ADC Anetumab Ravtansine Does Not Improve PFS vs Paclitaxel in High-Grade Serous Ovarian Cancer

Anetumab ravtansine (BAY 949343) plus bevacizumab (Avastin) failed to demonstrate superior efficacy compared with standard weekly paclitaxel plus bevacizumab in patients with platinum-resistant/refractory high-grade serous/endometrioid ovarian cancer, according to findings from a phase 2 study (NCT03587311) published in Clinical Cancer Research.1

At the time of the futility analysis, which occurred after 35 progression-free survival (PFS) events, the median PFS was 5.3 months (3.7-7.4) with anetumab ravtansine plus bevacizumab and 12.7 months (7.5-17.4) with paclitaxel plus bevacizumab (HR, 2.02; 1.06-3.86; P = .03). Based on results from the futility analysis, the study was ended, and 1 patient from the anetumab ravtansine arm switched to the paclitaxel arm.

“This study was terminated early due to the higher overall response rate [ORR] and longer PFS in the control arm, validating the activity of weekly paclitaxel/bevacizumab,” the study authors wrote in the paper. “In addition, it is notable that patients with platinum-refractory disease and prior bevacizumab exposure benefit from bevacizumab rechallenge.”

Study Background

Mesothelin is highly expressed in high-grade serous and endometrioid ovarian cancers and is an attractive target for antibody-based therapies paired with cytotoxic agents, study authors noted. Anetumab ravtansine is a mesothelin-directed antibody-drug conjugate (ADC). In vitro studies have shown that this agent binds to human mesothelin, is internalized by tumor cells, and inhibits cell proliferation.2 Furthermore, mesothelin-expressing xenografts, such as ovarian patient-derived xenograft models, have demonstrated susceptibility to the antitumor activity of anetumab ravtansine.

Moreover, a phase 1 study (NCT01439152) evaluating anetumab ravtansine in patients with advanced or metastatic solid tumors showed early signals of safety and efficacy, including in the cohort of patients treated with the ADC at a weekly dose of 2.2 mg/kg.3

Phase 2 Trial Design

The current randomized, open-label, multicenter phase 2 study was conducted following a phase 1 safety run-in study and investigated the safety and efficacy of anetumab ravtansine plus bevacizumab compared with standard-of-care weekly paclitaxel plus bevacizumab in patients with platinum-resistant or refractory high-grade serous/endometrioid ovarian cancer.1

The trial enrolled patients at least 18 years of age with histologically confirmed high-grade serous or high-grade endometrioid ovarian, fallopian tube, or primary peritoneal cancer. Patients needed to have an ECOG performance status of 0 to 2, and have platinum-resistant disease with a platinum-free interval of less than 6 months or platinum-refractory disease, defined as disease that had progressed during or within 4 weeks after the last dose of frontline platinum-based chemotherapy. For the phase 1 run-in portion, mesothelin testing was not required for enrollment and was conducted retrospectively. For the phase 2 portion of the study, patients needed to have measurable disease per RECIST 1.1 criteria and centrally determined positive mesothelin tumor expression on archival tumor tissue (defined as at least 30% of tumor cells with membrane staining intensities of at least 2+ by immunohistochemistry). Patients were permitted to enroll if they had previously received weekly paclitaxel or bevacizumab in the platinum-sensitive setting, and the trial placed no limits on the number of prior lines of systemic therapy.

Notably, patients were excluded if they had previously received weekly paclitaxel in the platinum-resistant-refractory setting; had a history of severe allergic reactions to bevacizumab, paclitaxel, or anetumab ravtansine; were receiving any medications or substances that are strong inducers or inhibitors of CYP3A4; or had a history of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within 6 months prior to day 1 of study treatment.

In the run-in phase, 7 patients were enrolled. These patients received weekly intravenous anetumab ravtansine at 2.2mg/kg in combination with the standard dose of bevacizumab of 10 mg/kg every 2 weeks. Notably, all patients who received at least 1 dose of anetumab ravtansine and at least 1 dose of bevacizumab were evaluable for dose-limiting toxicities (DLTs) during the safety run-in phase, and safety data from these patients were analyzed along with all enrolled patients. These patients were included in the overall efficacy analysis but not in the primary randomization analysis.

In the phase 2 portion, between October 12, 2018, and November 14, 2022, 57 patients were randomly assigned 1:1 to receive biweekly bevacizumab at 10 mg/kg in combination with either weekly anetumab ravtansine at 2.2 mg/kg (n = 28) or weekly paclitaxel at 80 mg/m2 (n = 29) in 28-day cycles until disease progression, withdrawal of consent, or unacceptable toxicity. Patients were stratified by platinum resistance status (resistant vs refractory) and prior bevacizumab use in the frontline or platinum-sensitive setting (yes vs no).

PFS served as the primary end point. Secondary end points included ORR, safety, pharmacokinetics, and blood-based angioma biomarker assessment.

Safety Run-In Findings

In the safety run-in phase, no DLT was observed, and the combination of anetumab ravtansine plus bevacizumab at the tested dose levels was deemed safe. Patients received a median of 10 cycles (1-25) of the combination. Best responses included partial response (PR; n = 4) and stable disease (SD; n = 2); 1 patient was not evaluable for response. The most common grade 1/2 treatment-related adverse effects (TRAEs) included dry eyes and arthralgia (n = 5 each) and fatigue (n = 4).

Additional Phase 2 Findings

Among all screened patients in the phase 2 portion, 88% were mesothelin positive. A total of 42% of patients had received prior bevacizumab, and 23% of patients were platinum refractory.

The ORR was 21% in the anetumab ravtansine arm, including 1 complete response (CR) and 5 PRs; the disease control rate (DCR) was 71%. In the paclitaxel arm, the ORR was 66%; no patients achieved CR in this arm, but 19 PRs were observed, and the DCR was 86%.

Subgroup analyses did not show statistically significant PFS differences based on platinum-refractory status in each arm. In the anetumab ravtansine and paclitaxel arms, respectively, the median PFS for platinum-refractory patients was 5.1 months (1.6-6.0) and 13.6 months (5.1-not reached [NR]).

Among the 12 patients in each arm who had received prior bevacizumab, the median PFS in the anetumab ravtansine and paclitaxel arms, respectively, was 3.7 months (1.6-7.4) and 19.7 months (3.5-NR; HR, 7.68 [1.64-35.93]; P = .003). Among the patients in these respective arms who had not received prior bevacizumab (n = 33), the median PFS was 5.4 months (3.8-10.8) and 9.6 months (7.2-16.3; HR, 1.29 [0.58-2.87]; P = .53).

Of the 15 patients in each respective arm who had received prior PARP inhibitors, the median PFS was 5.2 months (1.5-6.2) and 16.3 months (7.5-19.7; P < .001). Among the patients who had not received prior PARP inhibitors, the median PFS was 5.5 months (1.7-20.5) and 7.4 months (3.2-16.4), respectively (P = .86).

Safety Data

In the phase 2 portion, the most common any-grade TRAEs in the anetumab ravtansine arm included elevated AST levels (86%), elevated alanine aminotransferase (ALT) levels (71%), fatigue and thrombocytopenia (64%), and peripheral neuropathy (50%). In the paclitaxel arm, the most common any-grade TRAEs were anemia (79%), neutropenia (69%), fatigue (55%), and peripheral neuropathy (48%).

Grade 3 or higher AEs included anemia (anetumab ravtansine arm, 18%; paclitaxel arm, 10%), neutropenia (4%; 24%), lymphopenia (4%; 10%), thrombocytopenia (4%; 0%), febrile neutropenia (4%; 3%), elevated aspartate aminotransferase levels (14%; 7%), elevated ALT levels (4%; 3%), weight loss (4%; 0%), intestinal stoma site bleeding (4%; 0%), fatigue (4%; 14%), peripheral neuropathy (11%; 10%), hypertension (14%; 7%), infusion-related reaction (4%; 0%), blurred/decreased vision (4%; 0%), early corneal microcysts (4%; 0%), dry eye (4%; 0%), and eye floaters (4%; 0%).

In the anetumab ravtansine and paclitaxel arms, respectively, patients received a median of 4 (1-31) and 8 (1-19) cycles of study treatment. Dose reductions were required by 1% and 20% of patients, respectively. Treatment discontinuations due to AEs occurred in 4 (1-31) and 3 (1-19) patients, respectively.

Pharmacokinetic Findings

Pharmacokinetic analyses were conducted in 16 patients. The mean ± standard deviation concentration vs time profile of anetumab ravtansine, ADC, total antibody, DM4, and DM4-Me ranged from 0 to 168 hours. Anetumab ravtansine ADC reached peak level at approximately the end of infusion, with a mean of 1.5 hours, and was detectable for a maximum of 168 hours in most patients.

The mean half-lives of anetumab ravtansine, total antibody, and DM4 were 61.8 hours, 87.6 hours, and 46.1 hours, respectively. The mean anetumab ravtansine clearance and distribution volume were 0.03 L/h and 2.62 L, respectively. After normalization to molar concentration, the mean ± standard deviation ratio of DM4 to anetumab ravtansine at an area under the curve (AUC)0-168h was 0.009 ± 0.003, and the mean ± standard deviation ratio of DM4-Me to DM4 at AUC0-168h was 1.61 ± 0.65.

Investigators observed a positive association between total body weight and anetumab ravtansine AUC0-inf in all patients (P = .012). This association was found to be mainly driven by the positive relationship between total body weight and anetumab ravtansine AUC0-inf in patients weighing less than 80 kg (P = .013). A positive association was also observed between total body weight and DM4 AUC0-168h (P < .001), which was mainly driven by the positive association in patients weighing at least 80 kg. Furthermore, a positive association was noted between total body weight and the ratio of DM4 to anetumab ravtansine AUC0-168h in all patients (P < .038). Additionally, the ratio of DM4 to anetumab ravtansine AUC0-168h was higher in patients weighing at least 80 kg, at 0.010 ± 0.003, vs patients weighing less than 80 kg, at 0.008 ± 0.002. However, these ratios were not statistically different (P = .032).

Investigators also did not see a significant association between PFS and anetumab ravtansine exposure, such as anetumab ravtansine AUC0-inf (P = 1.0) or DM4 AUC0-168h (P = .26). A non–statistically significant (P = .12) relationship was observed between anetumab ravtansine AUC0-inf and best response, with higher anetumab ravtansine AUC0-inf exposures seen in patients with PR (6648.4 mg/L x h ± 1572.9 mg/L x h) vs those with SD (5375.7 mg/L x h ± 1130.5 mg/L x h) or progressive disease (PD; 4562.8 mg/L x h ± 649.7 mg/L x h). Additionally, patients who achieved a PR had a higher DM4 AUC0-168h (0.285 mg/L x h ± 0.074 mg/L x h) vs those with SD (0.182 mg/L x h ± 0.052 mg/L x h) or PD (0.240 mg/L x h ± 0.012 mg/L x h; P = .02).

“Based on pharmacokinetic results from our study, anetumab ravtansine shared some similarities in pharmacokinetic disposition with other ADC drugs, such as slow clearance, long elimination half-life, and low percentage of DM4 released from anetumab ravtansine,” the authors noted.

Blood-Based Biomarker Profiling Data

At baseline in the intention-to-treat population (n = 55), 4 markers were shown to correlate with PFS on the Cox proportion hazard model for their log2 values, demonstrating that higher baseline plasma levels were associated with worse PFS. These markers were interleukin-6 (IL-6; HR, 1.34; 95% CI, 1.02-1.75; P = .03), VEGF (HR, 1.29; 95% CI, 1.03-1.63; P = .03), PDGF-AA (HR, 1.15; 95% CI, 1-1.32; P = .049), and TGF-b1 1.33 (HR, 1.33; 95% CI, 1.01-1.76; P = .049). Furthermore, baseline PIGF levels were higher in patients who had received prior bevacizumab (mean ± standard deviation, 4.35 ± 0.55) vs those who had not (mean ± standard deviation, 3.99 ± 0.42; P = .014).

An assessment of the levels of different blood angioma marker changes induced by each treatment arm between baseline and cycle 2 day 1, lower mean plasma ratios were observed in the anetumab ravtansine arm vs the paclitaxel arm for VEGFR2 (mean ± standard deviation, –0.46 ± 0.23 vs 0.08 ± 0.35; P < .001), ANG-2 (mean ± standard deviation, –0.91 ± 0.44 vs –0.63 ± 0.48; P < .04), and VEGFR3 (mean ± standard deviation, –0.85 ± 0.28 vs 0.45 ± 0.36; P < .001). Conversely, lower mean plasma level ratios were seen in the paclitaxel arm vs the anetumab ravtansine arm for HGF (mean ± standard deviation, –0.23 ± 1.41 vs 0.58 ± 1.06; P < .032), IL-6 (mean ± standard deviation, –0.1 ± 0.26 vs 0.14 ± 0.15; P < .001), VCAM (mean ± standard deviation, 0.24 ± 0.5 vs 1.04 ± 0.42; P < .001), ICAM (mean ± standard deviation, –0.06 ± 0.43 vs 0.28 ± 0.3; P < .004), and TSP2 (mean ± standard deviation, –0.18 ± 0.38 vs 0.53 ± 0.57; P < .001).

Limitations and Next Steps

The authors noted that limitations of this trial included a lack of somatic molecular profiling, and the fact that the study was terminated early and thus enrolled fewer patients than required by the power analysis. This indicates that the sample size could be underpowered for subsequent hypothesis testing.

“Although this is a negative study, it supports the clinical benefit of weekly paclitaxel/bevacizumab in this population,” the authors concluded. “In addition, our study has produced data that suggests that IL-6 is a potential negative prognostic marker for high-grade ovarian cancer, and its higher baseline levels may predict a better response to bevacizumab; this observation requires further investigation. Despite the outcome of the anetumab ravtansine arm, mesothelin may be a reasonable antigen target for ADC development in high-grade ovarian cancer and continues to be an active area of research to enhance ADC activity with new generations and potential combinations.”

References

1. Alqaisi HA, Cohn DE, Chern JY, et al. Randomized phase II study of bevacizumab with weekly anetumab ravtansine or weekly paclitaxel in platinum-resistant/refractory high grade ovarian cancer (NCI trial). Clin Cancer Res. Published online January 21, 2025. doi:10.1158/1078-0432.CCR-24-3128
2. Quanz M, Hagemann UB, Zitzmann-Kolbe S, et al. Anetumab ravtansine inhibits tumor growth and shows additive effect in combination with targeted agents and chemotherapy in mesothelin-expressing human ovarian cancer models. Oncotarget. 2018;9(75):34103-34121. doi:10.18632/oncotarget.26135
3. Hassan R, Blumenschein GR Jr, Moore KN, et al. First-in-human, multicenter, phase I dose-escalation and expansion study of anti-mesothelin antibody-drug conjugate anetumab ravtansine in advanced or metastatic solid tumors. J Clin Oncol. 2020;38(16):1824-1835. doi:10.1200/JCO.19.02085