In an interview with CancerNetwork, Don Dizon, MD, FACP, FASCO, discusses key updates that read out in both the gynecologic oncology and breast cancer fields over the course of 2021.
Although the year 2021 has come and gone, CancerNetwork® is reflecting back on key updates that took place within the women’s cancer space following an interview with Don S. Dizon, MD, FACP, FASCO.
Breakthroughs of interest he cited include updates for immunotherapeutic combinations such as regimens containing pembrolizumab (Keytruda) in both advanced cervical cancer and triple-negative breast cancer (TNBC), long-term findings with PARP inhibitors in ovarian cancer, and the emergence of CDK 4/6 inhibitors for patients with high-risk early breast cancer. Additionally, he highlighted what’s to come in 2022.
“There's going to be some important work that’s going to launch [in 2022], as well as work that’s going to report,” Dizon said. “We are seeing this explosion of newer ways to harness treatments based on biological clues. We’re going to start to see a better understanding of how to personalize treatments in another way. [Whether] everybody needs a 4-drug combination with pembrolizumab is an important question for the TNBC space, [for example].
“Also, in patients with residual disease after they [receive] neoadjuvant chemotherapy for breast cancer, what is the most appropriate way to [treat them] if they have a BRCA mutation? If they have PD-L1 positivity, if they have a mismatch repair [deficiency], we need to start exploring that. We’re likely going to see some results on personalizing therapy more in ovarian cancer beyond just BRCA.”
In the final instillation in our 4-part series on 2021 updates within the oncology space, Dizon, an oncologist and director of women's cancers at Lifespan Cancer Institute, director of medical oncology at Rhode Island Hospital, and professor of medicine at the Warren Alpert Medical School of Brown University, also highlighted a number of FDA approvals for breast cancer and gynecologic malignancies.
Don’t forget to check out part 1 of the series where Yael Cohen, MD, highlighted milestones in multiple myeloma; part 2 in which Matthew Davids, MD, discussed findings in chronic lymphocytic leukemia that read out in 2021; and part 3, in which Amy Comander, MD, shared her thoughts on breast cancer developments that took place last year.
Could you start off by speaking to the findings of the phase 3 KEYNOTE-826 trial (NCT03635567)?
KEYNOTE-826 was a trial that was performed in advanced or metastatic cervical cancer.1 The importance is to understand that the current standard of care calls for the use of chemotherapy in combination [with] a platinum and a taxane alongside the angiogenic inhibitor, bevacizumab [Avastin]. That treatment has to continue in perpetuity as long as the patient is benefiting and tolerating treatment. In reality, it’s very difficult to commit someone to lifelong therapy with a 3-drug combination, especially when the survival advantages, although present, are quite modest—about a 6-month improvement compared with not using bevacizumab.
KEYNOTE-826 builds on that current standard and asks the question of how much of a contribution does the checkpoint inhibitor pembrolizumab make. In this trial, there was over 500 [patients] who were randomly assigned to chemotherapy with or without pembrolizumab and, importantly, the use of bevacizumab was considered optional. But at the end of the day, the results were striking. There were improvements in PFS [progression-free survival] of about 2 to 3 months and an improvement in overall survival [OS] such that at 2 years, over half of the patients treated with pembrolizumab were alive versus a bit over 40%. When you look at the groups, specifically, the contribution to the survival advantage was also seen in those patients who received bevacizumab, as well.
We have now established that chemotherapy, with or without bevacizumab plus pembrolizumab, produces substantial and clinically significant survival advantages and commits people, not to lifelong chemotherapy, but to a finite number of cycles, after which they can proceed with maintenance pembrolizumab. The quality-of-life advantage of that last part is huge.
This research led to the FDA approval of pembrolizumab and chemotherapy plus or minus bevacizumab for patients with persistent, recurrent, or metastatic cervical cancer in October 2021. How has this regulatory decision affected this patient population?
Coming into KEYNOTE-826, we had the approval of pembrolizumab as a single agent after chemotherapy. I should also note that the only restriction towards use of pembrolizumab is that those tumors have to express PD-L1. Having said that, we are now moving pembrolizumab out from the second line to the first-line treatment space in advanced recurrent or metastatic disease. That leaves that it open and [raises] more questions; for example, can you reuse pembrolizumab after prior treatment in the frontline setting? There are also other drugs in the space, other checkpoint inhibitors like cemiplimab, which showed activity after chemotherapy. This does prompt the question of whether successive checkpoint inhibitor treatments are effective. This is going to come on the heels of ongoing clinical trials looking at the incorporation of checkpoint inhibitors in the definitive chemoradiation space for people who are newly diagnosed. It [also] brings up questions of sequencing [and] the most appropriate time to use these checkpoint inhibitors. While we’re expanding the advantage of its use, we have to question [whether we are] limiting the use of checkpoint inhibitors later on?
Pivoting to the breast cancer space, we also saw updates with pembrolizumab and chemotherapy for patients with TNBC. What did we learn from the phase 3 KEYNOTE-522 study (NCT03036488)?
For [patients] with TNBC, we do know that immunotherapy has activity. This has been one of the exciting places in breast oncology because we’ve had this increase in options for these [patients], from those who have a mutation in BRCA to those who have the PD-L1 marker that indicates checkpoint inhibitors will be effective.
Prior to KEYNOTE-522, there was an approval of a different checkpoint inhibitor in the treatment of metastatic disease and some other indications that it was also effective in this primary treatment space. KEYNOTE-522 comes in and is a clinical trial [for the neoadjuvant] paradigm.2 It tested the role of pembrolizumab when given with chemotherapy for patients presenting with a new diagnosis of TNBC. The randomization was chemotherapy alone vs chemotherapy plus pembrolizumab. In this study, which included over 600 [patients], results favored the use of pembrolizumab, both [in terms of] improvements in pathologic complete response rates, but also in survival outcomes, including progression as well as death.
Could you speak to the approval that this research led to?
[The KEYNOTE-522 regimen was FDA approved] because of the survival advantages. The backbone that was used in this trial was a complicated one. Typically, before this trial, when we we’re using chemotherapy alone, the standards would have been to use an anthracycline/taxane backbone and then take people to surgery. There has always been some debate on the role of platinum in TNBC, and what KEYNOTE-522 used as a backbone was a combination. [Patients] got carboplatin with paclitaxel followed by epirubicin and cyclophosphamide as the backbone chemotherapy. [The regimen] used all our known active agents in the neoadjuvant context [and] pembrolizumab throughout. It does change the paradigm for neoadjuvant therapy for [patients] with TNBC. It commits them to a longer course of chemotherapy prior to surgery to start, and that has been practice changing.
In the ovarian cancer space, the phase 3 SOLO-1 trial (NCT01844986) had some of the longest duration of follow up that we’ve seen with a PARP inhibitor for patients with newly diagnosed advanced disease. What were your thoughts on those findings?
SOLO-1 established the role of the PARP inhibitor olaparib [Lynparza] as maintenance therapy following chemotherapy for people with BRCA mutation–associated ovarian cancers, completing first line chemotherapy.3 All of the patients in SOLO-1 had either a high-grade serous or endometrioid cancer with a known mutation in BRCA, underwent surgery, underwent chemotherapy, and then were randomly assigned to olaparib or placebo. When the results were first presented in 2018, it was an incredible 3-year OS that significantly favored the use of olaparib with a hazard ratio of 0.3. But if you looked at the estimates, 3-year progression-free survival was 60% versus 24%. Over half of patients had not relapsed at 3 years with the use of olaparib.
That’s significant because, [for] people with advanced ovarian cancer—as with the ones who participated in SOLO-1—the risk of relapse is in the first 3 years, so [it’s] quite significant. Now, we have these results that were published in The Lancet Oncology, which extends the follow up periods to 5 years. What was published was that these benefits are durable; the hazard ratio stayed around 0.3, median survival was at 56 months, so very close to 5 years, with use of olaparib. With the use of placebo, it was [about] 14 months which is traditionally what we would expect. I have a feeling they have not been able to report OS because there haven’t been enough deaths with olaparib. If anything, I think this does more than confirm that olaparib must be used after chemotherapy for patients presenting with stage III or IV ovarian cancer associated with a BRCA mutation.
What developments in PARP inhibitors might we see in the ovarian space in 2022?
There are still these ongoing clinical trials looking, in the adjuvant context, at whether or not there’s an additive advantage with the use of checkpoint inhibitors and PARP inhibitors. We are still awaiting some important clinical trial results looking at a nonchemotherapy combination and its use in platinum-resistant or platinum-sensitive ovarian cancers. There are still a lot of questions [as to] how to maximize the use of PARP inhibitors. There was one trial that was presented at ESMO [European Society for Medical Oncology Congress] this year called the [phase 3b] OReO trial [NCT03106987], which is seeking to answer the question of [whether] there is a benefit to reusing a PARP inhibitor after someone has progressed on maintenance PARP inhibitors.4 Again, these are some questions that we will get answers to as we come into this new year that are also important to figure out.
I should just put a plug in that at Brown University, we are looking at the same population of people with a BRCA mutation who are presenting with advanced disease or may not be the best candidates for a primary surgical procedure. We are offering them the PARP inhibitor talazoparib [Talzenna] for 9 weeks prior to surgery as a means of providing nonchemotherapy neoadjuvant treatment. This is enrolling at Brown. This also is a question of [whether] we can hold off on platinum-based therapy in the newly diagnosed space. It’s an important question to answer.
CDK 4/6 inhibitors emerged into the adjuvant treatment landscape for patients with high-risk early breast cancer last year. How did the phase 3 monarchE trial (NCT03155997) trial pave the way for this?
Coming into 2021, CDK4/6 inhibitors have been shown time and time again to be important agents for the treatment of hormone receptor [HR]–positive metastatic breast cancer. This is a well-established standard of care, at least for people with metastatic HR-positive disease. MonarchE asks the question of the benefit of treatment with CDK4/6 inhibitors and the adjuvant context for HR-positive disease. In that clinical trial, it showed again there was an advantage to using that for people at high risk of relapse in either multiple node–positive disease, very large tumors, or both.
They stood to benefit from the use of abemaciclib [Verzenio] with both invasive disease-free survival [DFS] advantages and distant DFS advantages. This, like the checkpoint inhibitor trials in gynecologic malignancies, takes a drug that’s well established in the metastatic space and is moving it up to the adjuvant treatment space. Whether or not these DFS advantages will translate to an OS advantage is important to ask. Particularly, we’re going to use it adjuvantly. But for patients who are worried about their risk of relapse due to large tumor size or nodes or even biological factors like high K-i67, this does provide the option of helping them remain disease free, which I do think is important in its own right.