- Approximately 30% of patients with endometrial cancer have deficient mismatch repair (dMMR), and these patients have an intermediate prognosis compared with other endometrial cancer subtypes.
- dMMR can result from germline loss of MLH1, PMS2, MSH2, and MSH6 genes, as in Lynch syndrome, or can evolve epigenetically through protein expression in the tumor.
- Patients with dMMR endometrial cancer have shown greater response rates and duration of response with immune checkpoint inhibitors compared with patients with intact mismatch repair (MMR).
- Immune checkpoint inhibitors appear to be well tolerated by most patients. Treatment-related side effects may include fatigue, rash, itching, and gastrointestinal symptoms.
- To help increase access to immunotherapies, physicians can advocate for coverage and cost limits and, when applicable, call attention to the cost of these medications in their research.
An increased understanding of the molecular subtypes of endometrial cancer has led to an expansion of treatment options for patients suffering from this condition. For those with dMMR endometrial cancer, programmed cell death protein 1 (PD-1) checkpoint inhibitors have proven especially effective in improving response rates and duration of response, compared with patients with mismatch repair proficient (MMRp) tumors.
Rebecca A. Brooks, MD, is the division director and fellowship director in the Division of Gynecologic Oncology at the University of California, Davis, School of Medicine in Sacramento, California. Dr Brooks provides medical and surgical treatment for the full range of gynecologic cancers, with special interest in radical pelvic surgery, upper abdominal debulking, and robotic surgery, and her areas of research focus include mechanisms associated with metastases in endometrial cancer and topics related to medical education. Dr Brooks discusses the role of these novel therapies in the treatment of recurrent or advanced dMMR endometrial cancer.
Can you review current clinical outcomes of patients with advanced endometrial cancer who are microsatellite instability-high (MSI-H) or have dMMR?
The Cancer Genome Atlas taught us many things about endometrial cancer and has shifted our understanding of endometrial cancer behavior and outcomes based on 4 distinct molecular subtypes. From this, we know that the polymerase epsilon (POLE)-mutated group often demonstrates excellent outcomes, while patients with TP53 mutations typically have the worst prognosis. Moreover, dMMR endometrial cancer is characterized by the loss of MMR proteins MLH1, PMS2, MSH2, or MSH6 and results in MSI.1
MMR can be deficient from either germline loss of these genes, as in Lynch syndrome, or evolve epigenetically through the protein expression in the tumor. Approximately 30% of patients with endometrial cancer have dMMR in their tumors, though only 2% have Lynch syndrome. Patients with dMMR have an intermediate prognosis compared to those with other subtypes.1
Other molecular features, such as lymphovascular space invasion (LVSI), grade, histology, depth of invasion, and stage, are typically incorporated into treatment decisions for these patients. LVSI is a known predictor of lymph node metastases and an increased risk for recurrence and has been shown to be more frequent in patients with dMMR endometrial cancer. We also know that patients with Lynch syndrome may demonstrate a slightly better prognosis, as measured by the progression-free interval, compared with those with epigenetic loss.1,2
While MSI is a single variable among patients with endometrial cancer, these patients also demonstrated significantly improved response rates and duration of response to immunotherapy and thus have more treatment options available.3
In a recent interim analysis of data from the GARNET trial (ClinicalTrials.gov identifier: NCT02715284), the objective response rate (ORR) associated with dostarlimab monotherapy was 43.5% (95% CI, 34%-53.4%) in patients with advanced or recurrent dMMR/MSI-H endometrial cancer, compared with 14.1% (95% CI, 9.1%-20.6%) in patients with MMRp/microsatellite stable (MSS) disease.4 How do these outcomes compare to your observations in practice with currently approved therapy?
These outcomes are very similar to what I see in my practice in patients treated with immunotherapy. Typically, I have seen response rates of approximately 40% for patients with dMMR and other candidates (based on tumor mutational burden [TMB] or PD-L1 expression) for whom immune checkpoint inhibitors are options. We do know that these patients have improved response rates and duration of response to this class of drugs compared with those who have intact MMR (MMRp/MSS).
I have also seen some really nice, sustained responses in patients with dMMR on immune checkpoint blockade therapy, especially in those with relatively small-volume disease or isolated nodal recurrences not amenable to resection or radiation. In general, these drugs seem to be very well tolerated.
Our institution has been performing universal testing for MMR deficiency of all patients for some time, but the evolution of immune checkpoint blockade in patients with endometrial cancer has increased other providers’ awareness of the importance of performing MMR or MSI testing, leading to increased incorporation of routine testing in the community.
For patients without dMMR, other treatment options would include lenvatinib and pembrolizumab; cytotoxic chemotherapy with options such as carboplatin and paclitaxel, doxorubicin, liposomal doxorubicin, or other drugs; combination treatment with everolimus and letrozole; and hormone-based therapy. These decisions are made on the basis of residual side effects from previous therapy, molecular testing results, hormone receptor status, and individual patient goals. I am pleased to see patients with deficient mismatch tumors because I typically have more treatment options for these patients.
What are the monitoring considerations for potential treatment-related adverse events with PD-1 checkpoint inhibitors, such as increased alanine aminotransferase or aspartate transaminase levels? What other side effects do you commonly observe in patients treated with these therapies?
I am very lucky to have some amazing chemotherapy pharmacists whom we closely partner with to optimize safety and outcomes for our patients on immune checkpoint blockade therapy as well as other drugs. Although we see some elevations in alanine aminotransferase or aspartate transaminase levels when monitoring lab abnormalities, I have seen more thyroid abnormalities and elevations in creatinine.
In my experience, most patients tolerate these drugs very well. The most common treatment-related side effects I have seen include some fatigue, dermatologic side effects such as rash or itching, and gastrointestinal side effects — mostly diarrhea.5 I have had several patients with colitis, which has required me to hold the drug or sometimes admit the patient for hydration and steroids. Nausea is also sometimes seen but is usually mild.
Luckily, pneumonitis is relatively rare, but I have also seen a few cases of pneumonitis, and it can sometimes be significant. For some patients, this has resulted in hospitalization, oxygen administration, and a prolonged steroid taper. But in general, the therapy seems to be well tolerated. I tend to counsel patients that most individuals on immune therapy do well with few side effects, but those side effects can sometimes be significant in patients who do experience them.
The American Society of Clinical Oncology (ASCO) and other societies have done a very nice job of outlining definitions and algorithms for toxicity management,6 which have made providers, including myself, comfortable handling side effects that evolve while patients are on immune checkpoint blockade treatment.
In a cost-effectiveness study, Dioun et al concluded that dostarlimab and pembrolizumab are associated with longer survival in endometrial cancer but are less cost-effective than pegylated liposomal doxorubicin. They also concluded that policy-level efforts are needed to reduce the cost of PD-1 inhibitors.7 In your opinion, what measures might be effective in moving toward this goal? If applicable, what other efforts are needed to increase accessibility of these therapies?
This is a hard question to answer. I have not had many problems getting these drugs approved for patients with dMMR or other appropriate candidates based on TMB or PD-L1 expression. The indications have been pretty clear, and the National Comprehensive Cancer Network (NCCN) has done a very nice job of quickly incorporating these drugs into the uterine cancer treatment guidelines.8
However, approval has been a problem for patients with emergency Medi-Cal who can receive treatment only in the hospital. I do worry that with the rising cost of these drugs, insurance companies may become more restrictive regarding what is covered or the duration of therapy we will be able to provide for patients who are benefiting from these drugs. Generics and biosimilar drugs may be ways of decreasing cost, but it takes time to incorporate these into practice as possible alternatives.
Physicians and patients advocating for coverage and caps in cost are other possible options, and we can also work to contain cost in other ways. I think physicians can continue to call attention to the cost of these drugs in their research endeavors as well. For example, evaluating the cost of combination therapy can result in policy changes and coverage for a drug if the dose changes. These are really important things for us to keep discussing and considering as a community.
Regarding dostarlimab, Dioun et al also stated that “little is known about how clinicians should integrate this promising agent into their treatment algorithms when the disease progresses in patients on platinum-based therapy.”7 What are key clinical considerations that will be taken into account should this particular therapy be approved? Are there specific subpopulations of those with dMMR endometrial carcinoma who would be ideal candidates?
I think we are — or at least should be — quick to incorporate immunotherapy options as treatment for patients who progress on platinum-based therapy. KEYNOTE-775 (ClinicalTrials.gov identifier: NCT03517449) showed us that outcomes were better with a combination of PD-1-directed therapy (pembrolizumab) and multitargeted tyrosine kinase inhibition (lenvatinib) compared with standard chemotherapy after platinum-based therapy.9 For patients who are candidates based on dMMR, TMB, or PD-L1 expression, many oncologists — myself included — quickly move to immune checkpoint blockade therapy next. I have found this to be an effective treatment strategy, especially in patients who have relatively small-volume disease, such as nodal involvement, for which radiation or surgery is not an option.
Although we are routinely testing all patients for MMR at diagnosis, we are also sending more and more patients’ tumors for molecular testing early, especially for patients we think are high risk, and work is being done to find other predictors of who may respond to immunotherapy. When I am considering patients as candidates for immune therapy, I also might try to make sure any related overlapping comorbidities that may place them at higher risk are addressed before starting therapy. For example, if patients have uncontrolled thyroid disease or dermatologic conditions that might pose a toxicity challenge, I try to address these problems early on. I also try to include patients in discussion about immunotherapy early in their treatment course. Once I know that a patient has had dMMR testing, we discuss the implications of it for treatment and the possible role of immune checkpoint therapy blockade in the future.
In a 2020 article discussing the role of PD-1 checkpoint inhibitors in endometrial cancer treatment, Green et al wrote that “a more robust understanding of the molecular and immunologic drivers of response and resistance will be critical to optimally design next-generation studies in endometrial cancer.”10 Can you discuss more recent developments that have improved our understanding of these topics?
There have been several studies examining predictors of response and resistance to endometrial cancer treatment. A recent study applied a prognostic signature evaluating 9 proteins; the researchers first used it to divide patients into high-risk and low-risk groups and then created a prognostic nomogram to predict survival for patients. Finally, an algorithm was used to look at certain proportions of immune cell types that predicted response to immunotherapy, chemotherapy, and targeted therapy.11 Though interesting, studies like this have yet to make it to “real-time” clinical practice, but I do believe they demonstrate the shifting focus of oncology care toward really individualizing treatments for those who may benefit and away from the old one-size-fits-most treatment approach based on stage and histology alone. Other disease sites, such as breast, melanoma, and lung, have really made great strides with this approach.
The shift toward molecular classification of endometrial cancer as opposed to the older type 1 and type 2 classification has really permeated our view of the disease and refined our approach to treatment. More recent trials, such as PORTEC-4a (ClinicalTrials.gov identifier: NCT03469674), have been designed to individualize patient care using this information. In this trial, patients are being randomized 2:1 to either individualized therapy based on the molecular subtype of their tumor (POLE, dMMR, TP53 mutant, etc.) or standard-of-care treatment using conventional protocols based on stage and grade.12
Other clinical trials, such as the RAINBO clinical trial program (ClinicalTrials.gov identifier: NCT05255653), are similarly evaluating treatment on the molecular basis of the disease.13 These trials are exciting, and it will be interesting to see how the results shape the future of endometrial cancer care.
What are current efforts and remaining needs to help further treatment options for dMMR endometrial carcinoma?
Further refining predictors of who, among the dMMR population, will be long-term responders to immunotherapy is essential.14 As described above, several of the molecularly based clinical trials currently ongoing or under development are looking at this specific population. In PORTEC4a, one section of the intermediate risk group in the experimental arm comprises patients with dMMR.12
Similarly, the RAINBO program is a platform of 4 international clinical trials evaluating 4 adjuvant treatment strategies based on the molecular classification of the tumor.13 One of these trials comprises patients with MMRp or dMMR endometrial cancer, who will receive durvalumab, which is an anti-PD-L1-directed immune checkpoint blockade therapeutic agent that showed promising activity in the PHAEDRA trial conducted in Australia.15
In the PHAEDRA trial, patients with dMMR progressive endometrial cancer had a median progression-free survival of 8.3 months, with an objective tumor response rate of 47%.15 The incorporation of immunotherapy for the dMMR population demonstrates a shift in how we think about these patients and our understanding of endometrial cancer in general.
A number of other studies evaluating the combination of immune therapy and chemotherapy are also underway. Other potential future directions include tumor-directed vaccines, adoptive T-cell therapy, the effect of HLA allele variation, and a better understanding of resistance mechanisms. Therefore, the future treatment landscape for these patients is exciting.
This Q&A was edited for clarity and length.
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Reviewed March 2023