ESMO directly hit the rare target and there is also a breakthrough! The results of the KRYSTAL-1 study in coloral cancer are available

The 2022 European Society for Internal Oncology (ESMO) Annual Meeting was held

The KRAS^G12C mutation entered the field of cancer researchers as early as 40 years ago, but the development of drugs for this target has been slow to progress, so that the target was once considered a "non-druggable target"

As a carcinogenic driver gene, KRAS^G12C mutations occur in about 3-4% of CRCs and are associated

KRYSTAL-1 is a multi-cohort phase I/II study designed to assess the safety and efficacy of Adagrasib in patients with advanced solid tumors of KRAS^G12C mutation.

Figure 1 Study design of the KRYSTAL-1 experiment

As of June 16, 2022, a total of 44 patients received Adagrasib monotherapy and 32 patients received a combination of Adagrasib + cetuximab, and the baseline characteristics of patients were shown in

Figure 2 Patient baseline features

Efficacy and safety analysis of monotherapy

A total of 43 patients were able to assess efficacy, as shown in Figure 3, patients had an ORR of 19%, a disease control rate (DCR) of 86%, and a median duration of remission (DOR) of 4.

Figure 3 Disease remission in the monotherapy patient group

In Figure 4, patients had a median progression-free survival (PFS) of 5.
6 months (95% CI, 4.
1–8.
3) and a median overall survival (OS) of 19.
8 months (95% CI, 12.
5–23.
0).

Figure 4 PFS and OS in the monotherapy patient group

The safety analysis of monotherapy was shown in Figure 5 with a 93% incidence of treatment-related adverse events (TRAEs) at any level and 34% with ≥ grade 3 TRAEs, of which 2 cases were grade 4 and no grade 5 TRAEs
occurred.

Figure 5 Safety analysis of monotherapy patient groups

Efficacy and safety analysis of combination therapy

A total of 28 patients were able to assess efficacy, as shown in Figure 6, with an ORR of 46%, a DCR of 100%, and a median DOR of 7.
6 months (95% CI, 5.
7–NE).

Figure 6 Disease remission in the combination therapy patient group

In Figure 7, patients had a median PFS of 6.
9 months (95% CI, 5.
4–8.
1) and a median OS of 13.
4 months (95% CI, 9.
5–20.
1).

Figure 7 PFS and OS in the combination therapy patient group

The safety analysis of combination therapy was shown in Figure 8, with a 100% incidence of treatment-related adverse events (TRAEs) at any level and 16% with ≥ grade 3 TRAEs, of which 2 cases were grade 4 and no grade 5 TRAEs
occurred.

Figure 8 Safety analysis of the combination therapy patient group

Adagrasib monotherapy and combination therapy with cetuximab have shown good clinical activity and controlled
safety in patients with advanced CRC with KRAS^G12C mutation.

The researchers noted that the combination had higher response rates and longer PFS, and that a follow-up phase III study (KRYSTAL-10) of this combination strategy was underway, with the study design shown in
Figure 10.

Figure 9 Study design of the KRYSTAL-10 experiment

References

1.
S.
J.
Klempner, et al.
KRYSTAL-1: Updated efficacy and safety of adagrasib (MRTX849) with or without cetuximab in patients with advanced colorectal cancer (CRC) harboring a KRAS^G12Cmutation.
LBA24 2022 ESMO Congress.

Editor: Traveler

Reviewer: Jiang Zhou

Typesetting: Youshi

Execution: Small Garden