Osimertinib Plus Gefitinib Feasible for First-Line Treatment of EGFR-Mutated

In an interview with Targeted Oncology, Julia K. Rotow, MD, a medical oncologist at the Dana-Farber Cancer institute, discuses the results of the study of gefitinib in combination with osimertinib as frontline treatment of patients with EGFR-mutated NSCLC.

For patients with EGFR-mutated non-small cell lung cancer (NSCLC), the current standard of care in the frontline setting is EFGR tyrosine kinase inhibitors (TKI). However, resistance to early-generation TKIs remains a serious concern. New research suggests that EGFR inhibition with the combination of gefitinib (Iressa) and osimertinib (Tagrisso) may delay the emergence of acquired resistance.

The phase I/II dose-escalation study has a primary endpoint of maximum tolerated dose (MTD) and feasibility. Secondary endpoints included overall response rate, survival outcomes, plasma EGFR mutation clearance, and mechanisms of acquired resistance. Participants in the dose-escalation portion received 40mg or 80mg of osimertinib plus 250 mg of gefitinib daily.1 In order to participate, patients must have histologically confirmed stage IV NSCLC with either the L858R or exon 19 deletion activating EGFR mutation. Additionally, disease must be measurable, and patients cannot have prior history and any EGFR-directed therapy including TKIs or antibodies. In total, 27 patients were enrolled and evaluable for the primary endpoints.

Of the 27 patients, 81.5% completed 6 or more treatment cycles and the overall response rate was 85.2%. Of those who saw a response rate, 85.2% achieved partial response while 14.8 achieved stable disease. In terms of adverse events, the most common was rash followed by diarrhea. Median progression free survival (PFS) has not been reached.1

In an interview with Targeted Oncology, Julia K. Rotow, MD, a medical oncologist at the Dana-Farber Cancer institute, discuses the results of the study of gefitinib in combination with osimertinib as frontline treatment of patients with EGFR-mutated NSCLC.

TARGETED ONCOLOGY: Can you can you provide an overview of osimertinib and gefitinib and the agents respective activity against resistance mutations? What do we know so far with regard to that?

ROTOW: For many years for treatment, EGFR mutated lung cancer, we had a series of new EGFR TKI that have become available. It's just been very exciting to see happen. Gefitinib is a first-generation EGFR TKI, which showed activity both in the first-line setting patients who'd received a prior chemotherapy. The overall activity this drug, we see approximately PFS just under to about a year, and very good response rates approximately the 70% to 80% range. Osimertinib is a third-generation EGFR TKI, which was more recently approved in the first-line setting after it demonstrated improved PFS in the first-line setting over standard EGFR TKIs like gefitinib that was in the FLAURA study (NCT02296125). And it has shown a PFS about 18.9 months, about a year and a half, and also very good response rates of around the 80% range. This drug was exciting not only for the improved PFS, but also overall general improved tolerability over the earlier generation, EGFR TKIs, and also improved activity in the central nervous system (CNS). And we know for our patients with advanced lung cancer, the development of CNS disease is certainly a significant clinical challenge. That's also an exciting component.

When we think about resistance to these drugs, originally with the first-generation EGFR TKIs, we would see the classic EGFR T790M and gatekeeper mutations developed in about half of patients and then be able to go on to receive osimertinib in the second line, EGFR TKI setting as it has activity against this mutation. But for those patients without the mutations, options were more limited. For osimertinib, we've also now been having increasing knowledge of resistance mechanisms with more and more patients have been treated in the first-line setting, those are actually quite variable, and they do include EGFR second-site mutations. And among those, this C797S mutation is certainly most commonly seen. The reported rate of that mutation has varied from case series and report, but approximately 7% to 25%, depending on the series you look at, and this area remained a challenge. Fortunately, for the C797Smutation, we do expect the earlier generation EGFR TKIs like gefitinib to retain activity.

TARGETED ONCOLOGY: Could you dive a into some of the preclinical evidence that we've seen to suggest that dual EGFR inhibition may delay the emergence of this acquired resistance?

ROTOW: It's partly developed based on what we've seen with the use of these drugs as single agents. So, for example, osimertinib required mutations clinically, we know has good activity. And then we do have some clinical data for patients who had developed T790M and earlier generation EGFR TKIs and then gone on to receive osimertinib and developed a second, EGFR C797S mutation developing that compound mutation due to serial TKI therapy. And that setting depending on the specific orientation of these gene mutations, either in Cis or in-trans, you do see a differing degree of response. So, in the preclinical setting, people have looked at combining these drugs upfront and hoping that we could prevent these mutations and hopefully put patients in a more optimal setting in terms of their development. Some mutagenesis screens, for example, if you treat patients in cell culture setting with combination drugs, you do see this inhibition and development of these common mutations. And that's the rationale for the study in the abstract that's presented, where we looked at combining these two drugs together in a clinical setting.

TARGETED ONCOLOGY: Can you elaborate more on the ongoing phase 1/2 you presented during the ASCO Annual Meeting last year. What was the overall goal of this research?

ROTOW: This was a phase 1/2 study, which was conducted in patients with stage IV EGFR mutated non-small cell lung cancer with a class of EGFR activating mutation, either exon 19 deletion or the IVR mutation. These were not patients who had received prior EGFR TKI therapy. So, these were not patients with the C797S mutation for example, at baseline. The hope of this research is the attempt to both establish tolerability of this combination and also look at longer-term clinical efficacy. Certainly, when osimertinib is the backbone for combination regimens, it’s been very popular strategy recently given the good tolerability profile. That makes a focus on considering toxicity, the combination therapy, and overall long-term tolerability of therapy very important. In this study, after identifying the MTD and recommended dose in the dose-escalation portion, we really focused on feasibility as the primary endpoint of the dose-expansion portion, the patients continued on therapy. And we wanted to really emphasize evaluating a side effect considerations and feasibility going forward. In this case, we defined feasibility as completing at least 6 months of combination therapy.

TARGETED ONCOLOGY: What were the results of the study?

ROTOW: In the dose-escalation phase, we evaluated 2 different dose levels of concurrent dosing with both agents. Both dose levels patients received the FDA approved gefitinib 250 milligrams daily, which was the standard first-line dosing at time of study and also osimertinib either 40 or 80 milligrams. Ultimately, we identified that the 80 milligram osimertinib dose level, which is the highest dose level tested, was the preferred dose to proceed with in the dose-expansion phase. This was overall well-tolerated, we had approximately 82% of patients complete at least 6 months of combination therapy.

Overall, approximately 30% of patients did eventually discontinue gefitinib for toxicity. Most of those were mild grade 1 or grade 2 toxicities and overall, we put the combination where it was tolerable for patients over a longer-term period of treatment.

The response rate was also promising here. In the preliminary analysis, the study is still ongoing, we still have patients enrolling, and there will be updated results once the study is fully enrolled and the data is fully mature. And we saw a promising response rate of approximately 88%, which compares at least, is comparable, to the osimertinib monotherapy response rates and interesting to see as the data fully enrolls, how this looks over time. Of also great interest is PFS, certainly, when asking patients to undergo a combination treatment up front, take on additional toxicities upfront, we're very excited about pursuing this segment strategy, we think it may help forestall the development of resistance and improve the total duration of therapy. But it does mean that you want to see a real significant clinical benefit for patients if you're suggesting these combination strategies, I think long-term seeing the PFS at full data maturity will be critical to understand. This is something we recommend to patients in the first-line setting or not. And we have preliminary numbers on that we're presenting PFS of approximately 22.5 months that certainly that data is immature with additional confirmation pending.

TARGETED ONCOLOGY: What do you foresee some of those considerations being with this kind of combination in practice going forward?

ROTOW: I think, clinically, we've all been very fortunate with osimertinib that we've had lower of the most common side effects that we see with EGFR TKIs is in particular skin toxicities like rash, or heat from rash and dry skin that can be very, very problematic and do influence quality of life for patients. In the combination strategy in this study, we did see the expected spectrum of toxicities that we see on EGFR TKIs, most notably the rash and dry skin, as well as gastrointestinal side effects like diarrhea, which is also common with both agents as monotherapies. These toxicities are often manageable with effective supportive care. And I think as highlighted by the feasibility data, over 80% of our patients were able to continue on combination therapy, demonstrating I think the manageability of the side effects. I think the key the key side effects were really watching for we did not see the development of new toxicities that were unexpected for this drug class, which is also reassuring.

TARGETED ONCOLOGY: What are the next steps for this research and where do you see this approach being utilized in the future if the mature data are favorable?

ROTOW: The next step certainly is completing enrollment, seeing our full data, and trying to demonstrate the extent of clinical benefit that we hope to show. The challenge when you think about strategies for treatment of EGFR mutant disease is do you start with combination therapy upfront and hope of delaying resistance if you can target some of the most common mechanisms? Or do you wait until the acquisition of resistance and then in that setting, I certainly am a strong advocate for additional next-generation sequencing and genomic testing looking for targetable acquired alteration, which case there, you know, certainly and other active area of clinical research is the use of more personalized combination therapies at disease progression. So these are very two distinct strategies, both of which are undergoing evaluation, and both of which may offer benefit to patients and had the benefit of an upfront strategy is you need able to offer your more standard combination to all patients upfront, and then again, assess for mechanisms of resistance at progression. And there once again, assess for new targetable alterations, hopefully having maybe diverted away from the second set EGFR into other methods, other mechanisms.

TARGETED ONCOLOGY: What is your take home message to your colleagues regarding this research?

ROTOW: My first take-home message is that if you're seeing a patient with EGFR-mutated lung cancer, or any of these oncogene-driven subsets, I think it's very important to consider clinical trial options. We have some good clinical options, of course with our currently available monitor. I think for the patients, even you know, two or three years of time is not enough. So, getting patients connected with clinical trial options, wherever possible, I think is a very good thing, both upfront and at acquired resistance. Annual options like this and other trials are ongoing. I think the other key thing is if you're treating a patient, EGFR-mutant lung cancer and patients’ developers’ distance, you're really reassessing for mechanisms of resistance and trying to offer patients additional personalized kind of combinations, either ideally on study or off label can be a good option.

REFERENCE:
1. Rotow, J., Costa, D., Paweletz, C. Concurrent osimertinib plus gefitinib for first-line treatment of EGFR-mutated non-small cell lung cancer (NSCLC). J Clin Oncol. 2020;38(suppl 15); 9507-9507. doi: 10.1200/JCO.2020.38.15_suppl.9507