Biomarker Testing and Immune Checkpoint Inhibitor Counseling Shape Endometrial Cancer Care

In this Q&A with Pharmacy Times, Erin Zacholski, PharmD, BCOP, assistant professor, VCU School of Pharmacy, and clinical pharmacy specialist, gynecologic oncology, VCU Health, Massey Cancer Center, discusses the evolving role of pharmacists in the management of recurrent and metastatic endometrial cancer, particularly as immune checkpoint inhibitors become integrated into frontline treatment. She emphasizes the importance of comprehensive biomarker testing, including MMR, MSI, POLE, TP53, HER2, tumor mutational burden, RET alterations, and NTRK fusions, to guide personalized treatment decisions. Zacholski also reviews key counseling strategies for patients receiving immune checkpoint inhibitors, including discussions around survival benefits, immune-related adverse events, and long-term treatment expectations.

Pharmacy Times: How is the addition of immune checkpoint inhibitors to chemotherapy changing the standard of care for patients with advanced or recurrent endometrial cancer?

Erin Zacholski, PharmD, BCOP: Yes, there are currently 3 immune checkpoint inhibitors FDA approved for recurrent and metastatic endometrial cancer in the frontline setting in combination with carboplatin and paclitaxel. These are pembrolizumab and dostarlimab for both proficient mismatch repair (pMMR) and deficient mismatch repair (dMMR) recurrent and metastatic endometrial cancer, as well as durvalumab for the dMMR population. These are category 1 recommended options in the NCCN guidelines and are based on the NRG-GY018, RUBY, and DUO-E trials, respectively.

The addition of an immune checkpoint inhibitor to carboplatin and paclitaxel is now the standard of care in this setting. These data show that using an immune checkpoint inhibitor in combination with chemotherapy, followed by maintenance therapy, dramatically improves progression-free survival, with long-term overall survival benefit in the dMMR group. For example, the hazard ratio for progression or death in the RUBY trial was 0.28 in favor of dostarlimab. Long-term overall survival benefit in the dMMR population was met.

In the pMMR subpopulations of these trials, progression-free survival benefit was significant but less profound than what was observed in the dMMR populations. Overall survival has trended favorably in long-term follow-up but has not been formally significant.

Pharmacy Times: What key safety and toxicity considerations should pharmacists be aware of when managing patients receiving immune checkpoint inhibitors in combination with carboplatin and paclitaxel?

Zacholski: There are definitely some additional considerations now when we add immune checkpoint inhibitors to chemotherapy in this population. The immune-related adverse events are consistent with what we see, and have seen, in the wider oncology literature for years. The most common immune-related adverse effect is hypothyroidism, followed by dermatologic toxicity, gastrointestinal toxicity, and, less commonly, liver and lung toxicity.

I remember this with the acronym LEGS, where “L” stands for liver and lung, “E” stands for endocrine (most commonly hypothyroidism), “G” stands for gastrointestinal, and “S” stands for skin or dermatologic toxicity. This can also help you remember the typical onset of these toxicities. If you flip LEGS backward, skin toxicity occurs the fastest.

Of course, we need to incorporate treatment parameters into our plans for combination chemotherapy and immunotherapy regimens, and we need to think about these immune-related toxicities during patient assessments. Our patient assessments should pay attention to any abnormal symptom because these immune-related toxicities can occur in any organ system. Of course, we pay extra focus to the more common toxicities that I mentioned.

We also need to recognize where toxicities overlap between the immune checkpoint inhibitors and carboplatin plus paclitaxel used in combination. For example, paclitaxel and immune checkpoint inhibitors can both cause rash, so assessing where the rash is occurring, the location, and other associated symptoms is very important. A paclitaxel-associated rash is usually flexural or occurs in the folds of the skin, whereas immune checkpoint inhibitor-associated rashes can present diversely but are most commonly bilateral and maculopapular. Other overlapping toxicities may include fatigue, neurologic toxicities, and diarrhea.

Anecdotally, we are also noticing more arthralgia and diffuse pain during the combination portion of these therapies. There is something called taxane-associated pain syndrome, which presents as diffuse pain occurring in the week after a patient receives paclitaxel. This is thought to have an inflammatory basis, so it could make sense that immune checkpoint inhibitors are potentiating this effect slightly more.

Pharmacy Times: How can pharmacists help optimize patient selection and monitoring, particularly when considering biomarkers such as dMMR/MSI-H status?

Zacholski: Sure, I think the most important thing is that pharmacists can ensure biomarkers are being tested, period. This should happen at diagnosis, and if a patient does not have biomarker testing completed, pharmacists should ensure it is addressed whenever they encounter the patient. This sounds simple, but with so many transitions of care for these patients, testing is not always completed for reasons beyond clinician control.

There is also a guideline-recommended testing strategy for patients with endometrial cancer that involves separating endometrial cancer into 4 different subtypes using molecular testing of the POLE gene, mismatch repair (MMR), microsatellite instability (MSI), and TP53 to classify tumors into 4 distinct subtypes. This strategy can be found in the NCCN guidelines, for example. I think pharmacists have a responsibility to help ensure these biomarkers are being tested.

We also need to keep in mind that additional biomarkers should be tested in recurrent and metastatic cancers specifically, which is the population we are discussing. This includes HER2 overexpression, tumor mutational burden, RET alterations, and NTRK fusions because these can guide subsequent therapy decisions as well.

For selection of frontline therapy, it is safe to say that all dMMR cancers should receive immune checkpoint inhibitors. The risk-benefit conversation is a bit different for pMMR disease, where the benefit is not as profound, although still significant. You also have to remember that patients may receive years of maintenance therapy, so the risk-benefit discussion shifts somewhat in the pMMR population.

There is also more clinical controversy surrounding other biomarker-driven decisions, such as when a patient has HER2 overexpression, because frontline options may include HER2-directed therapies as well as clinical trials in this setting. As a result, there may be decision points where clinicians must choose between one of these approaches and an immune checkpoint inhibitor-based combination.

Pharmacy Times: What counseling strategies can pharmacists use to help patients understand the potential benefits and immune-related adverse effects associated with immune checkpoint inhibitor-based therapy in endometrial cancer?

Zacholski: In my counseling sessions, I always like to emphasize what we want the drug to do or the benefit the patient can receive. This is a great opportunity for pharmacists to connect back to the conversations patients have had with their oncologists. I often ask, “What did your oncologist tell you this therapy is going to do for your cancer, or could do for your cancer?” I think we can emphasize what we have seen in these studies, which is improved survival, many times in the order of multiple years for these patients. We would like this therapy to decrease tumor burden and, in some situations, potentially reduce it to nothing and keep it that way for as long as possible.

The risks are where more of my counseling conversations are focused, of course, and I think the main risks to discuss are the immune-related adverse events. NCCN has an infographic that I print out for patients showing different parts of the body where these immune-related adverse events can occur. I highlight the most common toxicities, symptoms to look out for, and parameters for when patients should call us. I also like to provide figures to capture the impact of these adverse events. I explain that immune-related adverse events occur in about one-third of patients and are most often mild, but in about 5% of patients they can result in hospitalization or even death. I also discuss that if a patient develops a serious immune-related adverse event, there is a chance they may need to be on high-dose steroids for a prolonged period of time.

I try to lay everything out clearly and empower patients to understand what to look for and the likelihood that these toxicities could happen to them because immune checkpoint inhibitors are not always benign. I think they are generally well tolerated, but serious adverse effects can occur.

I also note that there are important time and financial considerations when adding immune checkpoint inhibitors to chemotherapy. In the past, patients typically received 6 cycles of chemotherapy, but with these regimens, patients continue immune checkpoint inhibitor maintenance therapy for years. This includes 2 years of maintenance for pembrolizumab, 3 years for dostarlimab, and indefinite maintenance for durvalumab. This is a significant commitment for patients.

I think subcutaneous formulations available for some products may improve convenience in the maintenance setting, and all drug companies have robust patient assistance programs, so this is something we discuss as well. However, this is still a life-altering, long-term therapy plan, and I make sure to discuss that aspect with patients too.