FDA Considers Approval Application for Nivolumab Plus Ipilimumab With Chemotherapy for Unresectable Advanced ESCC

A supplemental biologics license application (sBLA) for nivolumab (Opdivo) in combination with ipilimumab (Yervoy) and fluoropyrimidine- and platinum-containing chemotherapy for the frontline treatment of adult patients with unresectable advanced, recurrent or metastatic esophageal squamous cell carcinoma (ESCC) has been accepted by the FDA, announced Bristol Myers Squibb, in a press release.¹

“Last year, over 19,000 people were diagnosed with esophageal cancer in the United States, and 15,000 people died as a result of this very aggressive disease,” said Ian M. Waxman, MD, development lead, gastrointestinal cancers, Bristol Myers Squibb, in the press release. “Additional treatment options are needed to improve upon outcomes achieved with the current standard of care. We are confident that our immunotherapy-based combinations can provide further clinical benefit and address this critical need.”

The Prescription Drug User Fee Act (PDUFA) for a decision on the sBLA has been set to May 28, 2022. The application is supported by data from the phase 3 CheckMate-647 clinical trial, which explored the combination in patients with unresectable advanced or metastatic ESCC including those with tumor cell PD-L1 expression ≥1%.

In the CheckMate-648 study (NCT03143153), investigators observed the coprimary end points of overall survival (OS) in the PD-L1-positive population and progression-free survival (PFS), as well as the secondary end points of OS and PFS in all randomized patients, and objective response rate (ORR). Following a 1:1:1 randomization ratio, 321 patients received nivolumab 240 mg twice per week (Q2W) with chemotherapy of fluorouracil plus cisplatin Q4W in the first treatment arm, and in the second, 325 patients were given nivolumab 3 mg/kg Q2W in combination with ipilimumab 1 mg/kg Q6W. In the third treatment arm, 324 patients received chemotherapy Q4W.²

All patients included in the study had an ECOG performance status of 0 or 1, received no prior systemic therapy for advanced disease, and had measurable disease. Patients were stratified by PD-L1 expression of 1% of more versus less than 1%, region, EGOC performance status, and the number of organs with metastases.

At baseline, the population was 70% Asian and 30% non-Asian in all treatment arms. The majority of patients had an ECOG performance status of 1 compared with 0, including 54% of those in the nivolumab/chemotherapy arm, 54% of the nivolumab plus ipilimumab group, and 53% of the chemotherapy-only group. PD-L1 expression was below 1% in most than half of the patients in each arm, but almost more than 45% of patients in each arm did show PD-L1 of 1% or higher.

In terms of metastases, 51% of patients in each arm who had metastatic disease showed metastases in 2 or more organs.

The median duration of study treatment was longest in the nivolumab/chemotherapy arm 5.7 months (range, 0.1-30.6). ninety-two percent of patients in the arm discontinued therapy due to either disease progression adverse events (AEs) related or unrelated to treatment, at the patient’s request for another reason. Patients who received nivolumab/ipilimumab had a median treatment duration of 2.8 months (range, 0.0-24.0) with 93% having discontinued treatment. Finally, those who received chemotherapy alone had a median duration of 3.4 months (range, 0.0-19.5) with 99% having discontinued treatment.

The combination of nivolumab in combination with either ipilimumab or chemotherapy achieved superior overall survival with durable responses in previously untreated patients with advanced ESCC compared with chemotherapy alone. Specifically, with nivolumab plus chemotherapy in those with PD-L1-positive tumors, the median OS was 15.4 months (95% CI, 11.9-19.5) compared with 9.1 months (95% CI, 7.7-10.0) with chemotherapy alone (HR, 0.54; 99.5% CI, 0.37-0.80; P <.0001). There was also an OS benefit with nivolumab/chemotherapy in the all-randomized population compared with the chemotherapy-only group (HR, 0.74; 99.1% CI, 0.58-0.96; P =.0021). The median PFS observed in this experimental arm was 6.9 months (95% CI, 5.7-8.3) compared with 4.4 months (95% CI, 2.9-5.8) in the chemotherapy-alone arm (HR, 0.65; 98.5% CI, 0.46-0.92; P = .0023). The PFS observed in the all-randomized population also favored the combination over chemotherapy alone ((HR, 0.81;98.5% CI, 0.64-1.04; P =.0355).

In terms of response, the PD-1-positive subgroup, the ORR was 53% (95% CI, 45%-61%) with nivolumab plus chemotherapy compared with only 20% (95% CI, 14%-27%) with chemotherapy alone. The median duration of response (DOR) was 8.4 months (9% CI, 6.9-12.4) with the combination compared with 5.7 months (95% CI, 4.4-8.7) with just chemotherapy.

In all randomized patients who were treated with nivolumab plus chemotherapy, the ORR was 47% (95% CI, 42%-53%) versus 27% (95% CI, 22%-32%) with chemotherapy alone. The median DOR was 8.2 months (95% CI, 6.9-9.7) versus 7.1 months (95% CI, 5.7-8.2), respectively.

Looking at the combination of nivolumab plus ipilimumab compared with chemotherapy in those with PD-L1 expression of 1% or higher, the median OS was 13.7 months (95% CI, 11.2-17.0) compared with 9.1 months (95% CI, 7.7-10.0). The HR for the difference was 0.64 (95% CI, 0.46-0.90; P =.0010). In the all-randomized population, the immunotherapy combination achieved a median OS of 12.8 months (95% CI, 11.3-15.5) compared with 10.7 months (95% CI, 9.4-11.9) with chemotherapy (HR, 0.78; 98.2% C, 0.62-0.98; P =.0110.

The median PFS was not met with the combination of nivolumab plus ipilimumab compared with chemotherapy, but it was assumed that the immunotherapy combination would improve PFS per investigator assessment in the PD-L1-positive population (HR, 0.83;95 CI, 0.64-1.07) and in the all-randomized population (HR, 1.01; 95$ CI, 0.85-1.21).

The ORR observed with nivolumab/ipilimumab was 35% (95% CI, 28%-43%) compared with 20% (95% CI, 14%-27%) with chemotherapy in the PD-L1-positive patients. The median DOR was 11.8 months (95% CI, 7.1-27.4) versus 5.7 months (95% CI, 4.4-8.7), respectively.

In all randomized patients, the ORR was 28% (95% I, 23%-33%) with nivolumab/ipilimumab compared 27% (95% CI, 22%-32%) in the chemotherapy arm. The median DOR was 11.1 months (95% CI, 8.3-14.0) compared with 7.1 months (95% CI, 5.7-8.2), respectively.

Safety results showed that any grade treatment-related AEs (TRAEs) occurred in at least 10% of patients. AEs were consistent in the PD-L1-positive and all-treated populations. There were few grade 3/4 events observed across the 3 treatment arms. The nature of the TRAEs observed was endocrine, gastrointestinal, hepatitis, pulmonary, renal, and skin-related.

_References:

_{1. U.S. Food and Drug Administration accepts Bristol Myers Squibb’s applications for Opdivo (nivolumab) + Yervoy (ipilimumab) and opdivo + chemotherapy for unresectable advanced, recurrent or metastatic esophageal squamous cell carcinoma. News release. Bristol Myers Squibb. September 27, 2021. Accessed September 27, 2021. https://bit.ly/3m5ED0a}

_{2. Chau I, Doki Y, Ajani JA, et al. Nivolumab (NIVO) plus ipilimumab (IPI) or NIVO plus chemotherapy (chemo) versus chemo as first-line (1L) treatment for advanced esophageal squamous cell carcinoma (ESCC): First results of the CheckMate 648 study. J Clin Oncol. 2021 39; (suppl 15; abstr LBA4001). doi: 10.1200/JCO.2021.39.15_suppl.LBA4001}