After Progression: Navigating Second-Line Options and Unmet Needs

This segment addresses one of the most pressing challenges in advanced SCAC: management after progression on first-line carboplatin, paclitaxel, and retifanlimab. POD1UM-303 established a clear first-line standard; however, optimal second-line strategies remain poorly defined and represent a significant unmet need.

Treatment decisions are largely guided by the timing and pattern of disease progression. Patients who progress early (within a few months of completing chemotherapy) are considered resistant to platinum, taxanes, and immunotherapy. In this setting, options are limited, and clinical trial enrollment is strongly preferred whenever available. In the absence of trials, clinicians may consider alternative chemotherapy backbones such as irinotecan-based regimens or off-label approaches. Anti-EGFR therapy combined with irinotecan is sometimes used, supported by small institutional experiences and the observation that most SCAC tumors are RAS wild-type.

For patients who experience more durable benefit, such as progression after a year or longer of disease control, treatment rechallenge may be reasonable. Options include oxaliplatin-based regimens (eg, FOLFOX) or other agents selected to minimize cross-resistance and account for residual toxicities such as neuropathy. Fluoropyrimidine-based therapies or capecitabine monotherapy may also provide disease stability in selected patients.

Both experts emphasized the limitations of current NCCN guidance, which lists multiple options but provides little direction on sequencing or patient selection. The discussion highlights the critical need for prospective studies to define evidence-based second-line strategies. Until such data are available, management remains individualized, with clinical trial participation prioritized and treatment selection focused on avoiding cross-resistance and preserving quality of life.