FDA Approves Two Nivolumab Combinations Unresectable Advanced ESCC

Nivolumab (Opdivo) in combination with fluoropyrimidine- and platinum-containing chemotherapy and nivolumab plus ipilimumab has been approved by the FDA for first-line treatment of adult patients with unresectable advanced, recurrent or metastatic esophageal squamous cell carcinoma (ESCC), regardless of PD-L1 status, according to Bristol Myers Squibb, in a press release.¹

Prior to the approval, a supplemental biologics license application (sBLA) for this combination was accepted by the FDA in September, 2021. The Prescription Drug User Fee Act (PDUFA) for a decision on the sBLA was set to May 28, 2022 and 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%.²

Acceptance was based on the phase 3 CheckMate-648 study (NCT03143153), where findings showed nivolumab plus ipilimumab and nivolumab plus chemotherapy to show statistically significant results.¹

“Today brings welcome news for many advanced or metastatic esophageal squamous cell carcinoma patients and oncologists,” said Jaffer A. Ajani, MD, CheckMate-648 co-first author and lead United Steats investigator, and professor of Gastrointestinal Medical Oncology at The University of Texas MD Anderson Cancer Center, in a press release. “Unresectable advanced or metastatic esophageal squamous cell carcinoma is a challenging disease, and there’s a need for additional treatment options that may extend survival in the first-line setting.3,4 In the CheckMate -648 trial, two nivolumab-based combinations showed a survival benefit compared to chemotherapy alone, offering new treatment options regardless of PD-L1 status.”

The study randomized 321 patients in a 1:1:1 ratio where they received nivolumab 240 mg twice per week (Q2W) with chemotherapy of fluorouracil plus cisplatin Q4W in the first treatment arm. In the second arm, 325 patients were given nivolumab 3 mg/kg Q2W in combination with ipilimumab 1 mg/kg Q6W. The third treatment arm had 324 patients who received chemotherapy Q4W.³

Eligibility was open to patients who 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, ECOG performance status, and the number of organs with metastases.

The population at baseline was 70% Asian and 30% non-Asian in all treatment arms with the majority of patients having an ECOG performance status of 1 compared with 0. This includes 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 over half of the patients in each arm. However, almost more than 45% of patients showed PD-L1 of 1% or higher in each arm.

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

Primary end points of the study included overall survival (OS) in the PD-L1-positive population and progression-free survival (PFS). Secondary end points consisted of OS and PFS in all randomized patients, in addition to objective response rate (ORR).

Median duration of study treatment was longest in the nivolumab/chemotherapy arm at 5.7 months (range, 0.1-30.6). Disease progression adverse events (AEs), related or unrelated to treatment, led to discontinued therapy of ninety-two percent of patients in this arm.

Those who received nivolumab/ipilimumab had a median treatment duration of 2.8 months (range, 0.0-24.0) and 93% discontinued treatment. Those who received chemotherapy alone had a median duration of 3.4 months (range, 0.0-19.5) and 99% discontinued treatment.

Superior overall survival with durable responses in previously untreated patients with advanced ESCC compared with chemotherapy alone was achieved in combination of nivolumab with either ipilimumab or chemotherapy. Nivolumab plus chemotherapy in those with PD-L1-positive tumors specifically showed a median OS of 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).

An OS benefit with nivolumab/chemotherapy was also shown in the all-randomized population compared with the chemotherapy-only group (HR, 0.74; 99.1% CI, 0.58-0.96; P =.0021). Median PFS was observed in this experimental arm at 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). In the all-randomized population, the PFS observed 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 had an ORR of 53% (95% CI, 45%-61%) with nivolumab plus chemotherapy compared with 20% (95% CI, 14%-27%) with chemotherapy alone. The median duration of response (DOR) with the combination was 8.4 months (9% CI, 6.9-12.4) compared with 5.7 months (95% CI, 4.4-8.7) with just chemotherapy.

The ORR was 47% (95% CI, 42%-53%) versus 27% (95% CI, 22%-32%) in all randomized patients who were treated with nivolumab plus chemotherapy and 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.

Comparing the combination of nivolumab plus ipilimumab with chemotherapy in those with PD-L1 expression of 1% or higher, showed median OS to be 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). The immunotherapy combination reached a median OS of 12.8 months (95% CI, 11.3-15.5) in the all-randomized population,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. However, it was assumed that PFS per investigator assessment in the PD-L1-positive population would improve with the immunotherapy combination (HR, 0.83;95 CI, 0.64-1.07) as well as in the all-randomized population (HR, 1.01; 95$ CI, 0.85-1.21).

Nnivolumab/ipilimumab had an observed ORR of 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).

The ORR was 28% (95% I, 23%-33%) in all randomized patients with nivolumab/ipilimumab compared to 27% (95% CI, 22%-32%) with chemotherapy. 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.

Treatment-related AEs (TRAEs)of any grade had occurred in at least 10% of patients. Between the PD-L1-positive and all-treated populations, AEs remained consistent, and across the treatment arms, few grade 3 or 4 events were seen. Those observed included endocrine, gastrointestinal, hepatitis, pulmonary, renal, and skin-related.

“Today’s approvals bring 2 first-line immunotherapy-based treatment options at once, Opdivo in combination with chemotherapy and Opdivo plus Yervoy as the first dual immunotherapy option, to newly diagnosed patients with unresectable advanced or metastatic esophageal squamous cell carcinoma, further building on the role of Opdivo-based regimens in upper gastroesophageal cancers,” stated Adam Lenkowsky, senior vice president and general manager, US, Cardiovascular, Immunology, Oncology, Bristol Myers Squibb.¹

_REFERENCES:

_{1. U.S. Food and Drug Administration approves two Opdivo® (nivolumab)-based regimens as first-line treatments for unresectable advanced or metastatic esophageal squamous cell carcinoma. News release. Bristol Myers Squibb. May 27, 2022. Accessed May 27, 2022. https://bit.ly/3z4SxYS}

_{2. 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}

_{3. 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}