What trials are testing immunotherapy combinations for MSS colorectal cancer and what early results exist?

Executive summary (2–3 sentences)

Microsatellite-stable (MSS) colorectal cancer has largely been refractory to single‑agent immune checkpoint inhibitors, so current clinical research is focused on rational combinations—checkpoint dual blockade, immunotherapy plus targeted agents, chemo/radiation priming, bispecifics and cellular/viral strategies—to convert “cold” tumors into immune‑responsive ones ^{[1] [2] [3]}. Early signals are mixed: some combination regimens show encouraging response rates in small or early‑phase studies (notably botensilimab + balstilimab and selected targeted‑immunotherapy pairings), while other randomized efforts have delivered disappointing or equivocal PFS/response results for unselected MSS populations ^{[4] [5] [1]}.

1. The problem: why MSS colorectal cancer resists single‑agent immunotherapy

Decades of trials have established that single‑agent PD‑1/PD‑L1 or CTLA‑4 inhibitors produce essentially no meaningful activity in chemotherapy‑refractory MSS colorectal cancer—early basket and cohort studies of pembrolizumab, nivolumab and atezolizumab showed negligible objective responses and very short median PFS in MSS patients (PFS ~1–2 months in some cohorts) ^{[1] [2] [5]}.

2. Dual checkpoint blockade and next‑generation CTLA‑4 agents — renewed hope in early studies

Combining PD‑1 pathway blockade with CTLA‑4 inhibition is a well‑tested tactic; classical combinations (nivolumab + ipilimumab or durvalumab + tremelimumab) produced poor signals in MSS cohorts in several trials, with median PFS measured in weeks and no clear clinical benefit in many analyses ^{[1] [6]}. By contrast, novel engineered CTLA‑4 agents paired with PD‑1 inhibitors have produced encouraging early data: the phase 1 trial of botensilimab (an Fc‑engineered anti‑CTLA‑4) plus balstilimab (anti‑PD‑1) reported tolerability and “encouraging clinical responses” in relapsed/refractory MSS mCRC, prompting attention to this class as a potential path forward ^{[4] [5]}.

3. Targeted therapy + immunotherapy: biological rationale and emerging signals

Targeted agents that remodel the tumor microenvironment—anti‑angiogenics, multikinase inhibitors—are being combined with ICIs to recruit T cells and potentiate responses; single‑center and phase II reports (eg, regorafenib + nivolumab or regorafenib + avelumab in REGOMUNE/REGONIVO–type programs) demonstrated activity in MSS patients in early cohorts and motivated larger trials and randomized testing ^{[7] [8] [6]}. Real‑world and exploratory analyses also indicate targeted‑immunotherapy combos may outperform targeted therapy alone in later‑line MSS mCRC, though these are largely nonrandomized and hypothesis‑generating ^[9].

4. Chemo, radiation and epigenetic priming: turning cold tumors hot

Several trials are evaluating whether cytotoxic chemotherapy, radiotherapy or epigenetic agents can “prime” MSS tumors for subsequent ICI by increasing neoantigen release or T‑cell infiltration; examples include trials adding PD‑1/PD‑L1 blockade to standard chemo+bevacizumab backbones (multiple proof‑of‑concept studies and the MODUL cohort testing FP+BEV+atezolizumab) and radiation‑added designs pairing stereotactic or fractionated RT with anti‑PD‑1 plus anti‑CTLA‑4 ^{[8] [6] [10]}. Results so far are heterogeneous: some cohorts report PFS gains or disease control in subsets, but randomized confirmation is limited and benefit appears to be enriched in molecularly or anatomically defined subgroups ^{[5] [8]}.

5. Bispecifics, vaccines and cellular approaches: targeted immune engagement

Novel modalities—CEA‑targeted T‑cell bispecifics combined with ICIs, autologous TIL programs and in situ oncolytic strategies—have produced early partial responses and disease stabilization in MSS patients in phase I studies (eg, CEA‑TCB + atezolizumab reported responses and prolonged PFS in some responders) and remain active areas of investigation ^{[11] [8]}. These approaches aim to bypass the need for a high baseline mutation/neoantigen load by directly engaging T cells with tumor antigens.

6. What the early results mean and what’s missing

The landscape is one of qualified optimism: novel CTLA‑4/PD‑1 pairings (botensilimab + balstilimab) and selected targeted‑IO combinations have produced “encouraging” early responses in refractory MSS mCRC and prompted larger studies, whereas older dual‑checkpoint and single‑agent strategies largely failed to move the needle ^{[4] [1] [7]}. Crucially, many positive signals come from small, early‑phase or nonrandomized cohorts and are frequently enriched in molecularly selected subgroups; randomized, phase III confirmation in broadly unselected MSS populations remains sparse and is the decisive unmet evidence gap identified across reviews ^{[2] [12] [9]}.