Sotorasib improves PFS over docetaxel in KRASG12C-mutated advanced NSCLC

The first-in-class KRAS^G12C inhibitor sotorasib significantly improved progression-free survival (PFS) in patients with previously treated non-small cell lung cancer (NSCLC) with KRAS^G12C mutations, according to results of the phase III CodeBreaK 200 trial presented at ESMO 2022.

Participants (n=345; median age 64 years, ~12 percent Asian) had locally advanced/unresectable or metastatic* KRAS^G12C-mutated NSCLC and ECOG performance status ≤1 with prior exposure to ≥1 treatment including platinum-based chemotherapy and checkpoint inhibitor (concurrent or sequential). They were randomized 1:1 to receive oral sotorasib (960 mg/day) or intravenous docetaxel (75 mg/m² Q3W). Twenty-seven and 40 percent of patients in the sotorasib and docetaxel groups, respectively, had PD-L1 expression ≥1 to <50 percent.

After a median 17.7-month follow-up, PFS (as per blinded independent central review) was significantly improved in the sotorasib than docetaxel group (median 5.6 vs 4.5 months; hazard ratio [HR], 0.66, 95 percent confidence interval [CI], 0.51–0.86; p_one-sided=0.002), with 12-month PFS rates of 24.8 and 10.1 percent in the sotorasib and docetaxel groups, respectively. [ESMO 2022, abstract LBA10]

The PFS outcomes favoured sotorasib over docetaxel across multiple subgroups including age, sex, number of previous therapies, and PD-L1 expression.

Objective response rate was also improved with sotorasib vs docetaxel (28.1 percent vs 13.2 percent). Disease control rate was 82.5 and 60.3 percent in the sotorasib and docetaxel groups, respectively. Time to response was shorter in the sotorasib than docetaxel group (median 1.4 vs 2.8 months) and duration of response longer (median 8.6 vs 6.8 months).

Analysis following 109 and 94 deaths in the sotorasib and docetaxel groups, respectively, showed that overall survival did not significantly differ between patients in the sotorasib and docetaxel groups (median 10.6 vs 11.3 months; HR, 1.01, 95 percent CI, 0.77–1.33; p_one-sided=0.53). However, the study was not powered to assess a statistical difference between groups for this outcome.

Grade ≥3 treatment-related adverse event (TRAE) incidence was lower with sotorasib than docetaxel (33.1 percent vs 40.4 percent), as was serious TRAE rate (10.7 percent vs 22.5 percent). TRAEs led to dose interruption in 35.5 and 15.2 percent of sotorasib and docetaxel recipients, respectively, dose reduction in 15.4 and 26.5 percent, respectively, and discontinuation in 9.5 and 11.3 percent, respectively. There was one fatal TRAE in the sotorasib and two in the docetaxel group. Patients in the sotorasib and docetaxel groups received treatment for a median 20 and 12 weeks, respectively.

The most frequently occurring grade ≥3 TRAEs in sotorasib recipients were diarrhoea and elevated liver enzymes, and in docetaxel recipients, neutropenia, fatigue, and febrile neutropenia.

In terms of patient-reported outcomes, there was no significant difference in symptoms of cough or chest pain between baseline and week 12. “[However,] change over time in global health status, physical functioning, and dyspnoea favoured sotorasib,” said study author Dr Melissa Johnson from the Sarah Cannon Research Institute at Tennessee Oncology, Nashville, Tennessee, US. In addition, time to deterioration in global health status, physical functioning, and cancer-related symptoms of dyspnoea and cough was longer with sotorasib vs docetaxel (HRs, 0.69, 0.69, 0.63, and 0.55, respectively).

Among those initially assigned to docetaxel, 46 patients crossed over to receive sotorasib, while 13 received a subsequent KRAS^G12C inhibitor. At data cut-off, 22 patients were still on sotorasib and seven on docetaxel.

“Historically, docetaxel has been the preferred treatment option following progression on platinum-based chemotherapy and/or immunotherapy,” remarked Johnson.

“[The present] findings support sotorasib as an important treatment option in this setting and reinforce the importance of [next generation sequencing] testing for KRAS^G12C,” she concluded.

Nonetheless, discussant Dr Natasha Leighl from The Princess Margaret Cancer Centre in Toronto, Ontario, Canada, suggested approaching the results with caution.

“Although sotorasib performed better than docetaxel in this study, we must strive for even better outcomes for our patients with KRAS-mutated lung cancer,” she said.

“Other challenges include the use of crossover in the study and lack of a survival difference between the two arms. This is commonly seen in targeted therapy trials, but several immunotherapy trials have demonstrated survival gains despite crossover, raising our expectations from novel treatments in lung cancer,” she said. [https://ascopost.com/issues/november-10-2022-supplement-conference-highlights-esmo-2022/epov-natasha-leighl/, accessed 9 November 2022]