Addition of TIL Therapy to Pembrolizumab Shows Efficacy in Advanced Melanoma, HNSCC, and Cervical Cancer

The combination of tumor-infiltrating lymphocyte (TIL) cell therapy with lifileucel (LN-144) or LN-145 and pembrolizumab (Keytruda) demonstrated encouraging efficacy and safety in patients with advanced melanoma, head and neck squamous cell carcinoma (HNSCC), and cervical cancer who were naïve to immune checkpoint inhibitors (ICIs), according to data from the phase 2 IOV-COM-202 (NCT03645928) and C-145-04 (NCT03108495) trials.¹

The findings, which were presented during the 2021 SITC Annual Meeting, showed that in 14 patients with cervical cancer who comprised cohort 3 of the C-145-04 trial, the overall response rate (ORR) with LN-145 plus pembrolizumab was 57.1% (n = 8; 95% CI, 28.9%-82.3%); this included 1 complete response (CR), 6 partial responses (PRs), 1 unconfirmed PR, and 5 best responses of stable disease (SD). At a median follow-up of 7.6 months, 71.4% (n = 5/7) of patients experienced ongoing confirmed responses.

In cohort 1A of the IOV-COM-202 trial, 10 patients with melanoma who received lifileucel plus pembrolizumab achieved an ORR of 60.0% (n = 6; 95% CI, 26.2%-87.8%); this comprised 3 CRs, 3 PRs, and 3 best responses of SD. Moreover, 66.7% (n = 4/6) had ongoing confirmed responses at a median follow-up of 11.5 months.

In cohort 2A of the IOV-COM-202 trial, 18 patients with HNSCC who received LN-145 plus pembrolizumab achieved an ORR of 38.9% (n = 7; 95% CI, 17.3%-64.3%); this included 1 CR, 1 unconfirmed CR, 4 PRs, 1 unconfirmed PR, and 7 best responses of SD. Additionally, 50% (n = 3/6) of patients had ongoing confirmed responses at a median follow-up of 7.8 months.

“The encouraging results for Iovance TIL plus pembrolizumab across several tumor types validate the combination of checkpoint inhibition and TIL cell therapy as a potential platform approach in solid tumors,” Friedrich Graf Finckenstein, MD, chief medical officer of Iovance, stated in a press release.² “We observed response rates that are approximately double compared with what was seen with single-agent pembrolizumab in early-line melanoma and head and neck cancers, as well as second-line cervical cancer. We are eager to continue our investigation of TIL combinations in melanoma, head and neck, cervical and non–small cell lung cancer patients in need of treatment options that provide higher response rates, and deeper responses with more complete responses.”

ICIs are a key component of standard-of-care treatment for several advanced cancers. TIL therapies such as lifileucel have produced encouraging efficacy in patients with advanced cancer following failed treatment with ICIs. Early-line treatment with pembrolizumab monotherapy has produced ORRs ranging from 33% to 17% in patients with advanced melanoma and HNSCC, respectively.^3,4 However, novel early-line combination regimens are required to further improve response rate and depth.

Regarding IOV-COM-202, cohort 1A included patients with unresectable metastatic melanoma who were naïve to anti–PD-1/PD-L1 agents (n = 12) and cohort 2A comprised of patients with advanced, recurrent, or metastatic HNSCC who were also naïve to anti–PD-1/PD-L1 (n = 19). Regarding C-145-04, cohort 3 was comprised of patients who had stage IVB, persistent, recurrent, or metastatic cervical cancer and who did not receive prior therapy except for chemoradiation or surgery for locoregional disease (n = 24).

The key eligibility criteria for the 2 trials required that patients have at least 1 resectable lesion for TIL manufacturing, with a diameter of at least 1.5 cm following resection. Patients also needed to have at least 1 measurable lesion for investigator response assessment per RECIST v1.1 criteria, and an ECOG performance status of either 0 or 1.

Patients were enrolled from March 2019 through August 2021. Participants underwent tumor resection for TIL manufacturing before receiving 1 dose of pembrolizumab at either 200 mg or 400 mg. Notably, patients in the C-145-04 trial were required to take a 200-mg dose of the immunotherapy compared with IOV-COM-202, which allowed patients to receive either dose.

The first dose of pembrolizumab was administered prior to nonmyeloablative lymphodepletion (NMA-LD), which was comprised of 2 daily doses of cyclophosphamide at 60 mg/kg on days -7 and -6, followed by 5 daily doses of fludarabine at 25 mg/m2 on days -5 through -1. Patients then received TIL infusion at doses ranging from 1 x 109 to 150 x 109 on day 0, followed by no more than 6 doses of interleukin-2 (IL-2) at 600,000 IU/kg every 8 to 12 hours. Pembrolizumab was continued at 200 mg every 3 weeks or 400 mg every 6 weeks for up to 2 years.

Concomitant anticancer therapy was not permitted.

The primary end points of the IOV-COM-202 trial were ORR and incidence of grade 3 or higher treatment-emergent adverse effects (TEAEs). Secondary end points included CR rate, duration of response (DOR), disease control rate (DCR), progression-free survival (PFS), and overall survival (OS). In C-145-04, the primary end point was incidence of grade 3 or higher TEAEs, and the secondary end points included ORR, DOR, DCR, PFS, and OS.

In cohort 1A of the IOV-COM-202 trial, the median age was 52.0 years (range, 34-68), and 80% of patients were male. These patients received a median number of prior systemic therapies of 0 (range, 0-2). Thirty percent of patients underwent prior chemotherapy, 20.0% of patients received prior BRAF or MEK inhibitors, and 10.0% received prednisone along with a chemotherapy regimen comprised of cyclophosphamide, doxorubicin, and vincristine. The majority of patients had disease metastasis of M1C at study entry (70.0%), followed by M1A (20.0%) and M0 (10.0%). Additionally, 50% of patients were PD-L1 positive, and the median number of target and non-target lesions was 4.0 (range, 2-7).

Patients enrolled to cohort 2A of the IOV-COM-202 trial had a median age was 59.0 years (range, 24-66), and 88.9% of patients were male. This group had received a median number of prior systemic therapies of 1.0 (range, 0-3). Moreover, 66.7% of patients underwent prior chemotherapy, 50.0% had prior radiotherapy, and 11.1% previously received anti-EGFR monoclonal antibody therapy. Most patients had disease metastasis of M1 at study entry (72.2%), followed by M0 (16.7%) and unknown status (11%). Additionally, 61.1% of patients were PD-L1 positive, and the median number of target and non-target lesions was 5.5 (range, 1-8).

Finally, of those included in cohort 3 of the C-145-04 trial, the median age was 46.5 years (range, 37-73). None of these patients received any prior systemic therapies, although 64.3% previously underwent curative or therapeutic surgery, 50.0% received chemoradiotherapy, and 21.4% received radiotherapy alone. Most patients had disease metastasis of M1 at study entry (92.9%), and 1 patient had unknown status. Furthermore, 71.4% of patients were PD-L1 positive, and the median number of target and non-target lesions was 7.0 (range, 1-10).

Among patients in all 3 cohorts (n = 42), 100% experienced at least 1 TEAE of any grade, and 95.2% experienced an effect that was grade 3 or 4 in severity. Additionally, 11.9% of patients experienced a grade 5 TEAE. The most common TEAEs reported across the 3 cohorts were chills (85.7%), pyrexia (78.6%), nausea (78.6%), fatigue (61.9%), hypotension (61.9%), and thrombocytopenia (61.9%).

“The TEAE profile across all 3 cohorts was consistent with the underlying disease and known [safety] profiles of pembrolizumab, NMA-LD, and IL-2,” according to the press release issued by Iovance Biotherapeutics, Inc.

The combination of TIL and ICIs warrant further investigation in patients with advanced disease, and the IOV-COM-202 and C-145-04 trials are ongoing.

References

1. O’Malley D, Lee SM, Psyrri A, et al. Phase 2 efficacy and safety of autologous tumor-infiltratinglymphocyte (TIL) cell therapy in combination with pembrolizumab in immune checkpoint inhibitor-naïve patients with advanced cancers. Presented at: Presented at: 2021 SITC Annual Meeting; November 10-14, 2021; Washington, DC. Abstracts 492.
2. Iovance biotherapeutics announces clinical data for lifileucel in combination with pembrolizumab in advanced cancers at society for immunotherapy of cancer (SITC) annual meeting. News release. November 13, 2021. Accessed December 21, 2021. https://bit.ly/32m1ezI
3. Robert C, Schachter J, Long GV, et al. Pembrolizumab versus ipilimumab in advanced melanoma. N Engl J Med. 2015;372:2521-2532. doi:10.1056/NEJMoa1503093
4. Burtness B, Harrington KJ, Greil R, et al. Pembrolizumab alone or with chemotherapy versus cetuximab with chemotherapy for recurrent or metastatic squamous cell carcinoma of the head and neck (KEYNOTE-048): a randomised, open-label, phase 3 study. Lancet. 2019;394:1915-1928. doi:10.1016/S0140-6736(19)32591-7