More Research Needed to Overcome Challenges in Targeting KRAS in NSCLC

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KRAS is commonly mutated in non-small cell lung cancer, but targeting KRAS directly has been unsuccessful.
KRAS is commonly mutated in non-small cell lung cancer, but targeting KRAS directly has been unsuccessful.

Despite clinical advances in understanding KRAS-mutant non–small cell lung cancer (NSCLC), more research must be conducted to find targeted therapies, a JAMA Oncology review has found.1

KRAS is a key player in transducing signals from receptor tyrosine kinases to intracellular molecules involved in several pathways—the most significant ones associated with cell survival and proliferation. In NSCLC, KRAS represents 1 of the 2 commonly mutated genes (the other being epidermal growth factor receptor [EGFR]); yet there has been little success in targeting KRAS in NSCLC or even other solid cancers.

Ravi Salgia, MD, PhD, of the City of Hope Comprehensive Cancer Center in Duarte, CA, and colleagues conducted a literature search of 61 articles using the words “RAS,” “KRAS,” NSCLC,” “synthetic lethality,” “oncogenic driver mutations,” “clinical trials,” and “phase 3 clinical trials.” Based on their findings, the team made conclusions about the involvement of RAS in NSCLC, its value as a prognostic and predictive indicator, and approaches for targeting RAS.

RAS and How It Functions

Three RAS genes code for 4 protein RAS isoforms—HRAS, KRAS (splice variants K4A- and K4B-), and NRAS—which are 85% identical in the amino acid sequences. Unlike kinases, which are targeted by specific inhibitors that bind to the ATP-binding pocket, RAS functions as a GTP-binding protein and is not a kinase. Its activity is dependent on the cellular ratio of GTP:GDP.

Once the protein is translated, it undergoes further changes that include farnesylation, geranylgeranylation, and palmitoylation. The reviewers noted that early attempts to target RAS through farnesyltransferase inhibitors were not successful because they lacked efficacy and were associated with excessive toxicity.

RAS in NSCLC

Of all RAS mutations seen in NSCLC, the reviewers noted that 90% were mutations in KRAS, which were not always mutually exclusive from EGFR mutations and EML4-ALK translocations. KRAS mutations occurred in 5% of squamous NSCLC, were more frequently found in smokers (43%), and were a result of GàT of GàC transversions. When KRAS mutations occurred in smokers, they were more frequently GàA transitions.

The frequency of KRAS mutations in metastatic disease is limited. But the reviewers found a small study that noted it may be associated with brain metastases.

Prognostic and Predictive Value of KRAS in NSCLC

The reviewers found no evidence that KRAS mutational status is of prognostic significance; its limited value is dependent on mutations in specific KRAS codons and disease state at diagnosis. Codon 12 substitutions do not impact overall survival, but codon 13 mutations may be associated with an inferior survival (13 months vs 16 months for wild-type KRAS).

In an altogether different study, patients with NSCLC harboring codon 13 mutations had a worse response to adjuvant chemotherapy, including overall survival. KRAS mutations in stage IV disease appeared to be associated with poor prognosis, including shorter survival.

The review also summarized conflicting findings from 4 clinical trials. In TRIBUTE (first-line carboplatin and paclitaxel ± erlotinib), effects of KRAS were only marginal for patients in the chemotherapy arm. In the Eastern Cooperative Oncology Group (ECOG) 3590, KRAS was of neither prognostic nor predictive significance.

Because EGFR is upstream to RAS in the signaling pathway, treatment with EGFR inhibitors such as erlotinib may be effective in patients with tumors with KRAS mutations, the team reported. Results from several studies were mixed.

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Data from BR.21 (second-line NSCLC) and TRIBUTE suggested erlotinib alone or in combination, respectively, improved survival in patients with tumors harboring wild-type KRAS. However, in the phase 3 TRUST trial in patients with stage III and IV NSCLC, KRAS status did not predict better survival. And in the phase 3 SATURN trial, benefits with maintenance erlotinib were marginal in 90 patients with KRAS-mutant disease. The reviewers suggested that “the small sample size in the TRUST trial and the wide confidence intervals in the SATURN trial are clear weaknesses in these studies.”

Durable responses in NSCLC with immunotherapy were seen regardless of KRAS status. “Further studies are needed to better understand the relationship between KRAS oncogenes and immunotherapy,” the reviewers stated.

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