Eganelisib/Nivolumab Combo Shows Positive Responses in Head and Neck Carcinoma, Melanoma

Ezra Cohen, MD, FRCPSC, FASCO

Positive response and disease control rates were observed in 2 separate studies when patients with head and neck squamous cell carcinoma (HNSCC) and melanoma received the combination of eganelisib (IPI-549), a selective PI3K-γ inhibitor, and nivolumab (Opdivo). In the first study, updated findings from an expansion cohort of the ongoing phase 1/1b MARIO-1 trial (NCT02637531), presented during the 35th Annual Meeting & Pre-Conference Programs of the Society for Immunotherapy of Cancer (SITC 2020) (FIGURE 1).¹

The overall response rate (ORR) in evaluable patients who had 2 or fewer prior lines of therapy (n=10) was 20.0% with the combination. In this population, 2 patients achieved a partial response (PR) and 2 achieved stable disease (SD). Further, the disease control rate (DCR) was 40.0% among these patients. The median progression-free survival (PFS) for patients who had 2 or fewer prior lines of therapy was 23 weeks (95% CI, 9-49).

“There is a significant unmet need for patients with head and neck cancer, especially those who are refractory to anti–PD-1 antibodies,” said lead study author Ezra Cohen, MD, FRCPSC, FASCO, chief of the Division of Hematology-Oncology and a medical oncologist at the University of California, San Diego Health, in a presentation during the meeting. “Checkpoint inhibitors are only active in about 16% of patients and there are limited treatment options for those who don’t respond.”

Eganelisib relieves immune suppression by reprogramming protumor macrophages or myeloid-derived suppressor cells. Further, T-cell activation can be maintained with the addition of checkpoint inhibitors, despite IFN-α–mediated upregulation of PD-L1, suggesting that the combination of eganelisib and nivolumab could offer synergistic antitumor benefit.

Twenty-one patients enrolled in the trial and received a combination of continuous eganelisib at 40 mg once daily plus a 240-mg flat dose of intravenous nivolumab once every 2 weeks in 28-day cycles.

All patients had previously been refractory to or relapsed following treatment with anti–PD-1/PD-L1 therapies. After starting therapy, patients were strat-ified as having progressive disease, SD, or objective response to determine the overall benefit of eganelisib.

The median age was 62 years (range, 29-80), and the majority of patients were male (n = 16; 76.2%). Patients had an ECOG performance status (PS) of 0 (n = 9; 42.9%) or 1 (n = 12; 57.1%).

Patients with known human papillomavirus (HPV) status (n = 12; 57.1%) were positive (n = 8; 38.1%), but the HPV status of 9 patients was unknown.

Twenty-one patients had received prior therapies. Ten patients had received 4 or more prior therapies (47.6%), 6 patients had received 3 therapies (28.6%), 3 patients had received 2 therapies (14.3%), and 2 patients had received 1 prior therapy (9.5%). Prior therapies included anti–PD-1/PD-L1 inhibition (100%), chemotherapy (n=14; 66.7%), anti-EGFR inhibition (n=12; 57.1%), anti–CLTA-4 inhibition (n=3; 14.3%), anti-CD20 inhibition (n=2; 9.5%), and an immune stimulatory agent (n = 2; 9.5%). As the last line of prior therapy, 85.7% of patients (n=18) received anti–PD-1/PD-L1 inhibition, 9.5% (n=2) received anti-CD20 inhibition, 4.8% received anti-EGFR inhibition (n=1), and 4.8% received an immune stimulatory agent (n=1).

Most patients (42.9%) had progressive disease as the best response to prior anti–PD-1/PD-L1 therapy, followed by 23.8% who achieved a PR, 19.0% who achieved SD, and 14.3% whose best response was unknown.

Among evaluable patients (n=20), the ORR was 10.0%; no patients who received 3 or more prior lines of therapy obtained a PR. Five patients who had 3 or more prior lines of therapy achieved SD. The DCR was 45.0% in the overall population and 50.0% in patients who had 3 or more prior lines of therapy.

Among evaluable patients, 11 developed progressive disease (n=6,≤2 prior lines; n=5, ≥3 prior lines). The median PFS in patients who had 3 or more prior lines of therapy was 20 months (95% CI, 16-33), and 17 months (95% CI, 9-24) in the total patient population.

Regarding patient disposition and exposure, all patients discontinued treatment for reasons including disease progression (n=15; 71.4%), adverse effect (AE; n=2; 9.5%), other (n = 2; 9.5%), death (n=1; 4.8%), and investigator decision (n=1; 4.8%).

The median duration of treatment exposure was 11.3 weeks (range, 2.6-48.7), with a median of 3 cycles of therapy completed (range, 1-14). The median rate of eganelisib dose compliance was 91.5%.

Regarding safety, the most common treatment-emergent AEs (TEAEs) occurring in 15% or more of patients included fatigue (n = 13; 61.9%), pyrexia (n = 9; 42.9%), decreased appetite (n = 9; 42.9%), pruritus (n=6; 28.6%), weight decrease (n=6; 28.6%), nausea (n=6; 28.6%), diarrhea(n=6; 28.6%), dyspnea (n=5; 23.8%), abdominal pain (n=5; 23.8%), vomiting (n=4; 19.0%), myalgia (n=4; 19.0%), dizziness (n=4; 19.0%), and headache (n=4; 19.0%).

Treatment-related adverse effects (TRAEs) included fatigue (n=8; 38.1%), pyrexia (n=3;14.3%), decreased appetite (n=3; 14.3%), pruritus(n=3; 14.3%), nausea (n=4; 19.0%), dyspnea(n=1; 4.8%), abdominal pain (n=2; 9.5%), vomiting (n=2; 9.5%), myalgia (n=2; 9.5%), and dizziness (n=1; 4.8%). Three patients experienced immune-related, treatment-related pruritus.

Grade 3 or greater TEAEs occurring in at least 5% of patients included anemia (n=3; 14.3%),disease progression (n=3; 14.3%), sepsis (n=2;9.5%), nausea (n=2; 9.5%), and abdominal pain(n=2; 9.5%). One patient each experienced treatment-related anemia, nausea, and abdominal pain. Investigators observed no immune-related, TRAEs of grade 3 or greater.

“Eganelisib has the potential to benefit HPV-positive patients who have a T-cell inflamed phenotype, and further exploration in this combination is warranted,” said Cohen.To that end, a phase 2 window-of-opportunity study (NCT03795610) of eganelisib is ongoing in patients with locally advanced HPV-positive and HPV-negative HNSCC.

Similar Efficacy Seen With Melanoma Cohort

Additional findings from another expansion cohort of the study, which were also presented at the SITC meeting, showed that the combination of eganelisib and nivolumab induced an ORR of 10.3% (n = 4) among patients with melanoma (n =39).² All 4 patients derived a PR. Ten patients had SD and 24 developed progressive disease.

Notably, all 4 patients had 2 or fewer prior lines of therapy, including those who progressed on immediate prior checkpoint inhibitors (n=19). This translated to an ORR of 21.1% in this subgroup; an additional 6 patients achieved SD and 9 had progressive disease.

“The significance of this efficacy within this [subgroup] is important as patients with melanoma, particularly BRAF wild-type melanoma, only usually have 2 or fewer lines of prior therapy with PD-1 and CLTA-4 [inhibitors] before needing to seek alternative treatment,” said lead study author Michael A. Postow, MD, a medical oncologist and chief of the Melanoma Service at Memorial Sloan Kettering Cancer Center in New York, New York, in a poster presentation of the data.

No patients who had 3 or more prior lines of therapy (n=21) derived a response. Four patients in this subgroup had SD, and 15 patients had progressive disease. Additionally, 1 patient’s best overall response was unknown.

The DCRs were 35.9% (n=14) in all patients, 52.6% (n=10) in patients with 2 or fewer prior treatments, and 20.0% (n = 4) in patients with 3 or more prior treatments. The median PFS was 9 weeks (range, 8-16), 17 weeks (range, 8-55), and 16 weeks (range, 8-19), respectively.

Baseline patient characteristics indicated that 100% of patients in the melanoma cohort were refractory to or relapsed following anti–PD-1/PD-L1 therapy. Moreover, 87.5% of patients (n=35) had immediate prior anti–PD-1/PD-L1 therapy.

Other prior treatments included anti–CLTA-4 therapy (n=28; 70.0%), investigational immunotherapy (n=17; 42.5%), MEK/ERK inhibitor(n =9; 22.5%), BRAF inhibitor (n = 5; 12.5%), and chemotherapy (n=4; 10.0%).

Ten percent (n=4) of patients derived a complete response as the best response to prior anti–PD-1/PD-L1 therapy; 7.5% (n =3) had a PR, 45.0%(n = 18) had SD, 25% (n = 10) had progressive disease, and 12.5% (n = 5) had an unknown best response to prior anti–PD-1/PD-L1 therapy.

All-grade TEAEs occurring in more than 15% of patients in the melanoma cohort included increased aspartate aminotransferase (AST; n=15; 37.5%) levels, increased alanine transaminase (ALT; n=15; 37.5%) levels, fatigue (n=11; 27.5%), and nausea (n=11; 27.5%). A proportion of each toxicity was found to be treatment related. Immune-related TRAEs included increased AST (n=13; 32.5%), increased ALT levels (n=13; 32.5%), pruritus (n=7; 17.5%),increased alkaline phosphatase levels (n=6;15.0%), and rash (n=7; 17.5%).

The MARIO-1 trial is ongoing, evaluating the combination of eganelisib and nivolumab in patients with non–small cell lung cancer (part E),triple-negative breast cancer (TNBC; part F), adrenocortical carcinoma (part G), mesothelioma (part G), and high-circulating myeloid derived suppressor cells (part H).

Investigators are also evaluating eganelisib in combination with nivolumab as second-line therapy for patients with advanced urothelial carcinoma in the phase 2 MARIO-275 trial (NCT03980041). In addition, they are examining the agent in combination with atezolizumab (Tecentriq), nab-paclitaxel (Abraxane), and bevacizumab (Avastin) as first-line therapy for patients with TNBC or renal cell carcinoma in the phase 2 MARIO-3 trial (NCT03961698).

_References:

_{1. Cohen EEW, Postow M, Sullivan RJ, et al. Updated clinical data from the squamous cell carcinoma of the head and neck (SCCHN) expansion cohort of an ongoing ph1/1b study of eganelisib (formerly IPI-549) in combination with nivolumab. Paper presented at: 2020 STIC Annual Meeting; November 9-14, 2020; virtual. Abstract 352.}

_{2. Postow M, Sullivan RJ, Cohen EEW, et al. Updated clinical data from the melanoma expansion cohort of an ongoing ph1/1b study of eganelisib (formerly IPI-549) in combination with nivolumab. Poster presented at: 2020 SITC Annual Meeting; November 9-14, 2020; virtual. Abstract 434.}