Gynecologic Oncologists Continue to Pursue Novel Agents, Immunotherapy in Ovarian Cancer

Caroline Billingsley, MD

The ovarian cancer armamentarium continues to evolve with novel agents, such as antibody-drug conjugates (ADCs) and immunotherapy, even with clinical trial findings showing mixed, yet intriguing, results with these classes of agents.

In a presentation during the 2020 Institutional Perspectives in Cancer webinar on Ovarian Cancer, Caroline Billingsley, MD, an assistant professor of obstetrics and gynecology at the University of Cincinnati Cancer Center, spoke to established and emerging treatment modalities in ovarian cancer and the successes and pitfalls of key clinical trials of ADCs and immunotherapy in this space.

Mirvetuximab Soravtansine Leads in Drug Development as Potential Novel ADC

ADCs have become a frontrunner in terms of novel therapeutic developments in oncology, Billingsley adds.

“ADCs have a really favorable pharmacokinetic feature in which they have specific tumor-targeting properties of an antibody, as well as this potent cancer-killing effect of the payload, all of which, in theory, are selected to the cancer cell and harmless to normal cells,” explained Billingsley.

However, ADCs require a targetable antigen, Billingsley said. “[Folate receptor alpha (FRα)] is a molecular target of interest in ovarian cancer. It is highly restrictive in normal tissues, and absent from normal ovarian epithelium. This differential distribution pattern makes FRα a good candidate for an antibody-drug conjugate”

Moreover, over 80% of ovarian epithelial cells express FRα to some degree on immunohistochemistry (IHC) or imaging with radiolabeled conjugates.

Mirvetuximab soravtansine is an investigational ADC that targets FRα-positive cancer cells. The toxic payload, tubulin-disrupting maytansinoid DM4 chemotherapy, is delivered directly into the tumor cell, leading to cell death.

The phase 1b/2 FORWARD II trial evaluated the combination of mirvetuximab soravtansine and bevacizumab (Avastin) in patients with platinum-resistant ovarian cancer.¹

The trial enrolled patients with platinum-resistant epithelial ovarian, fallopian tube, or primary peritoneal cancer and FRα positivity of 50% or greater by IHC. Additionally, prior bevacizumab was permitted.

Patients received 6 mg/kg of mirvetuximab soravtansine, adjusted to their ideal body weight, and 15 mg/kg of bevacizumab, once every 3 weeks. Adverse effects (AEs), tumor response, and progression-free survival (PFS) were evaluated.

Overall, 66 patients were treated with the full-dose regimen during the escalation and expansion portions of the trial. These patients had a median of 3 prior lines of therapy (range, 1-8).

The confirmed objective response rate (ORR) was 39% with the combination (95% CI, 28%-52%). Twenty-six patients derived a tumor response with the combination, including 5 complete responses (CRs) and 21 partial responses (PRs).

The median duration of response (DOR) was 8.6 months (95% CI, 4.9-14.9). Moreover, the median PFS was 6.9 months (95% CI, 4.9-8.6).

The combination elicited increased activity in patients who were bevacizumab naïve, had received 1 or 2 prior lines of therapy, and whose tumors exhibited medium or high FRα expression (n = 16). In this subset of patients, which correlated with the target patient population of the AURELIA trial, the ORR was 56% (95% CI, 30%-80%), with a 12-month median DOR (95% CI, 6.0-14.9). The median PFS was 9.9 months in these patients (95% CI, 4.1-15.9).

Regarding safety, AEs were typically grade 2 or less. Common treatment-related AEs (TRAEs) included diarrhea, blurred vision, nausea, and fatigue. Additionally, 6 cases of grade 1/2 pneumonitis were reported.

Grade 3 AEs included diarrhea (n = 1), blurred vision (n = 1), nausea (n = 1), fatigue (n = 1), thrombocytopenia (n = 3), dry eye (n = 1), hypertension (n = 9), aspartate aminotransferase increase (n = 4), alanine aminotransferase increase (n = 3), vomiting (n = 1), and epistaxis (n = 2).

Serious AEs were observed in 42% of patients and included small intestinal obstruction (n = 4), diarrhea (n = 3), and gastrointestinal hemorrhage (n = 3).

“With the caveats of [having few patients in the AURELIA-like subgroup analysis] and doing cross-trial comparison, [these data] suggest that the combination of mirvetuximab soravtansine and bevacizumab may have similar efficacy to bevacizumab and paclitaxel in a similar patient population, but with a different safety profile,” said Billingsley. “Mirvetuximab soravtansine and bevacizumab doesn’t have the issue of neuropathy and causes negligible alopecia.”

During the 2020 ASCO Virtual Scientific Program, findings from the expansion cohort (n = 60) of the FORWARD II trial demonstrated an ORR of 43% (95% CI, 31%-57%) with mirvetuximab soravtansine plus bevacizumab in patients with medium or high FRα–expressing platinum-agnostic ovarian cancer.²

In patients with high FRα expression, the ORR was 61% (95% CI, 42%-77%). Notably, the ORR was at least 50% in platinum-resistant and platinum-sensitive patients within this subgroup. The DOR and PFS data remain immature at a median follow-up of 5.5 months.

Immunotherapy Introduces a New Modality, But Is Met With Challenges

Single-Agent Immunotherapy

As single agents, PD-1/PD-L1 inhibitors have demonstrated some activity in platinum-resistant ovarian cancer, regardless of PD-L1 expression.

For example, pembrolizumab (Keytruda) elicited an 11.5% ORR, with 1 CR and 2 PRs, at a median follow-up of 15.4 months in the KEYNOTE-028 trial.³ The study tested the agent in 26 women with PD-L1–positive advanced ovarian cancer.

Additionally, avelumab (Bavencio) has demonstrated similar response rates in patients with recurrent or refractory ovarian cancer, as shown in the phase 1b JAVELIN Solid Tumor trial.⁴ Among 125 patients treated with the agent, the ORR was 9.6%, with 1 CR.

“Immunotherapy in the recurrent setting has essentially looked at single-agent PD-1/PD-L1 inhibitors,” said Billingsley. “Given the modest activity of PD-1/PD-L1 inhibitors in ovarian carcinoma, combination trials of PD-1/PD-L1 antibodies with chemotherapy, antiangiogeneic agents, and targeted agents are important. Those are being developed and/or have been reported.”

Combination Immunotherapy Approaches

Armed with the knowledge that immunotherapy has a role in ovarian cancer treatment, combination strategies have become a leading research effort in the space.

However, the field received a setback when the combination of pegylated liposomal doxorubicin (PLD) and avelumab missed the primary end points of improved overall survival (OS) and PFS versus PLD alone in patients with platinum-resistant or refractory ovarian cancer in the phase 3 JAVELIN Ovarian 200 trial.⁵

Although combination chemoimmunotherapy missed the mark, preclinical models suggested that immunotherapy could have synergistic activity with PARP inhibitors, irrespective of homologous recombination deficiency (HRD) status or BRCA mutational status. As such, pembrolizumab in combination with the PARP inhibitor niraparib (Zejula) showed promising antitumor activity in patients with recurrent, platinum-ineligible ovarian cancer in the single-arm phase 1/2 TOPACIO trial.⁶

Patients enrolled in the study (n = 60) had received a median of 3 prior lines of therapy, 63% of which had received prior bevacizumab. Additionally, 79% of patients had BRCA wild-type disease and 53% were HRD negative.

An integrated efficacy analysis of phases 1 and 2 of the TOPACIO trial showed similar ORRs for all biomarker-identified populations. Overall, the ORR was 18% (95% CI, 11%-29%), with a disease control rate of 65% (95% CI, 54%-75%). Moreover, 3 patients achieved CRs, 8 achieved PRs, and 28 had stable disease.

A subgroup analysis of the baseline patient characteristics, including PD-L1, did not reveal specific driving markers of clinical activity.

Regarding survival, the median PFS was 3.4 months with the combination (95% CI, 2.1-5.1). The estimated 6- and 12-month PFS rates were 31% and 12%, respectively. The OS data are not yet mature.

The most common grade 3 or higher TRAEs were anemia (21%) and thrombocytopenia (9%).

Immunotherapy-Based Trials Continue Despite Clinical Setbacks

In December 2018, the phase 3 JAVELIN Ovarian 100 trial was stopped early after an independent panel determined the study would not meet its primary end point.⁷ The study was evaluating 3 arms: carboplatin/paclitaxel; carboplatin/paclitaxel with maintenance avelumab; or avelumab plus carboplatin/paclitaxel followed by maintenance avelumab in patients with locally advanced or metastatic ovarian cancer.

At a planned interim analysis, an independent data monitoring panel determined that neither of the 2 avelumab arms would demonstrate a PFS benefit over the control arm of chemotherapy alone. Similarly, the phase 3 IMagyn050 trial missed its primary end point of improved PFS with the addition of atezolizumab (Tecentriq) to bevacizumab, paclitaxel, and carboplatin as first-line treatment for women with newly diagnosed, advanced ovarian cancer.⁸

However, the pivotal phase 3 ATHENA trial, evaluating the safety and efficacy of rucaparib (Rubraca) in combination with nivolumab (Opdivo) as maintenance therapy following response to frontline platinum-based chemotherapy in patients with advanced disease, looks promising.⁹ The trial met its target enrollment of approximately 1000 patients.

The 4-arm study will randomize patients to receive rucaparib plus nivolumab (n = 400), rucaparib plus placebo (n = 400), placebo plus nivolumab (n = 100), or placebo plus placebo (n = 100). Investigator-assessed PFS in molecularly-defined HRD subgroups will serve as the primary end point of the study, with secondary end points including PFS by blinded independent central review in molecularly defined HRD subgroups, ORR and DOR in patients with measurable disease, OS, and safety.

In conclusion, Billingsley pointed to other clinical trials evaluating immunotherapy plus PARP inhibitors in the ovarian cancer space, including the ENGOT-ov44/FIRST (NCT03602859) and ENGOT-ov46/DUO-O (NCT03737643) trials, which are currently ongoing.

References:

1. O’Malley DM, Matulonis UA, Birrer MJ, et al. Phase Ib study of mirvetuximab soravtansine, a folate receptor alpha (FRα)-targeting antibody-drug conjugate (ADC), in combination with bevacizumab in patients with platinum-resistant ovarian cancer. Gynecol Oncol. 2020;157(2):379-385. doi:10.1016/j.ygyno.2020.01.037
2. Gilbert L, Oaknin A, Matulonis UA, et al. Mirvetuximab soravtansine, a folate receptor alpha (FRα)-targeting antibody-drug conjugate (ADC), in combination with bevacizumab in patients (pts) with platinum-agnostic ovarian cancer. J Clin Oncol. 2020;38(suppl 15):6004. doi:10.1200/JCO.2020.38.15_suppl.6004
3. Varga A, Piha-Paul S, Ott PA, et al. Pembrolizumab in patients with programmed death ligand 1–positive advanced ovarian cancer: analysis of KEYNOTE-028. Gynecol Oncol. 2019;152(2):243-250. doi:10.1016/j.ygyno.2018.11.017
4. Disis ML, Taylor MH, Kelly K. Efficacy and safety of avelumab for patients with recurrent or refractory ovarian cancer. JAMA Oncol. 2019;5(3):393-401. doi:10.1001/jamaoncol.2018.6258
5. Merck KGaA, Darmstadt, Germany, and Pfizer provide update on avelumab in platinum-resistant/refractory ovarian cancer. Merck KGaA and Pfizer. November 19, 2018. Accessed September 30, 2020. https://bit.ly/2PGGzPB.
6. Konstantinopoulos PA, Waggoner S, Vidal GA. Single-arm phases 1 and 2 trial of niraparib in combination with pembrolizumab in patients with recurrent platinum-resistant ovarian carcinoma. JAMA Oncol. 2019;5(8):1141-1149. doi:10.1001/jamaoncol.2019.1048 7. Merck KGAA, Darmstadt, Germany, and Pfizer provide update on JAVELIN Ovarian 100 Trial of avelumab in previously untreated advanced ovarian cancer. News Release. Published December 21, 2018. https://bit.ly/3kUl2hk
7. Roche provides update on phase III study of Tecentriq in women with advanced stage ovarian cancer. News release. Roche. July 13, 2020. Accessed September 30, 2020. bit.ly/2CsVGpV.
8. A study in ovarian cancer patients evaluating rucaparib and nivolumab as maintenance treatment following response to front-line platinum-based chemotherapy (ATHENA). clinicaltrials.gov. Updated August 2, 2019. Accessed September 30, 2020. https://clinicaltrials.gov/ct2/show/NCT03522246.