Nivolumab Followed by TIL Therapy Shows Early Safety, Clinical Activity in Metastatic NSCLC

Benjamin C. Creelan, MD

Nivolumab (Opdivo) followed by treatment with tumor-infiltrating lymphocytes (TILs) was generally safe and found to have clinical benefit in patients with metastatic non–small cell lung cancer (NSCLC), according to data from a phase 1 trial (NCT03215810) published in Nature Medicine.¹

Results from the trial showed that the primary end point of safety was met, with the approach resulting in a severe toxicity rate of less than 17% (95% CI, 3%-29%) per prespecified criteria. Additionally, of 13 evaluable patients, 3 achieved a complete response (CR) to treatment, with 2 patients experiencing ongoing CRs after 1.5 years. Moreover, 11 patients reported a reduction in tumor burden with a median best change of 35%.

“We found that excisional tumor biopsy and nivolumab followed by administration of cyclophosphamide, fludarabine, interleukin-2 with TIL infusion in pretreated metastatic lung cancer was feasible in an academic cancer setting and had manageable adverse effects [AEs],” lead study author Benjamin C. Creelan, MD, of Moffitt Cancer Center, and colleagues, wrote. “Based on its activity and safety profile, TILs are a rational therapy to further investigate for fit, motivated patients with metastatic NSCLC.”

Although PD-1 inhibitors have been examined in patients with metastatic NSCLC, many patients will not experience an objective response. Moreover, even when these agents are paired with platinum-doublet chemotherapy in the frontline setting, most patients will experience disease progression within 1 year. Efforts have been made to identify new partners for combinations with immune checkpoint inhibitors, but progress has been incremental in this arena.

Adoptive cell therapy (ACT) utilizing allogeneic or autologous TILs cultured from a patient’s tumor has surfaced as a potentially potent approach. Treatment with TILs have previously been shown to result in durable CRs in certain patients with metastatic melanoma, as well as durable tumor regressions in cholangiocarcinoma, cervical cancer, colorectal cancer, and breast cancer.

As such, in the phase 1 pilot trial, investigators set out to examine nivolumab followed by TILs in patients with metastatic NSCLC. To be eligible for enrollment, patients had to be at least 18 years of age, have a confirmed diagnosis of stage IV or recurrent NSCLC, and measurable disease. Patients were also required to have an ECOG performance status of 0 or 1, an expected survival of more than 6 months, and accessible tumors, defined as greater than 1.5 cm3 of resectable tumor amount.² Those who had received more than 5 prior lines of therapy, or treatment with a PD-1 or PD-L1 inhibitor were excluded.

At day -67 prior to infusion, all patients underwent TIL collection; this was followed by treatment with intravenous nivolumab at a dose of 240 mg every 2 weeks for 4 cycles (day -63 to day -21). If patients experienced clinical benefit with nivolumab alone, they continued on the agent every 4 weeks until progression. Those who experienced progression went on to receive lymphodepletion with cyclophosphamide and fludarabine at day -7, TIL infusion on day 0, and IL-2 from day 1 to day 5.

The primary end point of the trial was safety, and key secondary end points included objective response rate (ORR), duration of response (DOR), and T-cell persistence.

Among the 20 patients enrolled to the study, the median age was 54 years (range, 38-75) and the median PD-L1 proportion score was 6%. Additionally, 40% of patients had no PD-L1 expression, and 30% had a PD-L1 expression of greater than 50%. The median nonsynonymous tumor mutation burden by whole-exome sequencing was 1.5 mutations per megabase of DNA (range, 0.1-10.2).

Four patients had EGFR mutations, 2 of which had classical exon 19 deletions, and 2 others had EML4-ALK translocations. Fifty percent of patients had not received prior systemic therapy. Moreover, the majority of patients were noted to have bulky disease, with a mean sum target lesion diameters of 8.5 cm prior to TIL therapy.

Overall, 16 patients received underwent lymphodepletion, followed by TIL infusion and IL-2, and 56% of patients received all doses of IL-2 treatment. TILs were expanded in 95% of patients at a dose of 95 billion CD3-positive cells (range 4.3-175).

Additional data showed that initial tumor regression occurred in 11 out of the 16 evaluable patients by the time that their first CT scan was performed, which was 1 month after TIL infusion. The median best change in sum of target lesion diameters was -35.5% (range +20 to -100).

Six of 13 evaluable patients experienced a radiographic response, including unconfirmed response. Two patients had unconfirmed partial responses because of subsequent new brain metastases, and another 2 patients maintained clinical remission by receiving local ablative therapy for a new “escape” lesion between 6 months and 17 months following TIL infusion.

Among the 20 patients enrolled, the median overall survival was not reached on an intention-to-treat basis, nor following TIL. therapy.

In terms of safety, most AEs were associated with the lymphodepletion and IL-2 treatment and were manageable. However, 2 patients died before a response assessment, both of whom had progressed to an ECOG performance status of 3 and required supplemental oxygen prior to lymphodepletion. Moreover, these 2 events resulted in a final severe toxicity rate of 12.5%.

The most common nonhematologic AEs of any grade experienced with the approach included hypoalbuminemia (88%), nausea (88%), hypophosphatemia (75%), hyponatremia (69%), and diarrhea (56%). One patient experienced severe thrombocytopenia after receiving 6 months of nivolumab maintenance therapy. Most treatment-emergent AEs were resolved within 1 month of TIL infusion.

“Future TIL trials will ideally enroll either patients with NSCLC who have progressed after combination chemotherapy and immunotherapy or patients who are predicted to have a poor chance of response to traditional immune-checkpoint inhibitors,” study authors wrote. “Larger trials are required to further define the optimal biomarkers of response and the efficacy of TIL collected from patients who have progressed on previous PD-L1-based treatments.”

References

1. Creelan BC, Wang C, Teer JK, et al. Tumor-infiltrating lymphocyte treatment for anti-PD-1-resistant metastatic lung cancer: a phase 1 trial. Nat Med. 2021;27(8):1410-1418. doi:10.1038/s41591-021-01462-y
2. Nivolumab and tumor infiltrating lymphocytes (TIL) in advanced non-small cell lung cancer. ClinicalTrials.gov. Updated March 2, 2021. Accessed August 12, 2021. https://clinicaltrials.gov/ct2/show/NCT03215810