Prevention, Detection, and Management of Ocular Adverse Events During Treatment with Elahere for Folate Receptor-Positive Ovarian Cancer

Written by Dr. Douglas Swords

Elahere is a first-in-class antibody drug conjugate (ADC) that is indicated in recurrent, FRα-positive, platinum resistant ovarian cancer when folate receptor positivity (greater than or equal to 75% of cells staining 2+ by immunohistochemistry). Approximately 35-40% of patients in this clinical context have sufficiently high FRα so as to qualify for Elahere.

The Mirasol trial, published in the New England Journal of Medicine in December, 2023, was a global, open-label confirmatory trial of Elahere vs. investigator’s-choice chemotherapy in patients with high-grade, serous ovarian cancer that had been treated with 1-3 previous lines of chemotherapy.

Patients were randomized 1:1 to Elahere (n = 227) and investigator’s-choice chemotherapy (n = 226). Median progression free survival (PFS) was 5.6 months (95% confidence interval [CI]) 4.34, 5.95) for patients receiving Elahere vs. 3.98 months (95% CI 2.86, 4.47) for patients receiving investigator’s choice chemotherapy. Median overall survival was also longer for patients randomized to Elahere at 16.46 months vs. 12.75 (hazard ratio for death 0.67, 95% CI 0.50, 0.89).

Patients randomized to Elahere also had lower rates of grade 3 or higher adverse events (41.7% vs. 54.1%) and serious adverse events (23.9% vs. 32.9%) than patients randomized to investigator’s-choice chemotherapy.

The trial’s significance

Oncologists involved in the treatment of advanced gynecologic malignancies have interpreted these findings as practice-changing. Dr. Helen Eshed, a Gynecologic Oncologist at Texas Oncology in Austin, told SurvivorNet, “It is incredibly exciting to have a targeted therapy for platinum-resistant ovarian cancer that has relatively limited treatment options.”

Dr. Marta Crispens, Professor of Gynecologic Oncology at Vanderbilt University also summarized the results: “It has been a big advance for patients with platinum resistant disease to have this medicine that maybe can help have more of a chance for them to respond to and also maybe help prolong their life more than or at least prolong the time to the next recurrence more than other drugs.”

The MIRASOL trial confirmed the safety profile of Elahere which had been previously observed in earlier work. The most common adverse events were low-grade gastrointestinal, neurosensory, and reversible ocular events. As mentioned above, the overall safety profile of Elahere was quite favorable as compared to investigator’s choice chemotherapy.

Adverse ocular events

The ocular events seen during Elahere treatment represent a fairly unique side effect profile, and there is emerging evidence about best practices for detection and management of these ocular events.

Ocular events were the most common adverse events seen in the phase I trials of Elahere, and a pooled exposure-response analysis of 542 patients enrolled in the first 3 trials of Elahere suggested a dose-response association between the amount of Elahere exposure and ocular events.

Ocular side effects have been observed in several other ADCs, and those seen with Elahere thankfully tend to be milder and more commonly reversible. Given the side effect profile seen in the first trials, a pooled safety analysis of 464 patients from 3 trials was performed.

In this pooled analysis, approximately 50% of patients had at least one ocular AE. The most common ocular AEs were blurred vision or keratopathy. Approximately 45% of patients had grade ≤ 2 ocular AEs, while only approximately 5% had grade 3 ocular AEs and only 1 patient (0.2%) had a grade 4 event (keratopathy). Only 1/464 patients (0.6%) had to discontinue treatment because of an ocular AE. Additionally, all ≥ grade 2 AEs of blurred vision and keratopathy resolved to grade 0-1 in patients with complete follow-up data. There were no cases of corneal ulcers or perforations.

After the first phase 1 trial, Elahere dosing was changed to minimize ocular toxicity, and ocular AE detection and mitigation strategies have also evolved. An excellent review on this experience was published in Gynecologic Oncology Reports by Hendershot et al in 2023.

The available experience with these AEs has emphasized the importance of a standardized, multidisciplinary, and proactive approach.

Dr. Eshed also spoke with SurvivorNet about the importance of the multidisciplinary team: “We work really closely with ophthalmologists who will see you regularly for eye exams to evaluate if you’ve had any adverse effects.”

She added that “many of the concerns in terms of the toxicity for your eyes are reversible.”

Preparing for treatment

Before starting Elahere, patients should be educated about best practices for eye health consisting of good eyelid margin health (cleaning around the eyes and applying warm compresses frequently), using sunglasses during full daylight exposure, avoiding contact lenses (unless otherwise instructed by their eyecare professional), and knowing and avoiding risks for dry eye disease.

Patients also need to be educated on and prescribed an appropriate eyedrop regimen. Patients should use preservative-free lubricating eye drops at least 4 times daily. During each cycle of Elahere, patients should take steroid eyedrops 6 times daily beginning on the day before each infusion, and the frequency is then decreased to 4 times daily for days 5-8. Additionally, it is important to wait at least 10 minutes after applying steroid eye drops before instilling lubricating eye drops.

Before starting Elahere, patients should be questioned about eye health and corneal disorders by their oncologist, and they should be referred to an eye care professional for an eye examination unless they have had an exam recently. This baseline examination is crucial as it allows the eye care professional and oncologist to later differentiate Elahere-associated adverse events from baseline ocular surface disease.

In addition to this baseline examination, scheduled eye examinations should also be completed by the eye care professional between every 2 cycles (i.e. approximately every 6 weeks) during treatment. This is particularly important as some adverse events are not symptomatic, and early detection allows prompt management.

Eye examinations should include best corrected visual acuity, silt lamp examination, and evaluation of intraocular pressure if steroid drops are being used. In addition to these protocolized visits, patient should also see their eye care professional promptly for any concerning symptoms to enable diagnosis, grading, and mitigation. Communication between the eye care professional and the oncologist is crucial, and the Elahere Prescribing Information contains up to date ocular AE management and dose-modification strategies.

Elahere is an important and practice-changing advance in FRα-positive, platinum resistant ovarian cancer. The ocular events experienced during treatment with Elahere tend to be low grade and manageable with prompt diagnosis and management, which contrasts the adverse event profile of some other ADCs.

The existing data emphasize the importance of patient education and empowerment, baseline and frequent exam by eye care professionals, and frequent communication between the patient’s eye care professional and their oncologist. Introduction of such strategies in a systematic manner should ensure that real world ocular events mirror those observed in clinical trials.