In the last few decades, research into immunotherapeutic agents for cancer has translated to more and more regimens for patients with solid tumors as well as hematologic malignancies who are receiving treatment in the advanced or metastatic settings.
At the forefront of these cutting-edge investigations are clinical trials assessing different immunotherapy strategies in melanoma, which has been a bastion for cancer research into immune mechanisms of antitumor response.
“I’ve specialized in melanoma for several years now, since early in my career. Of all the cancers that we were treating, melanoma seemed to have the strongest connection to our immune system,” Eric D. Whitman, MD, medical director of the Oncology Service Line of Atlantic Health System in Morristown, New Jersey, said in an interview with CancerNetwork®. “Melanoma was the first cancer to show any response to immune-based therapy, and that was really intriguing to me as a clinician.”
Whitman said that his interest in conducting research is a big part of the reason he wanted to specialize in the treatment of melanoma. He was an early investigator into the first wave of immunotherapies and continues to examine novel agents across treatment settings. In this modern research era, one strategy in the space is combating disease in patients who initially show resistance to traditional immune checkpoint inhibitors.
“There are now several drugs that are FDA-approved that use the immune system to fight cancer, but they’re not always effective. In the case of melanoma, about half of patients—for reasons that we really don’t understand—will still need treatment for their metastatic cancer, after traditional treatment failure.”
At Atlantic Health System, innovative cancer therapies are made available through a robust offering of open clinical trials that recruit participants across disease settings. One such trial for which Whitman is the site principal investigator for the phase 2 BNT111-01 trial (NCT04526899) from BioNTech SE regarding the use of a proprietary cancer vaccine with or without an anti-PD-1 checkpoint inhibitor.
Therapeutic cancer vaccines can work by training the patient’s immune system to recognize malignant cells and can be coupled with traditional immunotherapy to improve upon the native antitumor response. And since approved treatments for patients with advanced melanoma who do not respond to traditional immunotherapies are lacking, combining the 2 modalities has sparked interest and shown some promise in early trials.
One such agent is BioNTech’s FixVac program candidate BNT111, which is an intravenous immunotherapy encoding 4 specific cancer antigens delivered as an RNA-lipoplex formulation.
“Each of those drugs is trying to teach the immune system about a common protein [in melanoma] that should be recognized. Each component is similar in concept to a messenger RNA vaccine, so it’s a fragment of the RNA that makes up a melanoma-associated antigen or protein that our immune system should be recognizing,” Whitman said. “You give all four of these together, to increase the odds that at least 1 or 2 of them will help fight that person’s melanoma.”
The earlier phase 1 Lipo-MERIT clinical trial (NCT02410733) assessing BNT111 in patients with melanoma following exposure to an immune checkpoint inhibitor indicated that the agent has the potential to induce responses, either as a single agent or in combination with immunotherapy, while mounting strong immunity against the vaccine antigens.1
“The main takeaways from the phase 1 study are that it’s safe and now we know the dose,” Whitman stated. “The second thing was that there were some responses. It’s preliminary, but looking at these results, it gives you hope that this new drug will benefit patients, either by itself or in combination with more standard immunotherapy.”
In November 2021, BNT111 was granted fast track designation for the potential treatment of advanced melanoma, which is granted to agents that show promise in serious conditions for which there is an unmet need.2
“I believe that this designation will help get [BNT111] to patients quicker. Half our patients with advanced melanoma fail standard therapy, and now are without an FDA approved treatment option. In granting this fast track designation, [the FDA] is saying that this drug has a great chance of helping those patients and filling this unmet need,” Whitman said.
Currently, BNT111 is being investigated in a phase 2 trial—with arms for either a single agent therapy, in combination with cemiplimab (Libtayo), or cemiplimab alone–as a treatment for patients with anti–PD-1–refractory/relapsed stage III or IV melanoma. The estimated enrollment is 180 patients and the primary end point is objective response rate (ORR) in patients treated with BNT111 plus cemiplimab. Secondary end points include ORR in either monotherapy arm, response duration, disease control rate, and progression-free survival.
Patients are eligible for the trial if they are over the age of 18 years old with histologically confirmed unresectable stage III or IV metastatic cutaneous melanoma that is measurable per RECIST 1.1 criteria. They must have had previous exposure to an approved regimen containing an anti–PD-1 therapy for 12 consecutive weeks, radiological progression confirmed by 2 scans, and confirmed disease progression within 6 months of that therapy regardless of any intervening treatment.
“The ideal candidate for this trial is someone with advanced melanoma who has failed to respond to standard therapy,” Whitman said. “They’ve run out of FDA-approved options. One of the important things for this trial is that they can’t have had such severe adverse effects with FDA-approved immunotherapies.”
Another great feature of the trial that Whitman pointed out was the ability for patients who are randomized to a single-agent arm to cross over to receive the combination therapy. “[Patients] always worry about getting randomized. The nice part about this trial is if they get randomized to, BNC111 alone or cemiplimab alone, and the cancer grows through that, you can then be crossed over to get the combination.”