ODAC Votes Against PD-L1 as Efficacy Biomarker in Esophageal Cancers
Eleven votes were cast against the favorability of using anti–PD-1 inhibitors in patients with ESCC and a PD-L1 expression of less than 1.
Members of the committee discussed and voted on the use of PD-L1 as an efficacy biomarker across this population in the context of previous approvals for immune checkpoint inhibitors as treatment for patients with esophageal cancers.
The FDA’s Oncologic Advisory Drug Committee (ODAC) voted 11-to-1 against the favorability of using anti–PD-1 antibodies for patients with unresectable or metastatic esophageal squamous cell carcinoma (ESCC) with a PD-L1 expression of less than 1.1
Of note, 1 committee member abstained from voting.
"I voted no based on the totality of the data. Despite the small numbers, this was a statistically sound analysis," Neil Vasan, MD, PhD, a physician-scientist in the Department of Medicine and the Herbert Irving Comprehensive Cancer Center at Columbia University Irving Medical Center, said in the meeting.
Although prior data have shown that PD-L1 expression status may predict clinical efficacy with anti–PD-1 therapy in this ESCC population, investigators have used different strategies to evaluate PD-L1 expression and thresholds for defining PD-L1–positive disease. The FDA asked ODAC members to consider the strength of PD-L1 expression as a predictive biomarker for patient selection, varying risk-benefit assessments across different PD-L1 expression subgroups, and the adequacy of prior data to restrict subsequent approvals of immune checkpoint inhibitors based on PD-L1 expression.
Members of the committee discussed and voted on the use of PD-L1 as an efficacy biomarker across this population in the context of previous approvals for immune checkpoint inhibitors as treatment for patients with esophageal cancers. These previously approved agents include pembrolizumab (Keytruda), nivolumab (Opdivo), and ipilimumab (Yervoy). Additionally, the ODAC discussed these questions in the context of a supplemental biologics license application (sBLA) for tislelizumab (Tevimbra), which is currently under review by the FDA.
Pembrolizumab Data
In March 2021, the FDA approved pembrolizumab plus platinum- and fluoropyrimidine-containing chemotherapy for patients with metastatic or locally advanced esophageal or gastroesophageal (GEJ) carcinoma not eligible to undergo surgical resection or definitive chemoradiotherapy.2 Supporting data for this approval came from the phase 3 KEYNOTE-590 trial (NCT03189719).
In this trial, 749 patients were randomly assigned 1:1 to receive pembrolizumab or placebo plus cisplatin and fluorouracil until progressive disease or unacceptable toxicity. The trial’s primary end points were overall survival (OS) and progression-free survival (PFS) per investigator assessment using RECIST v1.1 criteria.
The median OS with pembrolizumab/chemotherapy was 12.4 months (95% CI, 10.5-14.0) compared with 9.8 months (95% CI, 8.8-10.8) in patients who received chemotherapy alone (HR, 0.73; 95% CI, 0.62-0.86; P <.0001). Data also showed a median PFS of 6.3 months (95% CI, 6.2-6.9) vs 5.8 months (95% CI, 5.0-6.0) in each respective arm (HR, 0.65; 95% CI, 0.55-0.76; P <.0001).
Frequent adverse effects (AEs) in the pembrolizumab arm included nausea, diarrhea, constipation, vomiting, stomatitis, fatigue, and decreased appetite.
Nivolumab/Ipilimumab Data
The FDA approved frontline nivolumab plus fluoropyrimidine- and platinum-based chemotherapy for patients with unresectable advanced or metastatic ESCC regardless of PD-L1 status in May 2022.3 Additionally, the agency approved nivolumab in combination with ipilimumab for the same patient population. Supporting data for these approvals came from the phase 3 CheckMate-648 trial (NCT03143153).
Investigators of the CheckMate-648 trial randomly assigned patients 1:1:1 to receive nivolumab/chemotherapy (n = 321), nivolumab/ipilimumab (n = 325), or chemotherapy alone (n = 325). The primary end points were OS and PFS per blinded independent central review (BICR) among patients with PD-L1 expression of at least 1%.
Treatment with nivolumab/chemotherapy elicited an OS improvement compared with chemotherapy alone among patients with PD-L1–positive tumors (HR, 0.54; 95% CI, 0.41-0.71; P <.0001) as well as all randomly assigned patients (HR, 0.74; 95% CI, 0.61-0.90; P = .0021). Data also showed PFS improvements with nivolumab/chemotherapy in the PD-L1–positive population (HR, 0.65; 95% CI, 0.49-0.86; P = .0023) and all patients, although the improvement in the latter population did not reach statistical significance (HR, 0.81; 95% CI, 0.67-0.99; P = not significant).
Combining nivolumab with ipilimumab improved OS vs chemotherapy among those with PD-L1–positive disease (HR, 0.64; 95% CI, 0.49-0.84; P = .0010) and all randomly assigned patients (HR, 0.78; 95% CI, 0.65-0.95; P = .0110). PFS outcomes with nivolumab/ipilimumab did not reach statistical significance in the PD-L1–positive population; this end point was hierarchically tested for all randomly assigned patients (HR, 1.02; 95% CI, 0.78-1.34; P = not significant).
Among patients who received nivolumab/chemotherapy and nivolumab/ipilimumab, respectively, 62% and 69% experienced serious AEs. Serious AEs across both treatment arms included pneumonia (11.0% vs 3.7%) and dysphagia (7.0% vs 3.7%).
Tislelizumab Data
In September 2023, the FDA accepted a sBLA for first-line tislelizumab in unresectable, recurrent, locally advanced, or metastatic ESCC after prior platinum-based chemotherapy.4 The agency assigned a Prescription Drug User Fee Act date in the second half of 2024 for approving tislelizumab in this population.
Supporting data for the sBLA came from the phase 3 RATIONALE 306 trial (NCT03783442). Investigators presented updated findings from the RATIONALE 306 trial at the 2024 American Society of Clinical Oncology (ASCO) Annual Meeting.5
As of the data cutoff date of November 24, 2023, 649 patients were randomly assigned to receive tislelizumab at 200 mg (n = 326) or placebo (n = 323) once every 3 weeks in combination with platinum plus fluoropyrimidine or paclitaxel until progressive disease or intolerable toxicity. The trial’s primary end point was OS across the intent-to-treat (ITT) population, with secondary end points including investigator-assessed PFS, objective response rate (ORR), OS in patients with PD-L1 expression of 10% or higher, and safety.
Among all evaluable patients, the median OS was 17.2 months (95% CI, 15.8-20.1) with tislelizumab/chemotherapy vs 10.6 months (95% CI, 9.3-12.0) with chemotherapy alone (HR, 0.70; 95% CI, 0.59-0.83). Additionally, the median OS in each arm was 16.6 months (95% CI, 15.3-23.4) vs 10.0 months (95% CI, 8.6-13.3) for patients with a PD-L1 tumor area positivity (TAP) score of 10% or higher (HR, 0.70; 95% CI, 0.52-0.95). Among those with a PD-L1 TAP score of lower than 10, the median OS was 16.0 months (95% CI, 12.3-19.6) vs 10.4 months (95% CI, 9.0-13.4) in each respective arm (HR, 0.77; 95% CI, 0.60-0.99).
At least 1 treatment-related AE (TRAE) occurred in 96.6% of patients in the tislelizumab arm vs 96.3% of the chemotherapy alone arm. Grade 3 or higher TRAEs affected 67.0% vs 64.5% from each arm; the most common toxicities of this type included neutrophil count decreases (30.9% vs 32.7%), anemia (14.8% vs 12.8%), and white blood cell count decreases (10.8% vs 15.6%).
References
- September 26, 2024 Meeting of the Oncologic Drugs Advisory Committee (ODAC). Streamed live September 26, 2024. Accessed September 26, 2024. https://tinyurl.com/mt6276np
- FDA approves pembrolizumab for esophageal or GEJ carcinoma. News release. FDA. March 22, 2021. Accessed September 26, 2024. https://tinyurl.com/yc7r28fe
- 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 September 26, 2024. https://bit.ly/3GGDd6j
- BeiGene announces positive regulatory updates in Europe and the U.S. after recently regaining global rights for TEVIMBRA®. News release. BeiGene, Ltd. September 19, 2023. Accessed September 26, 2024. https://tinyurl.com/2w3zd73c
- Yoon HH, Kato K, Raymond E, et al. Global, randomized, phase III study of tislelizumab plus chemotherapy versus placebo plus chemotherapy as first-line treatment for advanced/metastatic esophageal squamous cell carcinoma (RATIONALE-306 update): Minimum 3-year survival follow-up. J Clin Oncol. 2024;42(suppl 16):4032. doi:10.1200/JCO.2024.42.16_suppl.4032
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