Lung cancer focus – drugging the undruggable KRAS

Analysis

It is ironic that in the age of biomarker-driven therapies lung cancer patients harbouring KRAS mutations still have no available treatments. And this week Lilly’s Verzenio joined Astrazeneca’s selumetinib in flunking a large trial in this hard-to-treat indication.

The fact that KRAS mutations are thought to account for as much as 30% of lung adenocarcinomas shows that there is a significant prize on offer here, and industry seems undeterred by the setting’s intractability, as shown by the number of ongoing trials (see table below).

But the trouble with KRAS is that, while it is thought to be the single most commonly mutated gene in NSCLC, the protein is extremely hard to target directly; it is typically seen as “undruggable”.

Downstream

This is why work has focused on identifying targets that lie downstream of a faulty KRAS protein that is causing abnormal signalling and driving tumour growth. Such targets include Braf, Mek, ERK, MAPK and PI3k.

The vast majority of ongoing clinical work here uses Mek targeting as its basis, driven by a mid-stage study of Array/Astrazeneca’s selumetinib. This 87-patient trial showed prolonged progression-free survival versus placebo, and spurred additional clinical work.

However, the idea came unstuck when Astra’s larger phase III study, Select-1, failed to replicate the findings. This should leave investors feeling pessimistic about a study with Array’s rival Mek inhibitor binimetinib, at least as monotherapy.

There is some hope that combinations could hold the key, however, and various Mek inhibitors are in trials together with assets against EGFR, mTOR, Her and PD-L1. And Novartis’s Mek inhibitor Mekinist is in trials both as a standalone agent and combined with EGFR or PD-1 inhibition.

Selected studies targeting KRAS-mutated NSCLC
Interventions Sponsor Mechanism Note Trial ID
CDK4/6 inhibitors
Verzenio Lilly CDK4/6 inhibitor Juniper trial; failed to extend OS vs Tarceva NCT02152631*
Ibrance + PD-0325901 Dana-Farber CDK4/6 + Mek inhibitor Tumours incl KRAS-mutant NSCLC NCT02022982
Ibrance + binimetinib Pfizer & Array CDK4/6 + Mek inhibitor Versus standalone components NCT03170206
Mek inhibitors
Selumetinib Astrazeneca Mek inhibitor Select-1 trial; failed vs placebo NCT01933932*
Selumetinib + Gilotrif Astrazeneca & Boehringer Mek + EGFR inhibitor KRAS-mutant & PIK3CA-wildtype NSCLC vs docetaxel NCT02450656
Selumetinib + vistusertib Astrazeneca Mek + mTOR 1 & 2 inhibitor Tumours incl KRAS-mutant NSCLC NCT02583542
Selumetinib + Imfinzi Astrazeneca Mek + PD-L1 inhibitor Dosing trial, no comparator NCT03004105
Binimetinib Novartis Mek inhibitor Non-squamous lung cancer, incl KRAS-mutants NCT02185690
Binimetinib + Tarceva Array Mek + EGFR inhibitor KRAS-mutant & EGFR-mutant NSCLC NCT01859026
PD-0325901 + dacomitinib Pfizer Mek + pan-Her inhibitor Single-arm trial NCT02039336
Mekinist NCI Mek inhibitor Single-arm trial NCT02642042
Mekinist + Keytruda Merck & Co & Novartis Mek + PD-1 inhibitor Dosing trial NCT03299088
Mekinist + Tykerb Glaxosmithkline Mek + EGFR & Her2 inhibitor Single-arm trial NCT02230553
Other approaches
Avastin Netherlands Cancer Institute Anti-VEGFr MAb 1L KRAS-mutant non-squamous NSCLC vs Alimta NCT02743923*
RXDX-105 Ignyta RET inhibitor Tumours incl KRAS-mutant NSCLC NCT01877811
LXH254 + LTT462 Novartis C-Raf kinase + ERK inhibitor KRAS or Braf-mutant NSCLC NCT02974725
Antroquinonol Golden Biotechnology Fungus-derived Chinese medicine KRAS-mutant & wildtype NSCLC NCT02047344
Selinexor Karyopharm XPO1 inhibitor Single-arm trial NCT03095612
Velcade Takeda Protease inhibitor Never-smokers or those with KRAS G12D NCT01833143
Source: Clinicaltrials.gov. *Phase III trial; all others are phase I and/or II. 

Meanwhile, the rationale for targeting CDK4/6 in KRAS-mutated NSCLC arises from preclinical models suggesting that CDK4 is required for tumour progression in adenocarcinoma, and that ablation of CDK4 affects the ability of KRAS-expressing cells to divide.

However, the failure of Verzenio in Lilly’s phase III Juniper trial on overall survival calls this theory into question, too. Juniper was a study that had sailed under investors’ radar, but it could have given Verzenio a unique indication; in its filed use, HR-positive, Her2-negative breast cancer, it faces competition from Pfizer’s Ibrance and Novartis’s Kisqali.

Still, Juniper had a curious design in that it used Roche’s EGFR inhibitor Tarceva as comparator. EGFR inhibition on its own is thought to confer no benefit in KRAS-mutated tumours – something that should have made life easy for Verzenio – but in fact Lilly said patients in Juniper’s control arm lived longer than expected.

It is also curious that there might have been a PFS and remission rate benefit in Juniper with Verzenio. Another CDK4/6, Ibrance, is in two trials in KRAS-mutant NSCLC, both in combination with a Mek inhibitor, but it might be that further work to drill down into patient subgroups is needed to hit a successful outcome.

Two such promising subgroups are KRAS G12C and KRAS G12D mutants, and at least one study, involving Velcade, specifically looks to recruit KRAS G12D mutant NSCLC subjects.

And what about the more novel approaches? While the rest of the industry pipeline looks to hit other targets upstream of KRAS, including RET and C-Raf kinase, two other assets stand out: Karyopharm’s XPO1 inhibitor selinexor, and anthroquinolol, being taken forward by Golden Biotechnology.

In selinexor’s case it appears that perturbation of XPO1, a nuclear export receptor, causes KRAS-mutated cells to become vulnerablein vivo. As for anthroquinolol, a traditional Chinese medicine, the jury is still out – both on its precise mechanism and on whether it can be synthesised with anything like the necessary consistency.

Perhaps the fact that Golden Biotechnology is undertaking such an implausible strategy against such a tough disease shows just how much more work needs to be done to identify amenable targets.

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