CHICAGO – Iovance Biotherapeutics' Amtagvi (lifileucel) combined with Merck's Keytruda (pembrolizumab) may benefit advanced melanoma patients in an earlier treatment setting, according to data presented Friday at the American Society of Clinical Oncology's annual meeting.
The US Food and Drug Administration in February approved Amtagvi as a treatment for advanced melanoma, making it the first autologous tumor-infiltrating lymphocyte (TIL) therapy to reach the market and the first cell therapy approved in a solid tumor setting. To be eligible for Amtagvi, the agency specified that melanoma patients must have previously received immune checkpoint inhibitors like Keytruda.
The latest data reported at the meeting now suggest that combining the bespoke, one-time infusion of TILs with Keytruda earlier, rather than having Amtagvi follow first-line Keytruda, may be beneficial for advanced melanoma patients.
Sajeve Thomas, an oncologist at Orlando Health Cancer Institute, presented results from 23 patients in cohort 1A of the IOV-COM-202 clinical trial. Iovance designed IOV-COM-202 as a basket trial and included patients with multiple tumor types such as non-small cell lung cancer, melanoma, and head and neck cancers across various cohorts. During his presentation, Thomas focused on the cohort of unresectable or advanced melanoma patients who were immune checkpoint inhibitor-naïve.
While patients in cohort 1A had not received any prior immune checkpoint inhibitors, they could have received other systemic treatments such as chemotherapy or prior BRAF/MEK inhibitors if they had BRAF-mutated tumors. Three patients did receive prior BRAF/MEK inhibitors and three received prior chemotherapy. Thomas pointed out that two patients had received immune checkpoint inhibitors as adjuvant treatment, but since they'd received it more than a year before enrolling in the Amtagvi study and not in the first-line setting, they met the enrollment criteria. All in all, the median number of prior therapies was zero.
As of a December 2023 data cutoff, Thomas reported that the overall response rate to the Amtagvi-Keytruda combo among 22 efficacy-evaluable patients was 65.2 percent. The complete response rate was 30.4 percent, and the partial response rate was 34.8 percent. All the patients experienced tumor shrinkage, and two patients experienced complete responses after the data cutoff, although those responses haven't been confirmed.
The median time it took for patients to have an initial response to the combination treatment was 2.6 months, and 66.7 percent of patients who responded to the treatment are still responding. Over time, patients' responses to the Amtagvi-Keytruda combination seemed to deepen, Thomas noted.
He also shared data from an exploratory T-cell receptor (TCR) sequencing analysis in which investigators looked into the number of TCR clonotypes that overlapped between patients' resected tumor samples and their Amtagvi product. Thomas reported that the overlap of TCR clonotypes was higher in responders than in non-responders.
"A higher shared TCR clonotype may potentially be predictive of a TIL response," he said.
Safety concerns with conditioning regimen
Beyond the autologous TIL product itself, the Amtagvi regimen involves lymphodepleting chemotherapy and high-dose interleukin-2. These treatments can be challenging for patients to tolerate. In cohort 1A of the IOV-COM-202 study, Thomas reported that almost all the patients experienced grade 3 or 4 hematologic abnormalities, including neutropenia, leukopenia, thrombocytopenia, and anemia.
"We're all very concerned about the toxicities of the TIL regimen, whether it's the lymphodepleting chemotherapy or the high-IL2 or the lifileucel infusion," Sunandana Chandra, a medical oncologist at Northwestern Medicine, said during a discussion of the IOV-COM-202 data. "Whether they were determined to be treatment-emergent adverse events or not, the vast majority of them were hematologic in nature."
That said, both Thomas and Chandra pointed out that most of these toxicities resolved or were downgraded to grade 2 or lower severity 30 days after treatment. "They are quite short-lived … although they can be quite significant," Chandra said, contrasting these intense, shorter-lasting, side effects with some of the more chronic side effects that patients might experience with other treatments.
During her discussion, Chandra also said that the response data from IOV-COM-202, considered together with data from prior National Institutes of Health-sponsored studies of autologous TIL therapy in melanoma, suggest that there may be a role for frontline TIL therapy, whether given alone or in combination with Keytruda. She pointed to a past NIH trial, which showed a 56 percent response rate among 192 immune checkpoint inhibitor-naïve advanced melanoma patients who received upfront autologous TIL therapy on its own. In response to a question from the audience about whether the addition of the immune checkpoint blockade to upfront TIL might really be adding much benefit, Thomas said it would take future prospective studies to know for sure.
Phase III plans raise questions
Ultimately, Thomas concluded that the results he presented at ASCO further bolster the rationale for the TILVANCE-301 trial, a randomized, registration-directed Phase III study that Iovance has already begun. The company hopes to enroll roughly 670 treatment-naïve advanced melanoma patients and randomize them to receive either Amtagvi and Keytruda or Keytruda alone, although patients who progress on single-agent Keytruda will be able to cross over to receive the TIL therapy arm.
During a panel discussion following Thomas' presentation, however, several oncologists raised deep concerns about the design of the TILVANCE-301 trial — particularly as it relates to Iovance's choice of a comparator. In TILVANCE-301, advanced melanoma patients not randomized to the Amtagvi-Keytruda combo will receive single-agent Keytruda, but as oncologists at ASCO's annual meeting pointed out, Keytruda monotherapy is not the standard of care in the frontline setting for all advanced melanoma patients.
Instead, many patients receive combinations of checkpoint inhibitors, such as Bristol Myers Squibb's PD-1 checkpoint inhibitor Opdivo (nivolumab) plus its CTLA4 inhibitor Yervoy (ipilimumab). In recent years, BMS's PD-L1/LAG3 inhibitor combination Opdualag (nivolumab plus relatlimab) has also gained a foothold as an upfront option for advanced melanoma patients. And new data presented this year at ASCO also hint at the benefits of combining all three checkpoint inhibitor classes — anti-PD-1, anti-CTLA4, and anti-LAG3 drugs — in the upfront setting.
For all of these reasons, oncologists at the meeting challenged whether single-agent Keytruda is the right comparator to Amtagvi-Keytruda in TILVANCE-301, with one panelist even going as far as to suggest the comparison was bordering on unethical.
"I think it's a real problem, honestly," said Caroline Robert, the director of the melanoma program at the Gustave Roussy Cancer Center in France. "I think it should be at least ipi plus nivo as the comparator. … It's almost at the limit of the ethical."
In an investor event that Iovance held on Friday evening following Thomas' presentation, Iovance Chief Medical Officer Friedrich Finckenstein defended the firm's choice to design TILVANCE-301 with single-agent Keytruda as the comparator. For one, he said it made less sense, from a mechanistic standpoint, to make dual immune checkpoint inhibitors the control arm since that would mean that the experimental arm would have to be Amtagvi plus a PD-1 checkpoint inhibitor and a CTLA4 checkpoint inhibitor.
The combination of TIL therapy with Keytruda is a rational combination, Finckenstein argued, because interrupting the PD-1 axis that inhibits T cells makes sense and adding an anti-CTLA4 drug to the mix as a three-drug combination may not do much mechanistically.
Ultimately, though, Iovance attributed the decision to have Keytruda as the comparator to regulatory demands. Reviewers would not accept a dataset where a TIL is combined with Keytruda and Opdivo-Yervoy, Finckenstein said, noting that a combination would make it difficult to isolate which treatments were contributing to efficacy. "[Regulators are] going to send it right back and say, 'No, that doesn't work for us,'" he said.
After having wrestled with regulatory demands for several years while seeking Amtagvi's first approval, Iovance is likely attuned to what the agency is looking for. "We've had discussions with the regulators, and we've presented this design to them," Finckenstein said. "They agreed to it wholeheartedly. It's not unethical. It's a very straightforward drug development strategy that makes a lot of sense and is aligned with the health authorities."