Experimental Drugs Hit KRAS and Downstream Targets in NSCLC

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The KRAS mutation in lung cancer is an especially thorny problem, as it is an indicator of a poor prognosis and has not, in the past, been targeted specifically by any medications.

David Gandara, MD

The KRAS mutation in lung cancer is an especially thorny problem, as it is an indicator of a poor prognosis and has not, in the past, been targeted specifically by any medications.

But there are many promising methods for treating this subtype of non-small cell lung cancer (NSCLC), the newest of which involves targeting the mutation directly for the first time, David Gandara, MD, said yesterday in a presentation at the 15^th Annual International Lung Cancer Conference in Huntington Beach, California.

“KRAS has always been considered a particularly bad prognostic and predictive factor,” said Gandara, professor of Medicine in the Division of Hematology/Oncology at the University of California Davis Comprehensive Cancer Center, in Sacramento, prior to the talk on overcoming KRAS mutations. “It is an oncogene that has been very difficult to directly target, so a variety of drugs have been developed that work downstream of KRAS, and we’ll talk about several of those categories; one is MEK inhibitors.”

In a recent development, Gandara added, a paper by Ostrem et al¹ discussed experimental cysteine-reactive small molecules directed to the G12C mutation of KRAS-mutated NSCLC. In preclinical studies, the drugs demonstrated tumor growth inhibition and induction of apoptosis, he said.

“These have been developed to target only mutated KRAS and only that subtype, and in that regard they are quite different from anything we’ve had,” he said. “These drugs are not only possible, but in preclinical studies have been quite effective.”

Gandara, who is also director of the Thoracic Oncology Program and senior advisor to the director at the university, reviewed some background about KRAS mutations for his audience and discussed some new thoughts on the treatment of patients with these mutations.

Some mutations are associated with smoking, and tend to occur along with other mutations, including those of the tumor suppressor genes P53 and/or LKB1, he said. When a patient has a KRAS mutation, he typically will not have EGFR mutations or a de novo ALK rearrangement, Gandara continued. “But now,” he cautioned, “data show that that’s not the case in ALK-positive cancers after exposure to ALK inhibitors like crizotinib.”

“There’s been a long association with KRAS and a lack of response to EGFR TKIs and chemotherapy, but even that has been brought into question,” he added. “It may be because of the different types of mutations and co-mutations present.”

Gandara also outlined subtypes of KRAS-mutated lung cancer, noting that the G12C subtype is the most common among smokers, while G12D crops up more frequently in people who have never smoked.

There are multiple classes of drugs—predominantly experimental protein kinase inhibitors, lipid kinase inhibitors, and dual lipid/protein kinase inhibitors—designed to treat the disease by hitting targets downstream of KRAS, including Raf, MEK, ERK, PI3K, AKT, and mTOR. An example of a Raf inhibitor is vemurafenib; selumetinib is a MEK inhibitor, perifosine an AKT inhibitor, and everolimus and temsirolimus mTOR inhibitors, he pointed out.

In his talk, Gandara focused on MEK inhibitors.

He cited a study that looked at LKB1/STK1 loss and the TP53 mutation, each of which represent a different subtype of KRAS-mutated lung cancer. In a study of mice with G12D NSCLC that exhibited either LKB1 loss, the TP53 subtype, or KRAS mutation alone, subjects were given docetaxel with or without selumetinib.² Tumor volume “changed rather dramatically [for the better] with the introduction of the MEK inhibitor in combination with docetaxel for all categories except LKB1 loss,” Gandara said.

In a trial that looked at chemotherapy with or without selumetinib (AZ6244) in stage IIIB to IV KRAS-mutant NSCLC,³ progression-free survival (PFS) was 2.1 months with docetaxel and 5.3 months in the combination group. Response was 0% in the chemotherapy cohort and 37% in the combination cohort, and overall survival was 5.3 months vs 9.4 months in the control and experimental groups, respectively.

Gandara called that response rate “astounding,” although, “admittedly, this was totally KRAS-mutated lung cancer patients, not typical lung cancer patients.”

Similar results were seen with a combination of docetaxel and the MEK inhibitor trametinib that Gandara presented at the annual meeting of the American Society of Clinical Oncology last year,⁴ he said. The phase 2 expansion of a phase 1 trial demonstrated a 28% overall response to the combination in KRAS-mutated cancers, and the same response rate among those with KRAS wild-type lung cancers. “The disease control rate with G12C was also quite good,” he said. “These patients all had a tumor response, so they were headed in the right direction even if they didn’t meet the RECIST partial response criteria.”

Finally, Gandara drew the audience’s attention to a trial of an AKT inhibitor that will start enrolling this fall. SWOG 1408 will be a randomized, phase 2 study in which patients with pretreated, advanced-stage, KRAS-mutated NSCLC will be randomized between trametinib plus either docetaxel or AKTi (GSK795). “We can look at the EGFR mutation subtype, as well as co-mutations,” he said, “and hopefully, this will lead to a phase III trial.”

References

Ostrem JM, Peters U, Sos ML, Wells JA, Shokat KM. K-Ras(G12C) inhibitors allosterically control GTP affinity and effector interactions. Nature. 2013;503(7477):548—551.
Chen Z, Cheng K, Walton Z, et al. A murine lung cancer co-clinical trial identifies genetic modifiers of therapeutic response. Nature 2012;483(7391):613—617.
Janne PA, Shaw AT, Pereira JR, et al. Selumetinib plus docetaxel for KRAS-mutant advanced non-small cell lung cancer: a randomized, multicenter, placebo-controlled, phase 2 study. Lancet Oncology. 2013;14(1):38—47.
Gandara DR, Hiret S, Blumenschein GR, et al. Oral MEK1/MEK2 inhibitor trametinib (GSK1120212) in combination with docetaxel in KRAS-mutant and wild-type advanced non-small cell lung cancer: A phase I/Ib trial. J Clin Oncol. 2013;31 (suppl; abstract 8028).

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