Westin Highlights Key Clinical Trial Updates from ASCO 2023 in Ovarian Cancer and Gynecologic Oncology

Results from the phase 3 KEYNOTE-826 trial (NCT03635567), SHAPE trial (NCT01658930), and phase 3 MIRASOL trial (NCT04209855) presented at the 2023 ASCO Annual Meeting highlighted a wealth of new data emerging in the gynecologic oncology space, according to Shannon N. Westin, MD, MPH, FACOG.

“The gynecologic oral session [featured] exciting results of the [phase 3] DUO-O trial [NCT03737643], which is a randomized trial in ovarian cancer looking [durvalumab plus chemotherapy and bevacizumab] in the frontline. We saw extended survival results from KEYNOTE-826 in cervical cancer, and so many [other] positive trials. The 2023 ASCO Annual Meeting [was] very exciting,” Westin said in an interview with OncLive® News Network: On Location during the meeting.

In the interview, Westin, director of the Early Drug Development and Phase I Trials Department, and a professor in the Department of Gynecologic Oncology and Reproductive Medicine of the Division of Surgery at The University of Texas MD Anderson Cancer Center, in Houston, expanded on key clinical trial updates in gynecologic oncology shared at the 2023 ASCO Annual Meeting and highlighted what she is looking forward to seeing in the future of care for patients with gynecologic malignancies.

OncLive: SHAPE evaluated the use of radical hysterectomy vs simple hysterectomy and pelvic node dissection in patients with low-risk, early-stage cervical cancer.¹ Can you highlight the potential role for surgical de-escalation in this population?

A lot of times, patients with cervical cancer are young and have issues where they would like to spare their fertility or spare their ovaries. Therefore, [when] doing radical surgery on these patients, they often live for a long time later, and they could have sexual dysfunction, urinary dysfunction, or bowel dysfunction. Therefore, taking a step back and doing less surgery with a less-is-more approach is exciting.

The SHAPE trial follows other trials that have demonstrated the potential for less radical surgery. The bottom line for all these trials is that we need to be careful with our selection, making sure that we're not going into larger or deeply invasive tumors, and that we’re sticking with the stage IA/B or IIA, smaller tumors to ensure that we have good outcomes.

SHAPE showed that a simple hysterectomy was not inferior to a radical hysterectomy in terms of recurrence rates. Recurrence rates contribute to survival. They were exciting data, and it's also great to have multiple studies that confirm that same thing, therefore we know we're doing right by our patients, and we're not harming them by doing less.

We saw the results of the phase 3 KEYNOTE-826 and RUBY (NCT03981796) trials in cervical and endometrial cancer, respectively.^2,3 Can you highlight how these studies have shown the benefit of incorporating checkpoint inhibition into frontline therapy?

These are both well-designed, large, randomized phase 3 trials. KEYNOTE-826 [included] patients with either advanced or recurrent cervical cancer. For a long [time], the standard of care has been chemotherapy, and then we added bevacizumab [Avastin]. With these additions, we've seen an incremental benefit in overall survival [OS], as well as progression-free survival [PFS].

KEYNOTE-826 took the next step, looking at the addition of checkpoint inhibition to this patient population, specifically with pembrolizumab [Keytruda]. They found in the intent-to-treat [ITT] population and specifically in the PD-L1–positive population that the addition of pembrolizumab allowed for improved PFS and OS.

These were the final OS events that were presented. This is important, because there [have been some questions] on [whether] we should use all [these agents] at once. Should we use all our good drugs up-front, or should we be more measured [by] sticking with chemotherapy and bevacizumab, and then turn to a checkpoint inhibitor in the second line and beyond? I always [tell people] to say that out loud. Are you going to tell a patient we're going to wait for her [disease] to recur [to give a checkpoint inhibitor]? It's hard to say. However, the bottom line is that many of these patients went on to receive a checkpoint [inhibitor] in the second line, and the OS benefit was found in the group that got a checkpoint [inhibitor up-front]. These were definitive, practice-confirming results. This is absolutely the standard of care.

RUBY was in [patients with] advanced or recurrent endometrial cancer, and [the trial] allowed patients who had received prior chemotherapy at least 12 months [prior to enrollment]. Patients were randomly assigned to either chemotherapy with paclitaxel and carboplatin, with or without the addition of the PD-1 inhibitor dostarlimab-gxly [Jemperli]. Investigators [previously presented their exciting results around improvement in PFS both in the mismatch repair–deficient [dMMR] group and the benefit in the all-comers, ITT groups. We are getting an idea that, irrespective of [dMMR status], we may see benefit. We still need to see OS, so there is more to be heard here.

What was presented at the 2023 ASCO Annual Meeting was the blinded independent central review [BICR]. Our investigators did as good of a job at identifying who was truly progressing [compared with] a BICR of the radiology. That was very confirmatory.

More importantly, we saw quality-of-life data, which was great. We saw that the addition of dostarlimab did not negatively impact quality-of-life, and in later cycles of therapy, patients had improvement in some of their symptoms that are associated with disease progression, such as pain and fatigue. That's exciting because when we add new therapies, we always want to ensure we're not hurting patients. It does seem to confirm that the addition of [dostarlimab] is the right choice for this patient population.

The benefit of PARP inhibition has historically been limited to that homologous recombination–deficient (HRD) population. However, the results from DUO-O show that patients without BRCA mutations can potentially benefit from the incorporation of this agent into maintenance therapy.⁴ What are your thoughts on the results in the HRD and homologous recombination–proficient (HRP) populations?

This was a well-designed study at the time it was designed. However, we have had more information come in [during the study]. Therefore, we are left with question marks around [the study]. However, the bottom line is that this study was a positive study based on the way it was designed. What we saw is the addition of olaparib [Lynparza], durvalumab [Imfinzi], and bevacizumab [Avastin] to chemotherapy, provided PFS benefit in the population that was HRD without a BRCA mutation. It also demonstrated a benefit in the ITT population. Those were the two populations that were powered for planned a statistical analysis.

We did see a subset analysis in the HRP group, where we have an unmet need. We need to add more to what we have already shown. There was potentially a benefit there. The [PFS] curves were separating. However, we don't have statistical power to say if that's true. We don't know what the checkpoint inhibitor is adding to that triplet combination. This is very exciting, and we always love to see a positive study. However, it is hard to know how it's going to be incorporated. We need to see additional data from the manuscripts, and additional PFS and OS analyses to determine if this is going to change practice the way we're hoping it will.

We saw results of the MIRASOL trial.⁵ How did those data add to the results of the phase 3 SORAYA trial (NCT04296890)?

SORAYA had given us an accelerated approval [for mirvetuximab soravtansine-gynx (Elahere)], and MIRASOL was meant to be the confirmatory study. It met its primary end point. There were very exciting, consistent data, in this randomized study that compared mirvetuximab soravtansine to physician’s choice of chemotherapy. We saw an improvement in response with a 42% overall response rate [per investigator assessment] compared with a 16% response rate in the chemotherapy arm. There are strong data there.

PFS and OS were both positive. There was consistent reduction in the risk of progression and reduction in the risk of death from disease in this trial. Those are consistent data, and they should help us get that final approval of mirvetuximab. It is important to note that this [trial] was only in patients who had folate receptor α–positive in tumors, [which accounts] for about 30% of the population [of ovarian cancer]. Therefore, we still do have a large unmet need in platinum-resistant ovarian cancer, but we certainly made big strides. This is our first study to have an OS benefit in platinum-resistant ovarian cancer.

Notably, the results of RAMP 201 with avutometinib (VS-6766) with or without defactinib (VS-6063) in recurrent, low-grade ovarian cancer were also anticipated at the 2023 ASCO Annual Meeting.⁶ Can you tell us about the mechanism of action of these agents and the potential opportunity for synergy in this population?

Avutometinib is a RAF/MEK clamp; it hits 2 different members of the RAS/RAF pathway with the hope that it works better than just MEK [inhibition] alone. What we've seen with MEK inhibition and RAS pathway inhibition in general is that there are mechanisms of resistance and potentially FAK can overcome that. This combination is hoped to be revolutionary in patients with RAS-mutated ovarian tumors, and specifically what we are looking at is low-grade, serous ovarian cancer.

Early single-arm studies were intriguing, and we saw a lot of activity. RAMP 201 confirms that. We're seeing a [45% confirmed ORR], which is well over what we would expect from MEK [inhibition] alone; that's very exciting. Interestingly, there was activity both in RAS-mutant and RAS wild-type disease. There was higher activity with a 60% confirmed ORR in those patients with tumors that had a RAS mutation, and [29%] for the tumors that [were RAS wild-type]. Notably, [29%] is not a small amount of response, and we would anticipate that this would also yield progression PFS. These are intriguing data that we hope will move forward.

How do you think real-world data are going to influence thoughts surrounding the use of second-line maintenance niraparib (Zejula) following the restriction of the agent to the BRCA-mutated population?⁷

I don't know that real-world data are going to trump randomized clinical trial data. I don't know how much [these real-world findings] are going to impact [practice], and I certainly don't anticipate the regulatory authorities backing down or the company trying to reapply their drugs to a broader population.

However, the findings were interesting in this real-world population. There were not much data around HRD, so we don't know how many [patients] tested positive or negative. The majority hadn’t been tested or the results weren’t available for their analysis. Regardless, it did seem that there wasn't a detriment to OS in the patients who received niraparib as opposed to active surveillance. This was intriguing; it doesn't show a detriment. However, you never know with these real-world databases. How strong are the data that go in and how strong are the data coming out?

Also anticipated was a post-hoc analysis from the phase 3 PRIME trial (NCT03709316) of niraparib maintenance in patients with measurable residual disease.⁸ Do you think the results of this trial will help or hurt the case for routine measurable residual disease monitoring in clinical practice?

The PRIME trial was an Asian study that looked at up-front niraparibafter the completion of chemotherapy. This was a confirmatory trial, or a value-added trial to the [phase 3] PRIMA study [NCT02655016]. They initially found very similar results, and this was a subset analysis. [The term] MRD is tricky, because it [was not referring to] minimal residual disease, but rather to measurable residual disease [in this instance].

With measurable residual disease, they found responses to therapy more commonly in patients treated with niraparib, which makes sense because they were getting an active agent as opposed to placebo. That was across all the different molecular subtypes. Clearly, the drug has activity when there's measurable disease. We knew that in the recurrent setting. This basically confirms what we had already seen in that up-front trial.

Were there any other data that stood out at the 2023 ASCO Annual Meeting?

Some of the other data that I found intriguing are some of the subset analyses. A post-analysis of of the phase 3 PAOLA-1 trial [NCT02477644] in patients who had gotten bevacizumab [alone] or bevacizumab plus olaparib [looked at] what happened to them at the time of recurrence and the timing of the recurrence. I was excited about these data because we've always had a sense that patients that had a progression of disease while receiving a PARP inhibitor are going to be very different vs patients who progressed after a PARP inhibitor.

Investigators found that those patients who had progression on olaparib had worse subsequent response to chemotherapy and worse PFS to subsequent platinum-based chemotherapy. This is getting at sequencing and making sure we're making good decisions about what we give up-front and how that might impact what patients get later. I was intrigued by those data and look forward to seeing the full picture.

References

1. Plante M, Kwon J, Ferguson S, et al. An international randomized phase III trial comparing radical hysterectomy and pelvic node dissection vs simple hysterectomy and pelvic node dissection in patients with low-risk early-stage cervical cancer. J Clin Oncol. 2023;41(suppl 17):LBA5511. doi:10.1200/JCO.2023.41.17_suppl.LBA5511
2. Monk BJ, Colombo N, Tewari K, et al. Pembrolizumab + chemotherapy versus placebo + chemotherapy for persistent, recurrent, or metastatic cervical cancer: final overall survival results of KEYNOTE-826. J Clin Oncol. 2023;41(suppl 16):5500. doi:10.1200/JCO.2023.41.16_suppl.5500
3. Powell MA, Hietanen S, Coleman RL, et al. Dostarlimab for primary advanced or recurrent (A/R) endometrial cancer (EC): Outcomes by blinded independent central review (BICR) of the RUBY trial (ENGOT-EN6-NSGO/GOG-3031/RUBY). J Clin Oncol. 2023;41(suppl 16):5503. doi:10.1200/JCO.2023.41.16_suppl.5503
4. Harter P, Trillsch F, Okamoto A, et al. Durvalumab with paclitaxel/carboplatin (PC) and bevacizumab (bev), followed by maintenance durvalumab, bev, and olaparib in patients (pts) with newly diagnosed advanced ovarian cancer (AOC) without a tumor BRCA1/2 mutation (non-tBRCAm): Results from the randomized, placebo (pbo)-controlled phase III DUO-O trial. J Clin Oncol. 2023;41(suppl 17):LBA5506. doi:10.1200/JCO.2023.41.17_suppl.LBA5506
5. Moore KN, Angelergues A, Konecny GE, et al. Phase III MIRASOL (GOG 3045/ENGOT-ov55) study: mirvetuximab soravtansine vs. investigator’s choice of chemotherapy in platinum-resistant, advanced high-grade epithelial ovarian, primary peritoneal or fallopian tube cancers with high folate receptor-alpha (FRα) expression. J Clin Oncol. 2023;41(suppl 17):LBA5507.
6. 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
7. Coleman RL, Perhanidis J, Kalilani L, et al. Real-world overall survival in second-line maintenance niraparib monotherapy vs active surveillance in BRCA wild-type patients with recurrent ovarian cancer. J Clin Oncol. 2023;41(suppl 16):5592. doi:10.1200/JCO.2023.41.16_suppl.5592
8. Kong B, Wu L, Zhu J, et al. Efficacy and safety of niraparib maintenance therapy in patients with newly diagnosed advanced ovarian cancer who had measurable residual disease: A post-hoc subgroup analysis of the PRIME study. J Clin Oncol. 2023;41(16):5562.