In new findings, second-line therapy using harvested cells from patients with refractory advanced melanoma doubled the time to disease progression after their initial immunotherapy with the anti-programmed cell death protein 1 (PD-1) checkpoint inhibitor drug ipilimumab.
The M14TIL Phase III randomized study-reported as a late-breaking abstract at the ESMO Congress 2022-found that maintenance therapy with tumor-infiltrating lymphocytes (TILs) was superior in the investigational arm of the study compared with a control group of patients who received ipilimumab therapy to follow their initial treatment.
"When we looked at the overall responses, we saw that TIL had a 49 percent objective response [rate] versus 21 percent for the ipilimumab-treated patients," said first author John B. Haanen, MD, PhD, leader of Immunotherapy Research and Consultant in Medical Oncology at the Netherlands Cancer Institute in Amsterdam. "But very importantly, 20 percent of the patients had a complete remission on TIL versus 7 percent on ipilimumab. And these [patients with] complete remissions do very well. So, some of these patients may be cured," he told Oncology Times.
The investigators wanted to improve on the big benefits already notched up for patients with melanoma by pure immunotherapy. Although immune checkpoint inhibitors, including ipilimumab and other targeted therapies, had greatly improved outcomes for patients with advanced melanoma, approximately half did not have durable benefit. So there had been a large unmet need for additional treatment options. Adoptive cell therapy with TIL had given promising response rates in patients with advanced melanoma in Phase I and II trials, so the Netherlands-based study was designed to provide Phase III trial data to check if the approach could be recommended as an effective therapy.
"Checkpoint inhibitors have been extremely successful in patients with metastatic melanoma. But they don't cure all patients," Haanen said. "So, there was still a great need for innovative and effective treatment. TIL had consistently been shown to be effective in patients with melanoma-even in patients who had prior treatment. That's why we embarked on this study in patients who had failed checkpoint inhibition in the first place."
Haanen noted that the TILs they used were lymphocytes from each patient's own tumor and a proportion of them were "truly tumor-reactive." Within the tumor, they were not bringing benefit to the patients because, in patients refractory to anti-PD-1 therapy, these cells were no longer being activated by the immunotherapy. "But if you take these cells out of their natural environment, then culture them in the laboratory, activate them again and grow them to high numbers they become highly active cells," he explained. "And then you can infuse them as a large army into these patients, and you see that about half of them will respond to this treatment.
"We think that the mechanism of resistance to anti-PD-1 treatment is mostly delivered by the tumor microenvironment. So, when we take these cells out of their natural environment, reactivate them in the laboratory, grow them up to very large numbers, and give them back to the patients, we can overcome some of the escape mechanisms. And that's what we are seeing," Haanen stated.
Study Details
In a multi-center, open-label, Phase III trial, patients between the ages of 18 and 75 with unresectable Stage III-C or Stage IV melanoma were randomized to TIL or ipilimumab. All patients were tested for the V600 mutation of the BRAF oncogene. And those randomized to TIL therapy had resection of their melanoma lesion to harvest T cells for ex-vivo outgrowth and expansion of lymphocytes already primed to fight the tumor. Before they were infused with their personal armies of TILs, patients in the investigational arm of the study had non-myeloablative, lymphodepleting chemotherapy with cyclophosphamide plus fludarabine followed by high-dose interleukin-2.
The primary endpoint of the study was progression-free survival (PFS), with secondary endpoints of overall response rate (ORR), complete response rate, overall survival (OS), and safety. Out of 168 patients, the majority of whom (86%) had become refractory to anti-PD-1 treatment, 84 were randomized to TIL and the same number to ipilimumab. After a median follow-up of 33.0 months, median PFS was 7.2 months for TIL therapy, compared to 3.1 months for ipilimumab, with a statistically significant hazard ratio of 0.50. (P<0.001.)
ORR was 49 percent for patients in the TIL therapy group and 21 percent for those treated with maintenance ipilimumab. Twenty percent of patients had complete responses in the investigational arm compared with 7 percent of controls. Median OS for patients receiving TIL therapy was 25.8 months and 18.9 months for those receiving ipilimumab (P=0.39).
Even though Grade 3 or higher adverse events occurred in all patients treated with TIL therapy as compared with 57 percent of those randomized to ipilimumab, Haanen was not discouraged. "The side effects are well manageable and most resolve by the time patients leave the hospital after their TIL therapy," he said, noting that most side effects had been related to the other therapies (including chemotherapy and interleukin-2) that patients had received as part of the TIL regimen.
The researchers concluded that TIL therapy significantly improved PFS compared to ipilimumab in patients with advanced melanoma. Since the vast majority of such patients were refractory to anti-PD-1 immunotherapy, TIL therapy was judged to be a possible new treatment option in this patient population. Haanen urged cancer teams to consider recruiting patients into studies with TILs to get more data about an approach which he believed had great promise.
"This study shows for the first time in a randomized, controlled trial that cell therapy can be efficacious and beneficial for patients with solid cancers," he stated. "TIL has the potential to benefit patients with a wide range of solid tumors. And trials are currently underway in many cancer types, including lung, cervical, and head and neck cancers."
"TIL therapy is an extraordinary therapy," commented George Coukos, MD, PhD, Director of the Department of Oncology at the University Hospitals of Canton Vaud (CHUV) and Director of the Service of Developmental Therapeutic and the Ludwig Centre at the University of Lausanne, Switzerland, who was not involved in the study. "TIL is a new paradigm for treating cancers and, as these results clearly demonstrate, it's efficacious and feasible at large scale. The findings raise hopes for the management and potential cure of metastatic solid tumors."
Peter M. Goodwin is a contributing writer.