No phase III benefit with selumetinib in KRAS-mutant NSCLC

Oncogenic mutations of KRAS define the largest genomic subset of NSCLC (Figure). This patient group appears to derive less clinical benefit from chemotherapy than the overall NSCLC population. There are currently no targeted treatments specifically for patients with KRAS-mutant tumours of the lung. However, KRAS mutations are associated with activation of the RAS/RAF/MEK/ERK pathway, which converges at MEK1/2, making KRAS mutation in NSCLC a potential target of the oral MEK1/2 inhibitor selumetinib. Indeed, in a phase II trial, selumetinib has shown encouraging activity in combination with docetaxel, improving PFS and ORR to a significant extent compared to placebo plus docetaxel [1].
The phase III SELECT-1 study therefore tested selumetinib 75 mg twice daily plus docetaxel against placebo plus docetaxel in patients with KRASmutated advanced NSCLC (stage IIIB-IV) after failure of first-line therapy [2]. PFS by investigator assessment was defined as the primary endpoint. Overall, 510 patients were randomised. SELECT-1 was the first and largest prospective phase III, randomised, double-blind trial of second-line treatment for patients with KRAS-mutant NSCLC.

Figure: Molecular subsets of adenocarcinoma of the lung

Figure: Molecular subsets of adenocarcinoma of the lung

However, PFS did not differ significantly between the treatment arms (3.9 vs. 2.8 months with selumetinib plus docetaxel and docetaxel alone, respectively; HR, 0.93). This also applied to OS (8.7 and 7.9 months, respectively; HR, 1.05). There was no evidence of a statistically significant interaction of treatment by subgroup with regard to both PFS and OS. ORR was numerically improved in the experimental arm (confirmed responses, 13 % vs. 9 %); however, responses lasted only 2.9 months (vs. 4.5 months in the control arm). The safety profile of selumentinib plus docetaxel was consistent with historical data for docetaxel and emerging data for selumetinib.
At present, there is no clear reason why the phase II results did not translate into a positive phase III study. Exploratory analyses are ongoing or planned for different KRAS codon mutations, as well as for PD-L1, LKB1 and TP53 status.

REFERENCES

  1. Jänne PA et al., Selumetinib plus docetaxel for KRAS-mutant advanced non-small-cell lung cancer: a randomised, multicentre, placebocontrolled, phase 2 study. Lancet Oncol 2013; 14: 38-47
  2. Jänne PA et al., Selumetinib in combination with docetaxel as second-line treatment for patients with KRAS-mutant advanced NSCLC: results from the phase III SELECT-1 trial. ESMO 2016, abstract LBA47_PR

More posts

SCLC: genomic alterations pave the way to targeted approaches

Rapid growth and early development of metastatic disease are characteristic of small-cell lung cancer (SCLC), which constitutes approximately 15 % of all lung cancer cases. In limited-stage disease, a cure is possible with chemoradiotherapy. However, 68 % of patients present with extensive-stage SCLC (ES-SCLC). Although high initial responses to platinum-based chemotherapy and radiotherapy are observed, recurrence of chemo-refractory disease takes place as a rule.

Rare driver mutations: encouraging results in small patient populations

As well as ALK fusion mutations and EGFR mutations, studies of the genetic profiles of patients with NSCLC have identified other mutations that might be used for additional targeted therapies. Among these, ROS1 and RET rearrangements both occur in 1 % to 2 % of patients with NSCLC. Crizotinib is known to target not only ALK, but also ROS1, among others. Patients with ROS1-positive advanced NSCLC are being treated with crizotinib 250 mg twice daily in the ongoing phase I, open-label, PROFILE 1001 study.

EGFR-targeted therapy: at the right time in the right patient

Approximately 11 % of Caucasian patients with NSCLC have tumours that harbour EGFR mutations, which occur in exons 18, 19, 20 and 21 of the EGFR gene. Common mutations include exon 19 in-frame deletions and the exon 21 Leu858Arg point mutation (L858R). Exon 20 insertions are known to mediate resistance [3]. Little data are available for the other more uncommon mutations.

Next-generation ALK inhibitors excel after crizotinib failure

ALK fusion-gene–positive lung cancer occurs in approximately 5 % of patients with advanced NSCLC [1]. The ALK inhibitor crizotinib demonstrates significant initial efficacy in patients with ALK-positive advanced NSCLC.  However, most patients eventually develop resistance, with the central nervous system (CNS) being one of the most common sites of first progression.

Immune checkpoint inhibition: the picture is slowly completing itself

The anti–PD-1 antibody pembrolizumab has been approved for treatment of patients with PD-L1–expressing, advanced NSCLC. The KEYNOTE-024 study focused on the first-line comparison of pembrolizumab with platinum-doublet chemotherapy. Chemotherapy regimens comprised five options, two of which (pemetrexed plus carboplatin; pemetrexed plus cisplatin) were used with non-squamous non-small–cell lung cancer (NSCLC) only.