since the original report, there was one additional response. ORR increased and remained higher in the IXA + BEV arm (38.4% vs 8.1%, p = 0.003). Median OS was 10.3 versus 6.0 months (HR 0.56, 90%CI 0.38–0.84, p = 0.02); this is virtually unchanged from the previous estimates. There were no complete responses, but in the combination arm, 14 patients achieved a durable response (stable disease or partial response > 6 months) (Fig. 2).
No new safety signals emerged since the original report. Among all participants, there were 30 patients who tolerated the initially prescribed dose, 25 patients who received at least one cycle at one dose reduction (16 mg/m2) and 21 who received at least one cycle at a second dose reduction (12 mg/m2). PFS benefit persisted in the combination arm despite dose reduction (HR 0.49, 95%CI 0.22–1.07, p = 0.074 [full dose]; HR 0.25, 95%CI 0.10–0.62, p = 0.003 [one dose reduction], HR 0.17, 95%CI 0.05–0.54, p = 0.002 [two dose reductions]) (Fig. 3-upper). OS was not affected (HR 0.7, 95%CI 0.33–1.49, p = 0.354 [full dose]; HR 0.6, 95%CI 0.26–1.36, p = 0.218 [one dose reduction]; HR 0.67, 95% CI 0.25–1.83, p = 0.438) [two dose reductions] (Fig. 3-lower).
Subgroup analyses: prior taxane response and prior exposure to weekly paclitaxel. Among both arms, most patients were paclitaxel-refractory/-resistant (51% [n = 19/37] on IXA and 67% [n = 26/39] on IXA + BEV). The addition of BEV to IXA conferred benefit in PFS (HR 0.31, 90%CI 0.20–0.48, 2-tailed Wald p < 0.001) and OS (HR 0.59, 90%CI 0.39–0.88, 2-tailed Wald p = 0.03) even in a multivariate analysis with prior taxane response as a covariate. Among 10 taxane-refractory patients in the IXA arm, best responses included SD in 40% (N = 4) and progressive disease (PD) in 50%(N = 5); one patient was not assessed due to rapid death. Among 13 taxane-refractory patients in the IXA + BEV arm, best responses included PR in 30.8% (N = 4), SD in 30.8% (N = 4) SD and PD in 38.5% (N = 5). Although the likelihood of increased PR with BEV did not attain statistical significance within any one prior-taxane subgroup (lowest p = 0.06), a Cochran-Mantel-Haenszel analysis with strata defined by prior taxane response yielded a common odds ratio of 0.71 (95%CI: 1.77–28.8; p = 0.003) favoring PR with IXA + BEV.
Among all 23 patients with prior weekly paclitaxel exposure (either in conjunction with carboplatin or as an AURELIA regimen in the recurrent setting), PFS was 6.0 (95%CI 2.9–13.0, IXA + BEV) versus 1.8 (95%CI 1.5–3.5, IXA) months (log-rank p = 0.005) (Fig. 4-upper; HR 0.26, 95%CI 0.10–0.71). OS estimates were 19.4 (95%CI 6.4 to not reached; IXA + BEV) versus 5.0 (95%CI 2.6–18.3, IXA) months (log-rank p = 0.10) (Fig. 4-lower; HR 0.46, 95%CI 0.18–1.18). In the subset of these patients who had received an AURELIA regimen (i.e., weekly paclitaxel with or without bevacizumab), PFS estimates were 2.9 (95%CI 2.0-6.9, IXA + BEV) and 1.7 (95%CI 0.9–2.2, IXA) months (p = 0.07). Following receipt of an AURELIA regimen of weekly paclitaxel with or without BEV, OS estimates were 20.2 (95%CI 2.2-not reached, IXA + BEV) and 4.5 (95%CI 0.9 to 18.3, IXA) months (p-0.17). Both patients treated with IXA + BEV following prior weekly paclitaxel and bevacizumab achieved a best response of SD, as did both patients treated with IXA + BEV following prior weekly paclitaxel monotherapy. One of two patients treated with IXA following prior weekly paclitaxel and bevacizumab achieved a best response of SD; one patient treated with IXA following prior weekly paclitaxel monotherapy experienced PD and one was not assessed due to death. The distribution of responses for all patients who received prior weekly paclitaxel are provided in Table 2. Among these 23 patients, there were 3 PRs in the combination arm but no responses in the IXA arm (p = 0.07). DDC was achieved in 4 patients in the combination arm but in none among the monotherapy arm (p = 0.02).