Background: This review will describe the unique mechanisms of action of Amivantamab (EGFR NSCLC) and Tebentafusp (uveal melanoma), two bispecific antibodies approved for solid tumors. It will trace their paths to FDA approval, from preclinical development through first-in-human and pivotal clinical trials, and examine the distinct safety profiles of each agent to provide insights into their therapeutic potential and clinical integration.

Methods: A PubMed search was conducted with the search terms “Bispecific Antibodies” AND “Solid Tumors” AND “EGFR-mutant NSCLC” AND “Uveal Melanoma” AND “Amivantamab” AND “Tebentafusp.”

Results: Amivantamab demonstrated efficacy in wild-type EGFR NSCLC tumors and is linked to immune cell-mediated killing and inhibition of binding to both EGFR and Met receptors. Preclinical studies of Ba/F3 cell lines containing EGFR exon20ins have found that amivantamab decreased EGFR and MET receptor expression. The phase I CHRYSALIS trial evaluated amivantamab in a dose escalation/dose expansion study. The phase 3 MARIPOSA trials investigated amivantamab in combination with chemotherapy and the tyrosine kinase inhibitor Lazertinib. Median progression-free survival was 8.3 months (95% CI: 6.5–10.9) and median overall survival was 22.8 months (95% CI: 14.6-NR). Grade 3 and higher AEs include dyspnea (7%), infusion-related reactions (5%), and hypoalbuminemia (4%). Tebentafusp is a bispecific protein fused to an anti-CD3 single-chain variable fragment that targets glycoprotein 100-positive cells, and was evaluated in two, open label phase 3 trials for uveal melanoma resulting in an overall survival of 73% in the tebentafusp group and 59% in the control group in one trial; and a median overall survival of 21.6 months in the tebentafusp group and 16.9 months in the control group (HR 0.68; 95% CI, 0.54 to 0.87) in the subsequent trial. The most common treatment-related adverse events in the tebentafusp group were cytokine-mediated events (due to T-cell activation) and skin-related events (due to glycoprotein 100–positive melanocytes), including rash (83%), pyrexia (76%), and pruritus (69%).

Conclusion: There is ample evidence for the clinical use of amivantamab and tebentafusp in non-small cell lung cancer and uveal melanoma with demonstrated efficacy and favorable safety profiles. Ongoing studies are focused on applying liquid biopsy to monitoring of treatment and prognosis.