In the setting of microsatellite-stable (MSS) metastatic colorectal cancer (mCRC), combining immune checkpoint inhibitors (ICIs) with targeted drugs is a potential approach to augment the immune response and increase immunogenicity [1]. For example, vascular endothelial growth factor receptor (VEGFR) inhibitors in addition to ICIs have shown promising activity in patients with pretreated mCRC [2-5]. Studies are exploring tyrosine kinase inhibitors (TKIs) combined with established immune checkpoint inhibitors, but also the addition of chemotherapy and the VEGF inhibitor bevacizumab to the novel antibodies botensilimab and balstilimab.

Cabozantinib/nivolumab after ≥ 4 treatment lines

The TKI cabozantinib that targets VEGFR2/KDR, MET, RET and KIT has demonstrated encouraging efficacy in heavily pretreated patients with mCRC [6]. Human immune system mouse models have revealed that cabozantinib sensitizes MSS CRC to immune checkpoint blockade [7]. Based on this observation, an investigator-initiated, single-arm, open-label, phase II study using an optimal Simon 2-stage design was conducted to test cabozantinib 40 mg OD plus nivolumab 480 mg Q4W in patients with metastatic or unresectable MSS CRC. Patients were refractory to chemotherapy in the third-line setting and beyond. Prior small molecule inhibitor therapy (including regorafenib) was not allowed. A total of 49 patients after a median of four lines of treatment were enrolled across five sites. Liver metastases were present in 35 individuals (74 %).

The trial met its primary endpoint, with a 16-week disease control rate of 40 % [8]. Partial responses and disease stability were observed in 9 % and 32 % of patients, respectively. Fourteen out of 35 patients with liver metastases (40 %) achieved disease control at 16 weeks. Median progression-free survival (PFS) and overall survival (OS) in the overall population were 3.4 and 10.9 months, respectively. Cabozantinib plus nivolumab was well tolerated and showed an adverse event (AE) profile similar to that of other ICI/TKI combinations. The most common AEs included diarrhea, fatigue, hypothyroidism, weight loss and nausea, with most of these being grade 1 or 2. None of the patients died due to side effects. Correlative data for biomarker analyses will be presented in the future from a cohort of 20 patients who underwent tumor biopsies and peripheral blood collection.

STELLAR-001: zanzalintinib ± atezolizumab

The novel oral TKI zanzalintinib targets multiple kinases including VEGFR, MET and TAM kinases (TYRO3, AXL, MER) [9]. Zanzalintinib alone and in combination with ICIs is being explored in the open-label, dose-escalation and expansion phase I STELLAR-001 study in patients with advanced solid tumors. Fontana et al. presented preliminary results from the expansion cohort of patients with MSS/mismatch repair proficient (pMMR) and RAS/BRAF wild-type mCRC at ASCO GI 2025 [10]. Patients had previously been treated with fluoropyrimidine-based chemotherapy, irinotecan and oxali­platin with or without targeted agents. Prior therapy with PD-(L)1–targeted ICIs, regorafenib, and/or trifluridine/tipiracil was exclusionary. Patients were ran­domized to either zanzalintinib 100 mg OD alone (n = 53) or zanzalintinib 100 mg OD plus atezolizumab 1,200 mg Q3W (n = 54). Almost the entire population had previously received anti-EGFR therapy, and approximately 70 % had liver metastases. PD-L1 CPS scores > 1 were present in 43 % and 37 % in the monotherapy and combination groups, respectively. Overall survival and investigator-assessed objective response rate (ORR) were the primary endpoints.

After a median follow-up of approximately 19 months, median PFS was 3.0 vs. 4.0 months with single-agent zanzalintinib compared to the combination (HR, 0.65). For OS, the analysis did not reveal a difference (11.1 vs. 11.7 months; HR, 0.89). The confirmed ORRs among evaluable patients were 1.9 % vs. 7.4 %. A sub-analysis conducted in patients without liver metastases showed that the addition of atezolizumab, compared to zanzalintinib alone, prolonged both PFS (8.2 vs. 3.3 months; HR, 0.37; Figure 1) and OS (21.1 vs. 18.5 months; HR, 0.74). In this subgroup, the 6-month OS rates were 87.8 % vs. 64.7 %, and the 12-month OS rates were 62.7 % vs. 52.3 %. As the biomarker analysis showed, PD-L1 CPS > 1 was associated with improved PFS and OS for zanzalintinib plus atezolizumab vs. zanzalintinib alone (HRs, 0.48 [95 % CI, 0.22-1.01] and 0.66 [95 % CI, 0.30-1.45] for PFS and OS, respectively).

Both regimens proved tolerable, with safety profiles consistent with each of the monotherapy agents. The most common treatment-related AEs (TRAEs) were nausea (any grade, 54 % and 36 % with the combination and monotherapy, respectively), diarrhea (52 % vs. 49 %), and fatigue (43 % vs. 21 %). Hypertension represented the most common grade 3/4 AE in the monotherapy group (13 %), while fatigue was the most common grade 3/4 AE with the combination (11 %). Treatment-emergent AEs leading to dose reductions and discontinuation of zanzalintinib occurred in 47 % and 19 % with the monotherapy, respectively, and in 50 % and 30 %, respectively, in the combination arm. Grade 5 TRAEs were reported in one patient each (2 %).

In summary, the authors noted that clinical activity was observed with zanzalintinib both as a single agent and in combination with atezolizumab in pretreated patients with mCRC, with improved outcomes with the addition of the ICI to zanzalintinib, especially in patients without liver metastases. The combination is currently being evaluated in the phase III STELLAR-303 study in patients with previously treated MSS/pMMR mCRC (NCT05425940).

Figure 1: Progression-free survival with zanzalintinib alone and combined with atezolizumab in patients without liver metastases

BOT, BAL, chemotherapy & bevacizumab

The combined use of the Fc-enhanced multifunctional CTLA-4 antibody botensilimab and the anti-PD-1 antibody balstilimab has been shown to improve clinical endpoints in the setting of MSS mCRC [11, 12]. In the phase I FOLFOX-3B study, chemotherapy with folinic acid, fluorouracil and oxaliplatin (FOLFOX) was assessed combined with the VEGF inhibitor bevacizumab as well as botensilimab at two dose levels and balstilimab over four 2-week cycles. The study followed a 3 x 3 escalation design with up to 9 patients per dose level. Botensilimab 25 or 75 mg was administered on day 1 of cycles 1 and 4. Balstilimab 240 mg, bevacizumab 5 mg/kg and FOLFOX were given on day 1 of cycles 1, 2, 3 and 4. Overall, 14 patients were enrolled, nine of whom had liver metastases. Up to two prior lines of therapy were allowed. Two patients were untreated at baseline, while five and seven received the study treatment as second-line and third-line therapy, respectively.

At ASCO GI 2025, Fakih et al. reported an encouraging ORR of 71 % in the total population, with ten patients experiencing partial responses (Figure 2) [13]. The ORR in the liver metastases cohort was 67 %. In the group of 12 patients treated in the second or third line, the ORR was 66 %. Median PFS was 7 months in the overall group. Severe immune-related AEs occurred infrequently, with only one patient requiring immune suppression for colitis and hepatitis. Two doses of botensilimab 75mg Q6W plus two doses of balstilimab 240 mg Q2W in addition to FOLFOX and bevacizumab was selected as the recommended phase II dose. This combination will be considered for further development in the first-line treatment of MSS mCRC. Additional cohorts of botensilimab 150 mg for two doses and 75 mg for four doses are currently under investigation based on a protocol amendment.

Figure 2: FOLFOX-3B: responses to FOLFOX, bevacizumab, botensilimab and balstilimab

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