Randomised Phase II Study of Erlotinib plus Tivantinib versus Erlotinib plus Placebo in Pretreated NSCLC Patients: have we found a KRAS targeting agent?

Giulio Metro

Recent advances in the understanding of the molecular aberrations that underlie and sustain the oncogenic process of non-small cell lung cancer (NSCLC) have progressively diversified treatment approach to this disease. However, if Epidermal Growth Factor Receptor (EGFR) mutant patients as well as those who express the anaplastic lymphoma kinase (ALK) fusion oncogene now emerge as clear subgroups of patients who derive great benefit from the EGFR-tyrosine kinase inhibitors (-TKIs) gefitinib or erlotinib and ALK-inhibitors, respectively, the role of KRAS mutations in selecting/excluding patients who are candidate to certain targeted agents (e.g. anti-EGFR monoclonal antibodies or EGFR-TKIs) is much less clear.

In the randomised phase II study reported by Sequist et al. the novel MET inhibitor tivantinib was added to erlotinib to test whether the combination could delay the onset of progressive disease as compared to erlotinib alone in pretreated, EGFR-TKI-naïve, advanced NSCLC patients. Although the study did not reach statistical significance in the primary progression-free survival end-point (HR=0.81 with erlotinib/tivantinib versus erlotinib/placebo), preplanned subgroup analyses according to molecular characteristics suggested an improved benefit from erlotinib/tivantinib for both the high MET gene copy number and KRAS mutant group of patients. Particularly, an impressive HR of 0.18 with erlotinib/tivantinib versus erlotinib/placebo was seen in the subset of patients carrying a KRAS mutation.

In NSCLC, KRAS is one of the most commonly mutated oncogene, being present in up to one fourth of patients, preferentially smokers and adenocarcinomas. Therefore, identifying KRAS as a therapeutic target in NSCLC could be crucial for the development of active treatments in patients selected based on the presence of a KRAS mutation. Unfortunately, unlike EGFR mutations and ALK translocations, no prognostic or predictive role has been demonstrated so far for KRAS mutations, and the attempts to correlate the presence of KRAS mutations with resistance to EGFR-TKIs have been inconclusive.

The study by Sequist et al. is very interesting in that a much better outcome was reported in favour of the experimental arm within the KRAS mutant subgroup. This finding, strongly suggest that tivantinib could extend the group of KRAS mutated patients who benefit from erlotinib. Nevertheless, the authors recognise as limitations of this finding the small number of patients on which this benefit was observed (n=15) and the baseline molecular imbalance existing between the two arms of the study in terms of distribution of KRAS mutations (twice as many patients with a KRAS mutation were randomised to the experimental arm). Furthermore, the putative increased efficacy of erlotinib/tivantinib in KRAS mutants has no apparent molecular explanation, since no known interaction between KRAS and the cMET receptor has ever been described. Nothwithstanding, further investigation is surely needed and the ongoing global phase III trial will definitively ascertain whether the erlotinib/tivantinib combination is specifically active in KRAS mutants or its activity is limited only to patients who have an increase in MET gene copy number. Currently, several studies are being conducted with agents specifically developed to target KRAS ; they are challenging the so far elusive role of KRAS as “driver” oncogene in NSCLC. Against this background, the “by-chance-found” KRAS-targetting agent tivantinib might be the first drug to be described as specifically active against KRAS mutated patients. Besides the confirmatory ongoing phase III trial, future steps may include testing tivantinib as monotherapy in the KRAS mutated subgroup and implementation of preclinical research that could serve as a solid background for this unexpected finding.

Randomised Phase II Study of Erlotinib plus Tivantinib versus Erlotinib plus Placebo in Pretreated NSCLC Patients: have we found a KRAS targeting ag...
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