Upfront Dual Immunotherapy vs Sequencing and Salvage Strategies in MSI-H mCRC

In this segment, the panel addresses a key clinical question in MSI-H/dMMR mCRC: should dual immune checkpoint blockade with nivolumab plus ipilimumab be used universally upfront, or can clinicians safely sequence therapies and reserve CTLA-4 inhibition for later lines?

Faculty reference data from CheckMate 8HW, noting that patients were allowed to receive immunotherapy in both first- and subsequent-line settings, enabling evaluation of second progression-free survival (PFS2). Although some argue that CTLA-4 blockade can be deferred and “salvaged” later, the panel emphasizes that dual immunotherapy consistently demonstrates higher response rates, on the order of a 15% absolute improvement, and markedly prolonged progression-free survival compared with PD-1 monotherapy. Given hazard ratios, Kaplan–Meier curves, and long-term outcomes showing median PFS not reached at five years for some patients, most panelists favor upfront dual therapy despite modestly increased toxicity.

The discussion highlights the importance of shared decision-making, with faculty noting that when presented with the data, patients overwhelmingly choose combination therapy. Panelists also point out that outcomes appear inferior when patients receive chemotherapy first and immunotherapy later, reinforcing the need for early and universal MMR/MSI testing to avoid missing the optimal treatment window.

Attention then turns to the smaller subset of patients who progress despite dual immunotherapy. Salvage strategies remain poorly defined and are largely anecdotal, including immunotherapy rechallenge, chemotherapy, or local therapies such as stereotactic body radiation therapy for oligoprogression. The panel acknowledges that emerging approaches, such as novel immune targets, face development challenges given the strong frontline efficacy of existing regimens.

Overall, this segment describes a growing consensus: for MSI-H/dMMR mCRC, dual checkpoint inhibition upfront offers the greatest chance for durable disease control, whereas effective salvage options remain limited and unpredictable.