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Gyn Advances: Latest Evidence
Recent Advances in the Management of Gynecologic Cancers: Experts Share Their Thoughts on the Latest Clinical Evidence

Released: August 06, 2021

Expiration: August 05, 2022

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In this commentary, Linda R. Duska, MD, MPH, and Robert L. Coleman, MD, FACOG, FACS, share their thoughts on the latest clinical evidence for gynecologic cancer, including new data presented at the 2021 annual meetings of the Society of Gynecologic Oncology (SGO) and the American Society of Clinical Oncology (ASCO).

Endometrial Cancer

Linda R. Duska, MD, MPH:
In endometrial cancer, the largest change in therapy in the past couple of years has emerged from the concept of the molecular classification of endometrial cancer, as well as the remarkable response rates seen with checkpoint inhibitors in women with microsatellite instability-high (MSI-H)/mismatch repair deficient (dMMR) tumors. For example, the ongoing multicohort phase II KEYNOTE‑158 trial evaluating pembrolizumab in patients with advanced solid tumors who had progressed on standard therapy reported an overall response rate (ORR) of 57% and a median progression-free survival (PFS) of 25.7 months (n = 49) in the endometrial cancer subset.

At the 2021 ASCO annual meeting, updated results were presented from the phase I GARNET trial confirming activity of the PD‑1 inhibitor dostarlimab in patients with endometrial cancer. With the caveat that these are early data, an ORR of 44.7% and disease control rate of 57.3% in 103 patients with dMMR endometrial cancer, classified as both advanced and recurrent, are quite remarkable. By contrast, in mismatch repair proficient (pMMR) tumors, the ORR was 13%. Dr. Coleman, why do you think the response rate in patients with pMMR tumors was 13% when it has been much lower with the other PD-1 and PD-L1 inhibitors?

Robert L. Coleman, MD, FACOG, FACS:
It’s true that response rates were much lower than what we have seen in the dMMR population, and that’s reflected in the tail of the PFS curves, as well. I suspect that there are as-yet-unidentified variables within the tumor microenvironment that result in these response differences; we do not yet understand everything about this disease, and there may be more to the story than the PD-L1 axis. These results are changing the treatment landscape for endometrial cancer, and I hope that the newer protocols may eventually be able to replace chemotherapy.

Linda R. Duska, MD, MPH:
I agree. Also, I have noted that responses to dostarlimab and pembrolizumab are generally durable, and these drugs are very well tolerated, especially with the new every-6-weeks dosing with pembrolizumab as a result of the COVID-19 pandemic. With high response rates and relatively low toxicity, the characteristics of these agents are ideal for patients with MSI-H/dMMR disease. But what about patients with pMMR disease?

I think results from the phase Ib/II KEYNOTE‑146 study are key and demonstrated that we can make the “cold” tumor “hot,” immunologically, by adding lenvatinib to pembrolizumab. In KEYNOTE-146, the addition of lenvatinib to pembrolizumab in patients with endometrial cancer who had been treated with ≤2 previous lines of therapy and were MSI‑H and microsatellite instability-low (MSI-L) yielded an ORR of 36% in patients with MSI‑L/pMMR tumors (n = 94) and 64% in patients with MSI-H/dMMR tumors (n = 11). The confirmatory phase III KEYNOTE‑775 study was presented at SGO 2021 and demonstrated remarkable results with the same combination following platinum-based therapy in patients with advanced endometrial cancer (N = 827). In KEYNOTE-775, we saw significantly improved median PFS (6.6 vs 3.8 months; HR: 0.60; P <.0001) and median overall survival (OS) (17.4 vs 12.0 months; HR: 0.68; P <.0001) with lenvatinib plus pembrolizumab vs chemotherapy in patients with pMMR disease. In addition, we saw a long median duration of response of 14.4 months compared with chemotherapy. The next logical step in the treatment evolution in endometrial cancer is to move immunotherapy into the frontline setting, which already is being assessed in multiple randomized trials.

Robert L. Coleman, MD, FACOG, FACS:
The results reported in KEYNOTE-146 and especially KEYNOTE-775 are like a triple win, right? In the latter trial, ORR, PFS, and OS, as well as the duration of response were all improved compared with chemotherapy—a remarkable accomplishment. Dr. Duska, after the FDA granted accelerated approval for lenvatinib and pembrolizumab, we started using it in the clinic, and it has now received regular FDA approval. I am curious about what your experience has been integrating it into the treatment paradigm.

Linda R. Duska, MD, MPH:
Our experience was similar to other clinics in that this can be a highly toxic regimen that requires extensive patient support and education about potential adverse events (AEs). This necessitates training nurses to support patients on this regimen, because otherwise patients are likely to stop treatment early despite any outstanding results from clinical trials.

For a patient who is very robust with a good performance status—and whom I think not only will be able to tolerate the AEs, but also will call me when she’s having trouble so that we can dose modify as needed—I would start at the FDA-recommended dose for lenvatinib of 20 mg. However, I live in a rural community with poor access to care, and many of my patients are not robust. Many have had prior radiation, already have diarrhea and hypertension, do not get regular medical care, and may have a poor performance status. They are, essentially, frail. In those patients, I am hesitant to start at the FDA-approved dose of lenvatinib because I am concerned that once they have significant AEs, they will never be able to restart the drug. In that patient, I might choose a lower starting dose of approximately 14 mg and then titrate up. If a patient cannot tolerate lenvatinib at all, I will sometimes just drop the lenvatinib and continue pembrolizumab as a single agent. The response rate will not be particularly high, but it is a well-tolerated drug by itself, and other options are more toxic and less effective.

Other physicians have found that a low threshold for dose reduction also works well. In either case, physicians and nurses—and patients—need to be highly mindful of debilitating fatigue, diarrhea, and hypertension. The hypertension that I have seen with lenvatinib was surprising, given my experience with other antiangiogenic therapies (eg, bevacizumab). It can become severe and can be difficult to treat. This emphasizes the importance of setting expectations for patients so they can stay on treatment for multiple courses.

Ovarian Cancer

Linda R. Duska, MD, MPH:
Let’s spend some time discussing ovarian cancer. Dr. Coleman, what do you consider the most exciting developments for women with ovarian cancer?

Robert L. Coleman, MD, FACOG, FACS:

Over the past 2 decades, incidence and mortality rates for ovarian cancer have slowly and steadily declined, but almost in parallel, so that the relative difference between them has not changed substantially. However, the disease prevalence, which is the number of women who have ovarian cancer at any one time, has increased to more than 230,000 in the United States alone. This is more than 10 times the incidence rate. Thus, the FDA no longer considers ovarian cancer an orphan disease. This shows that treatment is getting better over time, including personalized treatment.

Multiple phase III trials continue to advance the role of PARP inhibitors in ovarian cancer, most prominently SOLO1 (frontline olaparib), PRIMA (niraparib in higher-risk patients), PAOLA-1 (olaparib plus bevacizumab), and VELIA (veliparib plus chemotherapy). Each of these trials met its primary endpoint of PFS, and subsequently olaparib, niraparib, and olaparib/bevacizumab all have been FDA approved in ovarian cancer. Dr. Duska, how do you determine which PARP inhibitor to use in any specific situation?

Linda R. Duska, MD, MPH:
I typically use olaparib because that is the one we started using first and the one with which my clinic is most comfortable. I also would mention that each PARP inhibitor has different processes to get it approved and paid for each patient; part of why we often use olaparib is that my clinic is familiar with all the paperwork required.

We encountered some initial challenges with niraparib before dosing was adjusted for patient weight and platelet count—from 300 mg orally daily to 200 mg if <77 kg or baseline platelets <150,000/µL. Those types of experiences can influence later treatment choices. That said, I think the PARP inhibitors are all relatively equivalent in this setting, and I don’t feel strongly about recommending one over another.

Dr. Coleman, what is your opinion on using dostarlimab, bevacizumab, and niraparib at the same time, as in the ongoing phase II OPAL trial? Obviously, using 3 drugs increases toxicity and cost compared with using them sequentially. Do we have convincing data that this is worth it?

Robert L. Coleman, MD, FACOG, FACS:
This is an important question because these agents are available to us, yet how to use them optimally wasn’t clear from the studies. Looking back at the phase II MEDIOLA study, using the PARP inhibitor olaparib in combination with bevacizumab and the immune checkpoint inhibitor durvalumab seemed to be more effective as a triplet—certainly in platinum‑sensitive ovarian cancer—than as a doublet with durvalumab and no bevacizumab. I think this is an evolving story, and it is not yet clear what role the immune checkpoint inhibitors play in this tumor, though I still think combining a PARP inhibitor with an immune checkpoint inhibitor is an important strategy to formally study.

But what about this triplet makes it unique? How do we sort out the individual contribution of the 3 agents, each of which is active within these patient populations? Which combinations are more important than the others? Are there doublets that are more important than the triplet? Ultimately, the question is how to determine the true impact of a triplet‑based therapy in patients with ovarian cancer. We have a good predictive biomarker for PARP inhibitors, but not for either angiogenesis inhibition or immune checkpoint inhibitors in ovarian cancer.

Linda R. Duska, MD, MPH:
Dr. Coleman, in your clinic, when you use maintenance therapy as upfront treatment for women with ovarian cancer, what agents do you choose and why?

Robert L. Coleman, MD, FACOG, FACS:
For me, the question of maintenance therapy starts with the prior therapy. Based on results from ICON7 and GOG 218, I often use bevacizumab concomitantly with chemotherapy unless the patient is not a good candidate. For patients who do receive bevacizumab, I typically conduct homologous recombination-deficiency testing (HRD) to determine which patients are HRD positive and might benefit from the addition of olaparib to bevacizumab. For patients with a negative HRD test, I will keep them on bevacizumab maintenance only.

Cervical Cancer

Linda R. Duska, MD, MPH:
In the setting of cervical cancer, it was hoped that the phase III OUTBACK trial would show a survival benefit for adjuvant chemotherapy following chemoradiation. However, data presented at ASCO 2021 indicated that adjuvant chemotherapy for locally advanced cervical cancer after cisplatin-based chemoradiation did not improve OS or PFS and increased toxicity in this setting. In my clinical experience, I have found it very difficult to convince this group of women to get chemotherapy after finishing primary chemoradiation, in part due to significant financial toxicity and socioeconomic issues.

I am intrigued about moving immunotherapy into frontline treatment of patients with cervical cancer, and I am suggesting trial participation to my patients, but I also am unsure that this is the right way to go with this cancer. Dr. Coleman, what are your thoughts?

Robert L. Coleman, MD, FACOG, FACS:
Clearly, pembrolizumab has some activity in tumors who are PD‑L1 positive, so it may be suitable in the setting of cervical cancer. But, to your point, pembrolizumab is of interest not only concomitantly with chemoradiotherapy, but also as a primary maintenance strategy. I applaud you for supporting the clinical trials to try to address these very important questions.

In other settings, it is common to test for dMMR and MSI-H status, but in cervical cancer the occurrence of dMMR and MSI-H is so infrequent that we don’t routinely conduct these tests. That said, MSI testing in ovarian cancer is becoming more common; it’s possible that some of the patients in the tails of the survival curves had MSI-H tumors. MSI-H occurs in approximately 3% to 4% of patients with ovarian cancer, but I don’t typically look for it in patients with cervical cancer.

Linda R. Duska, MD, MPH:
I also don’t conduct those tests in patients with cervical cancer. But that brings up another question: Dr. Coleman, in your opinion, should all women with endometrial cancer have next-generation sequencing at the time of first recurrence?

Robert L. Coleman, MD, FACOG, FACS:
Yes. We routinely do this in our clinic, and it helps identify patients for clinical trials. But to be honest, few predictive mutations have been identified in this setting. We do see HER2 gene amplification and alteration, other rare mutations (eg, ALK or NTRK fusions and alterations), and PI3K. Based on randomized phase II data, we are using trastuzumab with carboplatin and paclitaxel for advanced or recurrent uterine papillary serous carcinomas. The molecular classification of endometrial cancer will continue to help us personalize therapy for these tumors.

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