Sotorasib shows activity in NSCLC with KRAS mutations
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Sotorasib conferred durable clinical benefit among previously treated patients with KRAS p.G12C-mutated non-small cell lung cancer, according to results of the phase 2 CodeBreaK 100 trial presented during the virtual ASCO Annual Meeting.
The findings, simultaneously published in The New England Journal of Medicine, showed treatment with sotorasib (Lumakras, Amgen), a first-in-class, irreversible and selective KRAS inhibitor, also appeared safe, with no new safety signals reported.
KRAS is the most common oncogenic driver in lung adenocarcinoma, with approximately 13% of patients harboring the KRAS p.G12C mutation. But, historically, finding treatments to target this mutation has been a challenge, according to the researchers. After failure of first-line treatment with immune checkpoint inhibitors alone or with chemotherapy, outcomes for patients with these mutations are generally poor.
Based on these study results, sotorasib received FDA accelerated approval last month for use in adults with KRAS G12C-mutated locally advanced or metastatic NSCLC who have received at least one prior systematic therapy.
“This is a group of patients whose tumors have been difficult to treat and for whom we did not have targeted therapies,” Ramaswamy Govindan, MD, Anheuser Busch endowed chair in medical oncology at Washington University School of Medicine in St. Louis, said in a press release. “The new drug is addressing an unmet need for these patients, targeting the most common mutation that we can go after. We’re also continuing to investigate this drug in combination with other experimental drugs to see if we can further improve responses and survival.”
In the CodeBreaK 100 trial, 126 patients (median age, 63.5 years; 50% women; 81.7% white; 92.9% former or current smokers) received 960 mg oral sotorasib once daily until disease progression. All patients had KRAS p.G12C mutations confirmed by central testing of tumor biopsies and had progressed on treatment with standard therapies; 81% had previously received platinum-based chemotherapy and PD-1 or PD-L1 inhibitors.
Objective response rate served as the study’s primary endpoint. Secondary endpoints included duration of response, disease control, PFS, OS and safety.
Median follow-up was 15.3 months.
As Healio previously reported, ORR among 124 evaluable patients was 37.1% (95% CI, 28.6-46.2), which included a 3.2% complete response rate and 33.9% partial response rate. Median duration of response was 11.1 months (95% CI, 6.9-not evaluable).
One hundred patients (80.6%; 95% CI, 72.6-87.2) achieved disease control.
During ASCO, Ferdinandos Skoulidis, MD, PhD, MRCP, assistant professor in the department of thoracic/head and neck medical oncology at The University of Texas MD Anderson Cancer Center, reported updated data on mature OS, safety and efficacy in patient subgroups from the trial.
Median PFS was 6.8 months (95% CI, 5.1-8.2), with 37.5% (95% CI, 28.4-46.5) of patients achieving 9-month PFS, and median OS was 12.5 months (95% CI, 10-not evaluable).
“These results make sotorasib the first KRAS inhibitor to demonstrate an OS benefit in a registrational phase 2 clinical trial,” Skoulidis said during his presentation.
Sotorasib showed consistent benefit across patient subgroups, including those aged 65 years or older (ORR, 44.1%), heavily pretreated patients (ORR per prior lines of therapy: two, 32.6%; three, 39.3%), and those who progressed on checkpoint inhibitors within the prior 3 months (ORR, 34.4%). Notably, patients who previously received PD-1/PD-L1 inhibitors but not platinum-based chemotherapy showed an ORR of 69.2% and median OS of 17.7 months.
Results of exploratory analyses of molecularly defined subgroups showed the likelihood of achieving response to sotorasib did not differ according to KRAS p.G12C mutant allele frequency (OR for each 0.1 increase in mutant allele frequency = 1.11; 95% CI, 0.88-1.39), tumor mutational burden (ORR for high vs. low, 40% vs. 42%) or co-occurring mutations (ORR for wild-type vs. mutated TP53, 40% vs. 39%; STK11, 39% vs. 40%; KEAP1, 44% vs. 20%).
“This is important because activating somatic mutations in STK11 and KEAP1 have previously been associated with worse clinical outcomes with standard-of-care systemic therapies,” Skoulidis said.
Further analyzing these co-occurring mutations, researchers found the highest ORR of 50% among patients with mutant STK11 and wild-type KEAP1. Median PFS was 11 months for this group, compared with 6.8 months for patients wild type for both genes and 6.3 months in the overall population.
“These results suggest that STK11 mutations, when present alone without co-occurring KEAP1 mutations, may be associated with improved sotorasib efficacy,” Skoulidis said. “On the other hand, patients with KEAP1-mutant tumors appear to derive less benefit from sotorasib, with a median PFS of 5.5 months for those with wild-type STK11 tumors and 2.6 months for those with KEAP1 and STK11 double-mutant tumors. However, it should be observed that [overall responses] to sotorasib occurred in 20% of KEAP1-mutant tumors.”
Sotorasib appeared well-tolerated, with 69.8% of patients experiencing treatment-related adverse events, most of which were grade 1 to grade 2 and manageable. No treatment-related deaths occurred.
The most common adverse events of any grade included diarrhea (31.7%), nausea (19%), elevated alanine aminotransferase and aspartate transaminase (15.1% each) and fatigue (11.1%).
Grade 3 or worse adverse events occurred among 19.8% of patients, the most common being elevated alanine aminotransferase (6.3%) and aspartate transaminase (5.6%), and diarrhea (4%). Treatment-related adverse events led to dose modifications for 22.2% of patients and treatment discontinuation by 7.1%.
“We are hopeful that this approach will be a new option for patients with lung cancer driven by this specific type of KRAS gene alteration,” Govindan said in the release. “KRAS gene alterations have long been considered not amenable for targeted therapies. ... This highlights work that Washington University has excelled at over the past few decades — studying the genomic alterations in tumors with the goal of identifying treatment targets. This early cancer genome research is now coming full circle to help our patients.”
References:
Skoulidis F, et al. Abstract 9003. Presented at: ASCO Annual Meeting (virtual meeting); June 4-8, 2021
Skoulidis F, et al. N Engl J Med. 2021;doi:10.1056/NEJMoa2103695.
Perspective
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Christine M. Lovly, MD, PhD
KRAS G12C is the most common KRAS variant, and multiple KRAS G12C inhibitors are being developed in the clinic. This is a novel class of drugs; they are targeted therapies, but not tyrosine kinase inhibitors. Rather, they are allele-specific inhibitors that target the cysteine residue. These drugs bind covalently to that mutant cysteine when the KRAS G12C is in the active GDP-bound form.
The ORR reported in this trial of 37.1% is a little lower than we are used to for TKIs targeting mutant oncokinases; however, it is important to remember that this is a different mutation and a very different class of drugs.
Researchers also reported no differences in ORR based on KRAS G12C variant allele frequency, tumor mutational burden, TP53 mutational status or STK11 mutational status.
Research in KRAS-mutant lung cancers is an area that is really exploding. Where do we go from here? There are novel KRAS-targeting agents, including other KRAS G12C inhibitors and novel RAS(ON) inhibitors, that target the active state of RAS and are not specific to the G12C variants. There are alternative approaches to target mutant RAS or the RAS signaling pathway, including ERK, SHP2 and SOS inhibitors, and there also are multiple combination therapies being tested.
We need to look at the efficacy of G12C inhibitors in other clinical scenarios, such as for central nervous system metastases and in the adjuvant setting, and we need mechanistic studies to understand primary and acquired resistance to KRAS G12C inhibitors. Innovative clinical trial designs are needed to accommodate co-mutational status, such as the Lung-MAP trial S1900E arm (NCT04625647), which is looking at the efficacy of sotorasib based on co-mutational status.
The data are becoming more granular in that we’re not just thinking of one gene, but which variant and which co-mutations can occur.
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Skoulidis F, et al. Abstract 9003. Presented at: ASCO Annual Meeting (virtual meeting); June 4-8, 2021.
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