Divarasib has demonstrated efficacy in KRAS G12C-mutated NSCLC with ORR 53.4% and PFS 13.1 months. Although adverse events were frequent (93%), the vast majority were grade 1 or 2. These positive phase I results have prompted further investigation with phase II/III as well as combination agent trials which are summarized in Table 2. In colorectal cancers divarasib is being studied in combination with cetuximab, FOLFOX, and FOLFIRI (NCT04929223). Early data on the divarasib plus cetuximab combination show an ORR of 62% [8]. Although grade 3 and higher adverse events were reported in 38% of patients, treatment discontinuation was not required in most cases. In NSCLC divarasib is being studied as monotherapy in phase II/III trials (NCT03178552) and in combination with pembrolizumab (NCT05789082). Additionally, an exploratory SHP2 inhibitor, GDC-1971, is being added to divarasib (NCT04449874).

Sotorasib (Lumakras, Amgen) was one of the first KRAS G12C inhibitors and was approved by the Federal Drug Administration (FDA) in 2021 in the second-line treatment of NSCLC with KRAS G12C mutations based on CodeBreak100. The trial enrolled 174 participants who received sotorasib at 960 mg daily after a median of two prior lines of therapy. In a pooled analysis of phase I/II sotorasib data, ORR was 41% (95% CI 33.3–48.4) with PFS of 6.3 months (95% CI 5.3–8.2) [9]. The duration of response (DOR) was 12.3 months (95% CI 7.1–15.0) with median OS of 12.5 months (95% CI 10.0–17.8). Importantly there were no adverse events that led to treatment discontinuation. In another analysis of real-world outcomes with sotorasib in recurrent, metastatic KRAS G12C-mutated NSCLC, authors reported a median PFS of 9.3 months (95% CI 7.3–11.8) and median OS of 16.8 months (95% CI 12.7–22.3) [10]. Efficacy has been limited by resistance through increased expression of integrin B4 triggering AKT-mTOR bypass signaling as well as upregulated activation of the WNT-beta-catenin pathway [11]. Table 3 compares divarasib to existing KRAS G12C inhibitors, sotorasib and adagrasib.

The phase III CodeBreak200 compared sotorasib with docetaxel in previously treated NSCLC patients with KRAS G12C mutations. Sotorasib demonstrated a median PFS of 5.6 months (95% CI 4.3–7.8) versus docetaxel of 4.5 months (95% CI 3.0–5.7). However the FDA’s Oncologic Drug Advisory Committee (ODAC) meeting voted that the PFS in CodeBreak200 could not be reliably determined [12]. This was a particularly interesting ODAC, where instead of voting on whether CodeBreaK 200 should be used to convert the accelerated approval of sotorasib to the traditional approval, committee members were asked to vote on whether the primary endpoint of PFS per blinded independent central review (BICR) could be reliably interpreted.

While the CodeBreaK 200 study met its primary endpoint, which was statistically significant, the difference in PFS was small between the two arms and there was no difference in OS. Additionally, the FDA shared concerns on the study conduct. For example, it observed that early dropouts were seen more often with the docetaxel arm, where the investigator assessments of “progression of disease” may have been biased and favored the sotorasib arm, as there were crossover of patients from docetaxel to sotorasib prior to the BICR assessment. Further concerns included lack of adherence to imaging assessment protocols as multiple evaluations appear to have been conducted by BICR to “resolve discrepancies” between investigator and BICR.

The field of KRAS is rapidly evolving. Especially with sotorasib falling short of initial expectations in CodeBreaK 200, this leaves the door open for multiple other KRAS G12C competitors to continue to be developed for use in KRAS G12C NSCLC as well as other tumor types.

In the phase I/II KRYSTAL-1 study, patients with KRAS G12C-mutated NSCLC received adagrasib (Mirati Therapeutics) at 600 mg twice per day (BID). At data cut-off, 116 patients with a median of two prior lines of treatment were enrolled and ORR was 42.9% [13]. The median PFS was 6.5 months (95% CI 4.7–8.4) and median OS was 12.6 months (95% CI 9.2–19.2). The median DOR was 8.5 months (95% CI 6.2–13.8). Adagrasib demonstrated central nervous system (CNS) activity with an ORR of 33% and disease control rate (DCR) 85% in patients with stable, previously treated brain metastases [13, 14]. Adagrasib treatment-related events were common (97.4% of participants), including grade 3 or higher adverse events in 44.8% [14]. The most common toxicities include diarrhea (70.7%), nausea (69.8%), fatigue (59.5%), and vomiting (56.9%). Adagrasib was discontinued owing to adverse events in 6.9% of participants. These findings led to accelerated approval by the FDA in December 2022 for previously treated NSCLC with KRAS G12C mutations.

Currently, sotorasib is priced at US$281.55 per 320 mg pill or US$844.65 per day. Adagrasib is priced at US$147.66 per 200 mg pill or US$885.96 per day. Although pricing information for divarasib is not yet available, additional competitors may drive the price down to decrease the financial toxicity associated with taking newer targeted agents.

Garsorasib or D-1553 is another potent and selective KRAS G12C inhibitor in development. In Phase I results of patients with KRAS G12C-mutated NSCLC, the optimal dose was 600 mg BID [15]. In the dose expansion cohort including 79 patients, 94.5% experienced adverse events including 38% grade 3 or 4 events. In efficacy analysis of 74 patients ORR was 40.5% with median PFS of 8.2 months and median DOR of 7.1 months. In patients with brain metastases, the ORR was 17%. Studies of garsorasib are ongoing.