Manageable Safety/Efficacy With Erlotinib/Binimetinib in EGFR+ or KRAS+ NSCLC

KRAS or EGFR mutations can be found in up to 40-50% of patients with non-small cell lung cancer (NSCLC). Because of this, a phase 1/1B trial (NCT01859026) was created to examine the efficacy and safety of the combination of erlotinib (Tarceva) and binimetinib (Mektovi) in this patient population.

Within the phase 1 dose escalation portion of the trial, patients were administered binimetinib orally on cycle 1, day 1, along with erlotinib on cycle 1, day 2. Binimetinib was dosed once daily or twice while erlotinib was dosed daily on a 28-day cycle. Then, the dose-expansion phase 1b portion of the trial will have 2 experimental groups who each will receive binimetinib 2 times a day, and erlotinib once a day on 28 day cycles.

Across phase 1 and 1B of the trial, a total of 43 patients aged 18 years or older with a histologic or cytologic diagnosis of NSCLC of the advanced stage, who have no known curative treatment options were enrolled. Of these patients, 40% (n=17) had an EGFR mutation, while 51% (n=22) had a KRAS mutation.

According to an investigator on the trial, Andreas Saltos, MD, dose escalation of both study drugs continued until a recommended phase 2 dose was determined. This maximum tolerated dose, consisting of 100 mg of erlotinib daily and 15 mg of binimetinib twice daily for 5 days a week, had a toxicity that was manageable. Further, investigators did not observe any significant drug interactions.

In an interview with Targeted Oncology^TM, Saltos, medical oncologist and clinical research medical director in the department of thoracic oncology at Moffitt Cancer Center, discussed treatment options for EGFR and KRAS-mutated NSCLC, and the investigational use of binimetinib to treat these tumors.

TARGETED ONCOLOGY: What does the current space for these patients look like?

Saltos: Things have changed a lot since this study started. [Since this] study launched, things have changed a bit. We now have multiple approved EGFR inhibitors, including, most recently, a third generation of osimertinib [Tagrisso] which is more selective for the EGFR, and is currently our standard of care for those patients.

In the KRAS space, especially about a year ago, things have changed dramatically with the approval of the first G12C specific KRAS inhibitor. Really, the novel mechanism of shooting KRAS through these binding pockets and specific mutants really transformed our ability to target KRAS in a way that we didn't have 5 or 7 years ago.

What unmet needs still have to be filled within this space?

Even with the newer drugs, with the third generation EGFR inhibitors, and with the novel KRAS G12C inhibitors, the development of resistance is still a problem. Even though these drugs have relatively high initial response rates, development resistance is nearly inevitable. There's also a wide variety of mechanisms of resistance in both populations. Strategies to prevent resistance are going to be very important, and also strategies to help overcome resistance for these specific populations are being actively explored.

You discussed the use of binimetinib for the treatment of NSCLC harboring either KRAS or EGFRmutations. Can you provide an overview of your presentation?

Our group here at Moffitt Cancer Center conducted this phase 1/1b clinical trial exploring the use of binimetinib, which is a MEK inhibitor, with erlotinib, an improved EGFR inhibitor, in patients with NSCLC harboring either KRASor EGFR mutations.

The rationale for the study came from the observation that patients with EGFR-mutant lung cancer inevitably develop resistance to EGFR inhibitors, and patients with KRAS mutations make up a large population of patients with this driver, KRAS, which until recently was undruggable. And with the theory that with dual inhibition in the MAP kinase pathway, where there's activation in both populations, we might be able to achieve better tumor control or better responses.

In this phase 1 trial, we first were able to ramp up from low doses of both drugs. In our case, we had to tune the doses down until we found ultimately a slightly lower dose than what's the approved use for both drugs was needed to manage the [adverse event] profile. Ultimately, we found that the dose of erlotinib, 100 mg daily with binimetinib, 15 mg twice a day, for 5 days a week, was our maximum tolerated dose or recommended phase 2 dose.

What were some of the key discoveries from the trial?

One of the things that we noted in the presentation is that there were not necessarily many signals of increased efficacy in the combination in patients with EGFR mutations. Maybe we saw with the KRAS mutations more so than you may expect. This could be reflective of the lower doses that we had with a combination.

I think it still remains to be seen whether strategies like this in EGFR may be valuable. We already are seeing a lot of clinical trials underway, combinations with the new standard of care, third generation EGFR tyrosine kinase inhibitors. Before coming to conclusions about the effectiveness of combination strategies, I'd like to see data from those as well.

What are the key messages you wish for community oncologists to take away from this presentation?

From this presentation, you can start to see that although there was limited efficacy in our populations with this combination, likely because we weren't able to achieve very highly therapeutic doses of both drugs through tolerability, we did see signals including in 1 or 2 patients with KRAS mutations who had some some degree of durable benefit from the combination.

I think with the up and coming, newer, more targeted, tailored drugs like the targeted G12C inhibitors, we may start to see some headway that these patients may be candidates for targeted therapy, where typically we would think that targeted therapy is not an option. We've already seen that in the KRAS G12C space for patients upfront.

We're also seeing preliminary data, some that was also shared at AACR. Recently, the KRAS G12C specific inhibitor, sotorasib [Lumakras] has been explored in some combinations where we see even more promising signals of efficacy with EGFR and MEK combinations. Again, tolerability toxicity remains an issue.

I think with emerging, tailored targeted drugs, that the field will bring us to a point where we'll be able to offer targeted therapy to more patients. Keep in mind that these patients have specific mutations, be on the lookout for clinical trial opportunities, and hopefully new drug approvals in the coming years for these patients.

What further developments and advancements excite you most for the future of this space?

I'm excited about the fact that this is a new territory for patients with these KRAS mutations, especially where the field has exploded. There's a lot of new combinations and a lot of new trials for these patients. With any luck, a few of these combinations will start to show a lot of promise preclinically. There's even more exciting work being done to combat the problems of early development of resistance, where I think some time on the horizon, there will be a day where patients with KRAS mutations and EGFR mutations will really be able to have quality targeted therapy that can control the disease for a long time.