Frontline Pembrolizumab or Methotrexate in Elderly, Frail, or Cisplatin-Ineligible Patients with Relapsed or Metastatic Squamous Cell Carcinoma of the Head and Neck: Results of the Randomized Phase 2 Study ELDORANDO (AIO-KHT-0115)

INTRODUCTION: Elderly, frail, or cisplatin-ineligible patients with recurrent or metastatic squamous cell carcinoma of the head and neck (R/M HNSCC) have a poor prognosis. To date, no standard of care has been defined for this population. METHODS: The randomized, open-label phase 2 study was conducted to determine whether first-line treatment with pembrolizumab (PEM) is superior to methotrexate (MTX) in elderly, frail, or cisplatin-ineligible patients with R/M HNSCC not amenable to local therapies. Patients were randomized 1:1 to receive PEM 200 mg q3w or MTX 40 mg/m2 IV weekly until disease progression or unacceptable toxicity. The primary end point was overall survival after 1 year (1YOS); secondary endpoints were time to failure of strategy (TTFS) at 1 year, objective response rate (ORR), progression-free survival (PFS), and overall survival (OS). RESULTS: Of 100 planned participants, 47 (23 in the PEM and 24 in the MTX group) were enrolled. The trial was terminated prematurely. Efficacy did not differ between the treatment arms (1YOS 17.4% for PEM vs. 37.5% for MTX [p = 0.12]). ORR was 17.4% with PEM vs. 12.5% with MTX (p = 0.70), TTFS at 1 year was 91% vs. 100% (p = 0.47), median PFS was 1.8 vs. 2.7 months (p = 0.83), and median OS was 6.1 vs. 9.7 months (p = 0.50), respectively. PD-L1 expression did not impact primary and secondary endpoints. Safety parameters favored PEM. CONCLUSION: ELDORANDO failed to demonstrate benefit of PEM over MTX regarding 1YOS, ORR, PFS, or OS. The optimal treatment strategy for fragile patients remains to be determined.