KRAS G12C inhibitors show promise in KRAS G12C-mutated NSCLC

07 Apr 2021 byChristina Lau
KRAS G12C inhibitors show promise in KRAS G12C-mutated NSCLC

Two KRASG12C inhibitors have demonstrated promising efficacy in patients with advanced or metastatic KRASG12C-mutated non-small-cell lung cancer (NSCLC), a population with an unmet medical need for whom no targeted therapy was available until recently.

Sotorasib: PFS and ORR results

Sotorasib, a first-in-class KRASG12C inhibitor, demonstrated a median progression-free survival (PFS) of 6.8 months in the phase II CodeBreaK 100 trial in 126 patients (median age, 63.5 years) with locally advanced or metastatic, KRASG12C-mutated NSCLC. The results, presented at the International Association for the Study of Lung Cancer 2020 World Conference on Lung Cancer (WCLC) Singapore held in January 2021, also showed an objective response rate (ORR) of 37.1 percent (partial response, 34.7 percent; complete response, 2.4 percent), and a median duration of response of 10 months. [Li BT, et al, WCLC 2020 Singapore, abstract PS01.07]

“Notably, the median time to objective response to sotorasib was 1.4 months, and 72 percent of responders saw responses as early as 6 weeks after treatment initiation,” reported investigator Dr Bob Li of the Memorial Sloan Kettering Cancer Center in New York, New York, US. “At the time of data-cut off, 43 percent of responders remained on sotorasib treatment without disease progression.”

The registrational, open-label, single-arm CodeBreaK 100 trial enrolled patients with disease progression on ≤3 prior lines of treatment who had no active brain metastasis. A majority of patients had received prior treatment with platinum-based chemotherapy (89.7 percent), PD-1/PD-L1 inhibitors (91.3 percent), or both (81 percent). Enrolled patients were treated with sotorasib 960 mg orally once daily until disease progression.

“Most treatment-related adverse events [TRAEs] associated with sotorasib were of grade 1 or 2. Grade 3 TRAEs occurred in 19.8 percent of patients,” said Li. “TRAEs led to treatment discontinuation in 7.1 percent of patients and dose modification in 22.2 percent of patients.”

The most common TRAEs of any grade were diarrhoea (31 percent), nausea (19 percent), increased alanine aminotransferase (ALT) or aspartate aminotransferase levels (15.1 percent each), and fatigue (11.1 percent).

In exploratory analyses, responses to sotorasib were observed across patients with PD-L1–negative, PD-L1–low or PD-L1–high tumours, as well as in those with co-occurring STK11 and/or KEAP1 mutations. In patients with co-occurring STK11 mutations, the ORR was 50 percent.

“With these results, sotorasib has been granted breakthrough therapy designation by the US FDA. The confirmatory phase III CodeBreaK 200 trial is currently enrolling patients,” said Li.

Adagrasib: ORR results

The second KRASG12C inhibitor that demonstrated efficacy in advanced or metastatic KRASG12C-mutated NSCLC is adagrasib. In the multicohort phase I/II KRYSTAL-1 trial reported at the European Lung Cancer Virtual Congress 2021 (ELCC 2021), adagrasib demonstrated an ORR of 45 percent in patients with previously treated, advanced or metastatic KRASG12C-mutated NSCLC. [Riely GJ, et al, ELCC 2021, abstract 99O_PR]

The NSCLC cohort included 79 patients, 92 percent of whom had received prior treatment with chemotherapy and a PD-1/PD-L1 inhibitor. Adagrasib was given at a dose of 600 mg twice daily.

“Among 51 patients evaluable for clinical activity, 23 [45 percent] had a partial response, while 26 had stable disease,” reported investigator Dr Gregory Riely of the Memorial Sloan Kettering Cancer Center in New York, New York, US. “Notably, the ORR was 64 percent in a subpopulation of patients [n=14] with co-occurring STK11 mutations, which are associated with inferior responses to immune checkpoint inhibitors in NSCLC.”

“The 45 percent ORR is unprecedented activity in patients with KRASG12C-mutated NSCLC,” commented Dr Myung-Ju Ahn of Samsung Medical Centre, Sungkyunkwan University School of Medicine, Seoul, Korea, who was not affiliated with the study. “A response of this magnitude could not be expected with other chemotherapy or immunotherapy in pretreated KRAS-mutated patients, suggesting that KRASG12C is a therapeutic target. The findings are potentially practice-changing, although further studies are needed as long-term follow-up data are currently limited.”

Adagrasib was tolerable in the trial. The most commonly reported TRAEs included nausea (54 percent), diarrhoea (48 percent), vomiting (34 percent), fatigue (28 percent), and increased ALT levels (23 percent).

“KRASG12C mutations are among the most frequent oncogenic drivers in NSCLC, occurring in approximately 14 percent of patients with lung adenocarcinomas. We are now, finally, seeing targeted therapies for this subgroup of patients with an unmet medical need,” said Riely.

“Given the low toxicity, adagrasib could potentially be combined with chemotherapy, immunotherapy, or other molecules to increase activity in patients with KRASG12C-mutated NSCLC,” Ahn suggested.