Oncologists Explore Treatment Options in LGSOC, Look Toward Promising Future

Shannon N. Westin, MD, MPH, FACOG

Although there are no FDA-approved treatments specifically indicated for low-grade serous ovarian cancer (LGSOC), therapeutic options for these patients are rapidly expanding, with promising new therapies progressing through clinical development, according to a discussion from expert oncologists in the field during an OncLive News Network program, “Expert Perspectives on Diagnosis, Management, and Emerging Therapies in Low-Grade Serous Ovarian Cancer.”

In the frontline setting, treatment options for patients with LGSOC include paclitaxel/carboplatin plus maintenance hormone therapy, hormone therapy, such as aromatase inhibitors or tamoxifen, clinical trial enrollment, and observation. Choosing the proper course of treatment for a given patient requires careful consideration of disease stage, attributes, and patient characteristics from clinicians.

“Early stage LGSOC does not [usually] require treatment, it’s something that can be potentially observed after surgery—many patients with stage I disease go on to not require further therapies,” Shannon N. Westin, MD, MPH, FACOG, clinical medical director, director of early drug development, and a professor in the Department of Gynecologic Oncology and Reproductive Medicine, Division of Surgery at The University of Texas MD Anderson Cancer Center in Houston, said during the program. “More commonly, we see patients at stage III or IV, more advanced stage disease. For those patients, we’ll be looking across a number of options. The traditional standard of care has been chemotherapy. [However], as we’ve learned about LGSOG and how it differs from high-grade [disease], there are data to tell us that LGSOC may respond better to hormonal therapies. [Although] paclitaxel and carboplatin remain the standard of care, there’s growing use of a drug called letrozole in this setting.”

In 2017, investigators published findings from a single-center study conducted at The University of Texas MD Anderson Cancer Center that compared the outcomes of patients with stage II to IV LGSOC who were treated with hormonal maintenance therapy vs observation after primary cytoreductive surgery and platinum-based chemotherapy. Among patients who were treated with hormonal therapy (n = 70), 54.3% received letrozole. Other hormonal therapies included anastrozole (2.9%), tamoxifen (28.6%), leuprolide acetate (7.1%), leuprolide acetate with either letrozole (2.9%) or tamoxifen (2.9%), and depot medroxyprogesterone acetate (1.4%).¹

At a median follow-up of 70.8 months, patients who received hormonal therapy experienced a median progression-free survival of 64.9 months (95% CI, 43.5-86.3) compared with 26.4 months (95% CI, 21.8-31.0) in the observational cohort (P < .001); however, there was no significant improvement in overall survival (OS), with patients experiencing a median value of 115.7 months vs 102.7 months, respectively (P = .42). Findings from a subgroup analysis showed that among patients who were disease free following chemotherapy, the median PFS was 81.1 months (95% CI, 54.9-107.2) vs 30.0 months (95% CI, 24.9-35.1), respectively.

These positive findings and data from other studies helped lead to the initiation of the phase 3 NRG-GY019 trial (NCT04095364). The study compares the safety and efficacy of letrozole monotherapy with those of intravenous paclitaxel/carboplatin plus maintenance letrozole in patients with primary stage II to IV LGSOC. The primary end point is PFS; secondary end points include safety, objective response rate (ORR), OS, and duration of response. Notably, the trial is 1 of the first studies performed in women with primary advanced LGSOC.²

For patients with recurrent LGSOC, current treatment options include MEK inhibitors, BRAF inhibitors, hormonal therapy, combination therapy, and chemotherapy.

Premal H. Thaker, MD, MS

“The landscape for recurrent LGSOC is rapidly changing, considering that we just discovered that this is a separate histology in 2004,” Premal H. Thaker, MD, MS, the David G. and Lynn Mutch Professor of Obstetrics and Gynecology and the director of gynecological oncology clinical research in the Division of Gynecologic Oncology at Washington University School of Medicine in St Louis, Missouri, said during the program. “We’ve been able to move from just standard of care chemotherapy that we used to offer patients with recurrent LGSOC to hormonal treatments and now precision medicine.”

An example of a targeted therapy that has been making waves in the recurrent space is the MEK inhibitor trametinib (Mekinist). In the phase 2/3 GOG281/LOGS trial (NCT02101788), trametinib was compared with standard-of-care chemotherapy in patients with recurrent LGSOC following receipt of at least 1 platinum-based regimen. Findings from the study demonstrated that the median PFS in the investigational (n = 130) and control (n = 130) arms was 13 months (95% CI, 9.9-15) vs 7.2 months (95% CI, 5.6-9.9), respectively (HR, 0.48; 95% CI, 0.36-0.64; P < .0001). The study authors concluded that trametinib could represent a new standard of care option for patients with recurrent LGSOC.³

Moreover, during the 2023 ASCO Annual Meeting, investigators presented findings from the phase 2 ENGOT-ov60/GOG-3052/RAMP201 study (NCT04625270), which examined the first-in-class RAF/MEK inhibitor avutometinib with or without defactinib for the treatment of patients with recurrent LGSOC. The study enrolled a total of 33 patients in the monotherapy arm, including patients with KRAS-mutated (n = 16) and wild-type (n = 17) disease, and 31 patients in the combination arm, including 16 with KRAS-mutated disease and 15 patients who were KRAS wild-type. The primary end point was ORR.⁴

Data from the trial demonstrated that the confirmed ORRs in the combination and monotherapy arms were 45% (95% CI, 26%-64%) and 10% (95% CI, 2%-24%), respectively. Moreover, patients with KRAS-mutated disease experienced an ORR of 60% and those with KRAS wild-type disease had an ORR of 29% in the combination arm; these rates were 13% and 6%, respectively, in the monotherapy arm. Study authors concluded that the key objectives of part A of the study had been achieved and that the combination of avutometinib and defactinib displayed exceptionally high response rates in heavily pretreated patients with LGSOC.

David M. O'Malley, MD

“RAMP201 is 1 of the more exciting trials which we’ve seen data for,” David M. O'Malley, MD, a professor in the Department of Obstetrics and Gynecology at The Ohio State University College of Medicine and director of the Division of Gynecologic Oncology at The Ohio State University Comprehensive Cancer Center–James in Columbus, said during the program. “It was interesting that we saw a clinical benefit in both cohorts. When you look at the waterfall plots [in the combination arm], it’s fairly amazing. Almost all patients, approximately 85% to 90%, had tumor regression. [However], the efficacy of these agents does come at a price. Many of these toxicities are grade 1 or 2 but can be challenging in the long term. The wonderful thing is that we do get long-term responses from these agents. [Approximately] 20% to 30% of patients will require dose reductions. The discontinuation rate was 12% in the latest report. Very interestingly, 4.9% were due to creatine phosphokinase [CPK)] elevations, which we don’t think has clinical relevance. As we learn more about this toxicity, we hopefully can eliminate the discontinuation rate or minimize the discontinuation rate from CPK [elevation].”

There are also other ongoing studies evaluating combination, checkpoint inhibitor, and immunotherapeutic approaches in recurrent LGSOC. For example, in the phase 2 PERCEPTION trial (NCT04575961), the PD-1 inhibitor pembrolizumab (Keytruda) in combination with chemotherapy is being evaluated in patients with platinum-sensitive recurrent LGSOC.5

References

1. Gershenson DM, Bodurka DC, Coleman RL, et al. Hormonal maintenance therapy for women with low-grade serous cancer of the ovary or peritoneum. J Clin Oncol. 2017;35(10):1103-1111. doi:10.1200/JCO.2016.71.0632
2. Fader AN, Gien LT, Miller A, et al. A randomized phase III, two-arm trial of paclitaxel, carboplatin, and maintenance letrozole versus letrozole monotherapy in patients with stage II-IV, primary low-grade serous carcinoma of the ovary or peritoneum. J Clin Oncol. 2021;39(suppl 15):TPS5601. doi:10.1200/JCO.2021.39.15_suppl.TPS5601
3. Gershenson DM, Miller A, Brady WE, et al. Trametinib versus standard of care in patients with recurrent low-grade serous ovarian cancer (GOG 281/LOGS): an international, randomised, open-label, multicentre, phase 2/3 trial. Lancet. 2022;399(10324):541-553. doi:10.1016/S0140-6736(21)02175-9
4. Banerjee SN, Ring KL, Nieuwenhuysen EV, et al. Initial efficacy and safety results from ENGOT-ov60/GOG-3052/RAMP 201: a phase 2 study of avutometinib (VS-6766) ± defactinib in recurrent low-grade serous ovarian cancer (LGSOC). J Clin Oncol. 2023;41(suppl 16):5515. doi:10.1200/JCO.2023.41.16_suppl.5515
5. Grabowski JP, Pietzke LJ, Zocholl D, et al. PERCEPTION: phase II investigational study of pembrolizumab combination with chemotherapy in platinum-sensitive recurrent low-grade serous ovarian cancer— A NOGGO trial. J Clin Oncol. 2022;40(suppl 16):TPS5613. doi:10.1200/JCO.2022.40.16_suppl.TPS5613