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Making a Case for Second-Line TKI in EGFR-Mutated NSCLC

– Is osimertinib ideal in this setting, FDA reps ask; also, Yasir Elamin, MD, shares study data


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Medical Today

"Insanity is doing the same thing over and over again and expecting different results." While there's some as to who actually said that off-quoted comment, there's less uncertainty about the kernel of truth it contains. When it comes to treatment for epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC), the idiom could apply to the continued use of osimertinib (Tagrisso) as second-line treatment even after first-line tyrosine kinase inhibitor (TKI) resistance has set in, FDA officials argued.

First-line osimertinib has "clinical benefits," conceded Bernardo H.L. Goulart, MD, MS, of the FDA Office of Oncologic Diseases in Silver Spring, Maryland, and colleagues in a "Comments and Controversies" article in the.

And "platinum-based chemotherapy remains the standard of care after progression on EGFR [TKIs]," the authors said. But they also noted that many experts advise "continuing osimertinib beyond progression and adding other agents to target the putative mechanism of TKI resistance." Justifications for this approach include:

  • Avoiding a "tumor flare" after stopping an EGFR TKI
  • Maintaining central nervous system disease control
  • Prolonging TKI clinical benefits especially in oligometastatic or oligoprogressive disease
  • "When the available evidence suggests that targeting the putative mechanism of resistance and the original EGFR mutation concomitantly is necessary to induce an antitumor effect. However, the evidence supporting this practice is limited and derives mostly from nonrandomized clinical data."

The article outlined the regulatory considerations that come into play when the FDA considers ongoing third-generation TKIs in second-line trials of EGFR-mutated NSCLC. These include adequate demonstration of the contribution of individual drug components to a combination regimen and the possibility that in the setting of high toxicity, it may just be the one drug that has the most benefit, Goulart and co-authors said.

For instance, the ongoing randomized controlled trial is testing osimertinib in combination with platinum chemotherapy and pemetrexed versus placebo plus platinum chemotherapy and pemetrexed in the post-osimertinib setting (estimated completion date is Dec. 2024).

"With a primary end point of progression-free survival (PFS) and a projected sample size of 204 patients, COMPEL is expected to generate relevant evidence regarding the efficacy and safety of continuing osimertinib post-progression," the authors wrote. "While the data from COMPEL may provide evidence of the benefit of continuing osimertinib when administering platinum-based chemotherapy, such results cannot necessarily be extrapolated to other potential partner drug(s) with differing mechanisms of action. The design of trials evaluating second-line, osimertinib containing combinations may need to be revisited to address individual contribution of drug component."

In that case, the phase I/II study is on the right track. The study is looking at an investigational, next-generation, oral TKI (BLU-945) as monotherapy and in combination with osimertinib in previously treated patients with advanced EGFR-mutant (EGFRm) NSCLC (estimated study completion date is ). Yasir Y. Elamin, MD, of the University of Texas MD Anderson Cancer Center in Houston, shared at this year's ASCO annual meeting.

What was the impetus for the SYMPHONY study?

Elamin: On-target and off-target resistance mechanisms develop inevitably following treatment with EGFR third-generation TKI, and optimizing EGFR-targeted therapy, particularly in the front-line setting where you have less tumor heterogeneity, may improve clinical outcomes.

One strategy is combining EGFR TKI-TKIs, and that has been tested with compounds like osimertinib, with gefitinib, but each of our wild-type related toxicities may be a limiting factor for the utility of these regimens.

BLU-945 is a novel, next-generation EGFR inhibitor that has nanomolar potency against classical EGFR mutations, exon 19 deletion, and L858R, as well as against acquired mutations such as C797 and T790M. It's a highly selective inhibitor that spares EGFR wild type, making it a potential good combination partner.

What are some study details?

Elamin: Eligible patients are patients with EGFR-mutant lung cancer who have had at least one prior EGFR TKI with T790M activity. The dose escalation phase had two parts. The first part was 945 monotherapy, with a starting dose of 25 mg daily. We also tested BID dosing. Part 1B was the combination part, which included BLU-945 at the starting dose of 200 mg, which was 50% of the highest dose studied for the monotherapy. And osimertinib was given at 80 mg standard daily dose.

It's important to note that for patients to be eligible for the combination part, they must have progressed on osimertinib as their last line of therapy. Primary endpoints included MTD [maximum tolerated dose] and RP2D [recommended phase II dose] and safety.

What were some of the main findings with monotherapy?

Elamin: BLU-945 as a single agent was overall well tolerated. EGFR wild-type related toxicities were infrequent, less than 10%, and they were mostly grade 1 and 2. We saw no grade 3 EGFR wild-type related toxicities.

However, we have seen some treatment-related toxicities. The most common one is ALT [alanine transaminase] -- 22% of the patients had grade 3 ALT toxicities. We have seen 12 DLTs [dose-limiting toxicities] in high doses of 400 mg up to 600 mg.

In terms of efficacy, BLU-945 monotherapy resulted in dose-dependent reduction and clearance of EGFR alleles [T790M and C797X], confirming the target potency of this drug.

In terms of responses in this heavily pretreated population with tumor heterogeneity, we observed two confirmed partial response. Most patients achieved stable disease with tumor shrinkage.

And with combination therapy?

Elamin: The combination with osimertinib was also well tolerated. The EGFR wild-type related toxicities were infrequent. We've seen only one grade 3 skin rash with the combination. Other treatment-related AEs [adverse events] were generally low grade, and the common ones were headache and nausea.

The dose escalation for the combination is ongoing, and the MTD is yet to be determined. I want to note here that exposure of BLU-945 on osimertinib when co-administered was comparable to PK [pharmacokinetics] data from BLU-945 as a monotherapy and the published data of single-agent osimertinib.

In terms of efficacy, we saw here as well molecular response, with reduction in ctDNA [circulating tumor DNA] and clearance of some patients. Again here, we're shown to the right the T790M alleles reduction and showing to the left reductions in C797S.

What's the take-home message?

Elamin: In summary, in heavily pretreated EGFR-mutant patients, BLU-945 monotherapy was active and well tolerated. BLU-945 in combination with osimertinib was also well tolerated post-progression on osimertinib, with infrequent EGFR wild-type toxicities.

Read the study here.

Goulart reported no relationships with industry; a co-author reported employment with Treeline Biosciences.

SYMPHONY was funded by Blueprint Medicines. One co-author is a company employee, and another is a Lilly employee.

Elamin disclosed relationships with, and/or support from, AstraZeneca, Bristol Myers Squibb/Medarex, Lilly, Sanofi Spectrum, Takeda, Turning Point Therapeutics, Blueprint Medicines, Elevation Oncology, Forward, Precision Therapeutics, and Xcovery; co-authors disclosed relationships with, and/or support from, multiple entities including Blueprint Medicines.

Primary Source

Journal of Clinical Oncology

Source Reference:

ASCO Publications Corner

ASCO Publications Corner