After a median follow-up of 7.8 months (range, 0.1 to 13.9), the median progression-free survival was 5.6 months (95% confidence interval [CI], 4.2 to 6.3) and 3.9 months (95% CI, 3.7 to 5.8) in the 960-mg sotorasib–panitumumab and 240-mg sotorasib–panitumumab groups, respectively, as compared with 2.2 months (95% CI, 1.9 to 3.9) in the standard-care group....In this phase 3 trial of a KRAS G12C inhibitor plus an EGFR inhibitor in patients with chemorefractory metastatic colorectal cancer, both doses of sotorasib in combination with panitumumab resulted in longer progression-free survival than standard treatment.

The study met its primary endpoint. Both soto+pani arms demonstrated statistically significant superior PFS compared to SOC: soto960+pani HR=0.49 (95% CI: 0.30, 0.80; p=0.006), and soto240+pani HR=0.58 (95% CI: 0.36, 0.93; p=0.03)….In the first phase 3 study for a KRASG12C-inhibitor plus an anti-EGFR antibody in chemorefractory mCRC, the primary endpoint was met and both doses of soto+pani showed superior PFS vs SOC. Soto960+pani demonstrated clinically meaningful benefit across PFS and key secondary endpoints (ORR, DCR, DOR) and was tolerable with lower rates of Grade ≥3 TRAEs vs SOC.

In this phase 3, multicenter, open-label, randomized trial, we assigned patients with chemorefractory metastatic colorectal cancer with mutated KRAS G12C who had not received previous treatment with a KRAS G12C inhibitor to receive sotorasib at a dose of 960 mg once daily plus panitumumab (53 patients), sotorasib at a dose of 240 mg once daily plus panitumumab (53 patients)...both doses of sotorasib in combination with panitumumab resulted in longer progression-free survival than standard treatment.

Objective response rate...24/40 (60) (43.3-75.1)...These data confirm the promising safety and efficacy for Soto + Pmab and FOLFIRI in previously treated KRAS G12C-mutated mCRC.

Tumor shrinkage of any magnitude was observed in 35 (87.5%) pts….This dataset provides further evidence of safety and tolerability for the combination of Soto and Pmab in heavily pretreated pts with KRAS G12C-mutated mCRC, with 3-fold higher response than previously observed with Soto monotherapy...

Early data from the CodeBreaK 101 phase Ib dose exploration (n=8) and expansion (n=18) cohorts showed promising antitumor activity for the combination of Soto and panitumumab (Pmab), an EGFR antibody, in chemorefractory KRAS G12C-mutated metastatic CRC (mCRC). Here, we report results from the fully enrolled dose expansion cohort of 40 pts with refractory mCRC....Confirmed ORR was 30% (95% CI: 16.6, 46.5). Disease control rate was 90% (95% CI: 76.3, 97.2). Tumor shrinkage of any magnitude was observed in 35 (87.5%) pts....This dataset provides further evidence of safety and tolerability for the combination of Soto and Pmab in heavily pretreated pts with KRAS G12C-mutated mCRC, with 3-fold higher response than previously observed with Soto monotherapy, supporting further development of this combination.

There was 1 confirmed partial response, 5 stable disease (SD), 1 progressive disease (PD), and 1 not evaluated but with clinical PD. Of pts with prior Soto, 4 had decrease in sum of target lesions; 4 had SD and 1 with PD developed new lesions despite a decrease in size of target lesions....Combination of Soto (960 mg QD) and PMab (6mg/kg IV Q2W) was safe and tolerable with promising efficacy in heavily pretreated pts with KRAS p.G12C-mutated CRC.

We also treated two KRASG12C PDX-CRC mouse models, B8026 and C1177, with sotorasib, panitumumab, trametinib, as well as doublet and triplet combos with sotorasib….In our PDX-CRC mouse models, both B8026 and C1177 are responsive to sotorasib and panitumumab....Both models however are responsive to doublet combos of sotorasib with either agent, with triplet combo providing the greatest effectiveness in reducing tumor volume.

In efficacy studies using the NCI-H358 xenograft model, significantly enhanced anti-tumor activity was observed with a minimally efficacious dose of sotorasib in combination with afatinib, RMC-4550, or a CDK4/6 inhibitor (palbociclib). Furthermore, enhanced anti-tumor activity was observed with sotorasib in combination with a MEK inhibitor or with the anti-EGFR monoclonal antibody panitumumab in a CRC KRAS p.G12C PDX model.