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Bavencio Presents Potentially Curative Option for Patients With Rare PD-L1-Expressing Gestational Tumors

NEW YORK – Two research groups have found that anti-PD-L1 immunotherapy avelumab (Pfizer/EMD Serono's Bavencio) showed promising results in chemotherapy-resistant gestational trophoblastic tumors (GTTs) and advanced urothelial carcinoma.

The studies were presented at the American Society of Clinical Oncology's virtual annual meeting, during which researchers also considered the role PD-L1 expression plays in patients' ability to respond to treatment.

In GTTs, researchers have found that all tumors are characterized by high PD-L1 expression and that the immunotherapy may be potentially curative in some chemotherapy-resistant patients. In bladder cancer, researchers have shown avelumab's potential as maintenance treatment for patients responding to platinum-based chemotherapy, regardless of PD-L1 expression status, although patients with high PD-L1 expression experienced a greater magnitude of benefit.

During the May 31 plenary session of the American Society of Clinical Oncology's virtual annual meeting, Benoit You of the Trophoblastic Disease Reference Center in Lyon, France, will present data from Cohort A in the Phase II TROPHIMMUN trial. The single-armed trial investigated the efficacy of avelumab in patients with GTTs, which are rare tumors that originate in cells that form the placenta during pregnancy. Cohort A included patients who were resistant to single-agent chemotherapy, which is typically prescribed for those with low-risk disease. Patients with high-risk disease tend to receive multiple chemotherapies.

Although rare, GTTs tend to occur in the placentas of young women during pregnancy and are characterized by increased levels of the hormone hCG. Doctors can track whether treatments are working by measuring blood hCG levels and monitoring whether they return to normal.

Standard chemotherapy may achieve cure rates of up to 90 percent. However, chemotherapies are also associated with significant toxicities and may cause potential long-term adverse effects on fertility and quality of life. During a press call earlier this week to discuss the data from the TROPHIMMUN study, You highlighted a need for more modern therapies with a better safety profile for patients.

The rationale for testing avelumab in this setting was based on previous research from the French Trophoblastic Disease Reference Center showing there was a strong and constant overexpression of PD-L1 and the presence of NK cells in all disease subtypes and settings of GTT.

"We looked at the expression of PD-L1 in detail in GTT, and [it occurred] in more than 100 patients. We saw that all tumors were highly expressing PD-L1," You said. He explained that the group did not select patients based on PD-L1 status because they expected all GTT patients to have PD-L1-overexpressed tumors.

In Cohort A, 17 patients were enrolled, of which 15 were evaluable for response. In eight patients, hCG levels normalized, which allowed for treatment discontinuation. None of the eight patients had relapsed at the 27-month follow-up after treatment discontinuation, indicating that the disease was potentially cured. You also noted that five of the eight patients had high initial hCG levels indicating high-risk disease, which would have qualified them for combination chemotherapy.

"A minimum of one third of patients could escape toxic polychemotherapy because they were successfully treated with avelumab," You said.

One of the eight patients who had normalized hCG levels became pregnant one year after discontinuing avelumab and recently delivered a healthy baby.

"This is the first report of a normal pregnancy from a patient previously cured from her tumor with immunotherapy," said You. "This provides reassuring data about the impact of immunotherapy on subsequent fertility."

Seven patients in Cohort A developed resistance to avelumab, but their disease was successfully managed with chemotherapy both with and without surgery. You said during the press call that there is some early interest in conducting a translational research project to understand why some patients responded well to avelumab and some patients did not.

You reported that avelumab was well-tolerated in patients, and there were no dose reductions or dose delays due to toxicity in the trial. Mild or moderate adverse events such as fatigue, nausea, vomiting, infusion-related reaction, dry eye, and diarrhea were observed during the trial. Thyroid disorders were seen in three patients.

You proposed that based on these results showing good tolerability and the potential of avelumab to cure some patients, the immunotherapy should be a new therapeutic option for monochemotherapy-resistant GTT.

An ongoing Phase I/II trial will further evaluate avelumab in combination with methotrexate as a first-line option for low-risk patients with gestational trophoblastic neoplasias.

Avelumab in bladder cancer

During the press conference, Thomas Powles from the Barts Cancer Institute at the Queen Mary University of London presented interim data from the randomized Phase III JAVELIN Bladder 100 trial that studied the efficacy of maintenance avelumab plus best supportive care versus best supportive care alone in chemotherapy pre-treated advanced urothelial carcinoma patients. Best supportive care in the trial included antibiotics, nutritional support, hydration, pain management, and palliative local radiotherapy.

The study met its primary endpoint by showing that both PD-L1-positive patients and the general population had significantly longer overall survival after receiving avelumab as first-line maintenance therapy following platinum-based chemotherapy.

In 2017, the US Food and Drug Administration approved avelumab in an all-comer urothelial carcinoma population whose disease progressed on or after platinum-based chemotherapy.

The standard of care for urothelial carcinoma is platinum-based chemotherapy, which can control disease in 65 percent to 75 percent of patients. Yet, progression-free survival and overall survival are undercut by chemotherapy resistance. PD-L1 inhibitors, like avelumab, are standard second-line treatments after patients have progressed on or after platinum-based chemotherapy, and currently only 25 percent to 55 percent of patients receive second-line treatment.

The JAVELIN Bladder 100 evaluated what would happen if avelumab was given as a maintenance therapy in patients who are responsive to standard first-line treatment but before the patients progressed.

PD-L1 status in the trial was defined by Roche's PD-L1 SP263 Assay, and 51 percent of the 700-patient cohort was PD-L1 positive.

The median overall survival in the arm containing avelumab was 21.4 months and was 14.3 months in the arm with best supportive care alone. The median progression-free survival was 3.7 months in the arm containing avelumab and two months in the arm with best supportive care alone. Powles noted that in a subgroup analysis of overall survival, the hazard ratio for PD-L1-positive patients is 0.56 compared to 0.86 for PD-L1-negative patients, which means that the PD-L1 positive patients had a greater reduction in risk of death with maintenance avelumab compared to PD-L1-negative patients.

"There are more similarities than differences behind the immune checkpoint inhibitors in urothelial cancer. We now have a positive randomized Phase III for pembrolizumab, avelumab, and atezolizumab all in slightly different settings," Powles said during a press call. "It's much easier to make the argument that all the drugs seem to work in a similar type of way, and the differences we've seen are probably more likely due to the trial design and the biomarker that's being used [to select patients] rather than differences between the drugs. I hope one day we can randomize these drugs against each other."