Adding Bevacizumab to Pembrolizumab Enhances Response Rates in Epithelial Ovarian Cancer

Adding Bevacizumab to Pembrolizumab Enhances Response Rates in Epithelial Ovarian Cancer

Patients with platinum-resistant epithelial ovarian cancer experienced elevated responses to pembrolizumab (Keytruda) following the addition of a short-term, flat dose of bevacizumab (Avastin) to the anti–PD-1 therapy, according to results from the phase 1 PEMBOV trial (NCT03596281) that were presented during the 2021 SITC Annual Meeting.¹

Results from the study showed that among the 19 patients enrolled, the combination yielded an overall response rate (ORR) of 26%; this was comprised of 1 complete response (CR; 5%) and 4 partial responses (PRs; 21%). Additionally, the disease control rate (DCR) with the doublet was 79%.

For patients with platinum-resistant ovarian cancer, there is an unmet medical need for more efficacious treatment options.

Previously, the phase 3 AURELIA trial (NCT00976911) examined the combination of chemotherapy and bevacizumab in platinum-resistant patients who were bevacizumab naïve and had received a maximum of 2 prior treatment regimens. Results showed that the median progression-free survival (PFS) was 3.4 months in those treated with chemotherapy vs 6.7 months in those who received the combination. Moreover, the ORRs reported in each group were 11.8% and 27.3%, respectively.²

Bevacizumab monotherapy has been shown to induce a median PFS of 4.4 months and an ORR of 15.9% in this patient population.³ Anti–PD-1/PD-L1 monotherapies have been shown to elicit ORRs ranging from 3.7% to 15.0%, and a median PFS ranging from 1.9 months to 3.5 months. The addition of chemotherapy to these agents appears to slightly improve outcomes, with ORRs ranging from 13.3% to 23.0%, and a median PFS ranging from 3.7 months to 8.1 months.^4-8

Prior phase 2 trials have also examined the combination of anti­–PD-L1 therapy and PARP inhibitors, a regimen that has been shown to elicit an ORR of 14.0% and a median PFS of 3.9 months,⁹ as well as anti­–PD-L1 therapy, PARP inhibition, and bevacizumab, a triplet which yielded an ORR of 28.0% and a median PFS of 4.1 months.¹⁰

Additionally, phase 1b/2 trials have previously examined pembrolizumab in combination with bevacizumab and chemotherapy. When pembrolizumab and bevacizumab were paired with pegylated liposomal doxorubicin (PLD), the regimen yielded an ORR of 32.0%.¹¹ When the 2 agents were combined with cyclophosphamide, the regimen induced an ORR of 43.3% and a median PFS of 7.6 months.¹²

Prior phase 2 clinical trials have investigated the combination of an anti–PD-1 blockade plus an anti–CTLA-4 blockade. Results from these trials have showed that this approach can produce an ORR of 31.4% and a median PFS of 3.9 months.¹³

The PEMBOV study enrolled patients with platinum-resistant epithelial ovarian cancer. There was no limit to the number of previous treatments patients could have received, and prior treatment with bevacizumab was permitted.

The study was comprised of 2 cohorts. Patients in cohort A received pembrolizumab plus PLD, and those in cohort B were given pembrolizumab plus bevacizumab. Here, investigators reported data from cohort B of the study.¹⁴

Patients enrolled to cohort B received 200 mg of pembrolizumab once every 3 weeks until disease progression, unacceptable toxicity, or withdrawal of consent, and 400 mg of bevacizumab every 3 weeks for 6 cycles.

The primary end point of the study was best overall response (BOR) per RECIST v1.1 criteria, and duration of response (DOR). Secondary end points included safety and tolerability, and key exploratory objectives were to examine PD-L1 status and the pharmacokinetics of bevacizumab.

Among the 19 patients enrolled, the median age was 70 years (range, 38-76), and most had an ECOG performance status of 0 (52.6%) with the ovary as their primary tumor location (79%). Additionally, most patients had serous high-grade disease (95%) and had received prior antiangiogenic therapy (68%). Sixteen percent of patients had a BRCA mutation, and 47% had received prior treatment with PARP inhibitors. Moreover, 95% of patients had received 2 or more prior chemotherapy regimens.

The median follow-up time was 7.6 months (95% CI, 6.7-19.5), with a minimum of 2.9 months and a maximum of 29.0 months. Time to progression (TTP) was not reached for 26.0% of patients (n = 5/19), and 42.0% of patients (n= 8/18) had a TTP that was 24 weeks or more.

For patients who had a PD-L1 combined positive score (CPS) of 10% or higher (n = 4), the ORR with the regimen was 50%; this was comprised of 2 PRs, and 1 patient had stable disease. Among those with a PD-L1 CPS of 1% or higher (n = 10), the ORR was 30%, which was comprised of 3 PRs and 4 patients achieved stable disease. For patients with a PD-L1 CPS of 1% or lower (n = 8), the ORR was 25%, and this was comprised of 1 CR, 1 PR, and 6 patients with stable disease.

In terms of safety, grade 3/4 treatment-related adverse effects (TRAEs) were reported in 20% of patients. The most common grade 3/4 TRAEs were cerebral ischemia (5%), sepsis (5%), bowel proliferation (5%), and proteinuria (5%).

No new safety signals were observed on the study, and correlative studies are ongoing.

References

1. Michels J, Frenel J-S, Genestie C, et al. Pembrolizumab and bevacizumab in platinum resistant epithelial ovarian cancer patients. Presented at: 2021 SITC Annual Meeting; November 10-14, 2021; Washington DC. Abstract 355.
2. Pujade-Lauraine E, Hilpert F, Weber B, et al. Bevacizumab combined with chemotherapy for platinum-resistant recurrent ovarian cancer: the AURELIA open-label randomized phase III trial. J Clin Oncol. 2014;32(13):1302-1308. doi:10.1200/JCO.2013.51.4489
3. Cannistra SA, Matulonis UA, Penson RT, et al. Phase II study of bevacizumab in patients with platinum-resistant ovarian cancer or peritoneal serous cancer. J Clin Oncol. 2007;25(33):5180-6. doi:10.1200/JCO.2007.12.0782
4. Hamanishi J, Mandai M, Ikeda T, et al. Safety and antitumor activity of anti-PD-1 antibody, nivolumab, in patients with platinum-resistant ovarian cancer. J Clin Oncol. 2015;33(34):4015-4022. doi:10.1200/JCO.2015.62.3397
5. Disis ML, Taylor MH, Kelly K, et al. Efficacy and safety of avelumab for patients with recurrent or refractory ovarian cancer: phase 1b results from the JAVELIN solid tumor trial. JAMA Oncol. 2019;5(3):393-401. doi:10.1001/jamaoncol.2018.6258
6. Matulonis UA, Shapira-Frommer R, Santin AD, et al. Antitumor activity and safety of pembrolizumab in patients with advanced recurrent ovarian cancer: results from the phase II KEYNOTE-100 study. Ann Oncol. 2019;30(7):1080-1087. doi:10.1093/annonc/mdz135
7. Pujade-Lauraine E, Fujiwarab K, Ledermannc JA, et al. Avelumab alone or in combination with pegylated liposomal doxorubicin versus pegylated liposomal doxorubicin alone in platinum-resistant or refractory epithelial ovarian cancer: Primary and biomarker analysis of the phase III JAVELIN Ovarian 200 trial. Presented at: 50th Annual Meeting of the Society of Gynecologic Oncology; March 16-19, 2019. Honolulu, HI.
8. Lee EK, Xiong N, Cheng S-C, et al. Combined pembrolizumab and pegylated liposomal doxorubicin in platinum resistant ovarian cancer: a phase 2 clinical trial. Gynecol Oncol. 2020;159(1):72-78. doi:10.1016/j.ygyno.2020.07.028
9. Lampert EJ, Zimmer A, Padget M, et al. Combination of PARP inhibitor olaparib, and PD-L1 inhibitor durvalumab, in recurrent ovarian cancer: a proof-of-concept phase II study. Clin Cancer Res. 2020;26(16):4268-4279. doi:10.1158/1078-0432.CCR-20-0056
10. Freyer G, Floquet A, Tredan O, et al. 733P Bevacizumab (bev), olaparib (ola) and durvalumab (durva) in patients with recurrent advanced ovarian cancer (AOC): the GINECO BOLD study. Ann Oncol. 2021;32(5):S734-S735. Doi:10.1016/j.annonc.2021.08.1176
11. Michels J, Ghiringhelli F, Frenel J-S, et al. Pembrolizumab in combination with bevacizumab and pegylated liposomal doxorubicin in patients with platinum-resistant epithelial ovarian cancer. J Clin Oncol. 2021;39(15):5522. Doi:10.1200/JCO.2021.39.15_suppl.5522
12. Zsiros E, Lynam S, Attwood K, et al. Efficacy and safety of pembrolizumab in combination with bevacizumab and oral metronomic cyclophosphamide in the treatment of recurrent ovarian cancer: a phase 2 nonrandomized clinical trial. JAMA Oncol. 2021;7(1):78-85. Doi:10.1001/jamaoncol.2020.5945
13. Zamarin D, Burger RA, Sill MW, et al. Randomized phase II trial of nivolumab versus nivolumab and ipilimumab for recurrent or persistent ovarian cancer: an NRG oncology study. J Clin Oncol. 2020;38(16):1814-1823. Doi:10.1200/JCO.19.02059
14. Pembrolizumab in combination with bevacizumab and pegylated liposomal doxorubicin in patients with ovarian cancer (PEMBOV). ClinicalTrials.gov. Updated July 22, 2021. Accessed November 17, 2021. https://clinicaltrials.gov/ct2/show/NCT03596281

This article was originally published on OncLive as “Addition of Bevacizumab to Pembrolizumab Improves Responses in Epithelial Ovarian Cancer.”