First-line treatment of EGFR-mutated non-small cell lung cancer: concurrent Osimertinib plus Gefitinib


First-line treatment with an EGFR tyrosine kinase inhibitor ( TKI ) is standard of care for patients with EGFR-mutated non-small-cell lung cancer ( NSCLC ).
The EGFR TKI Osimertinib ( Tagrisso ) is active against the acquired Gefitinib-resistant mutation EGFR T790M, as is Gefitinib ( Iressa ) against the Osimertinib-resistant EGFR C797S.
Preclinical evidence has suggested dual EGFR inhibition with Gefitinib + Osimertinib may delay emergence of acquired resistance.

A ongoing phase I/II study enrolled patients with stage IV EGFR-mutated ( L858R or del19 ) NSCLC, without prior therapy for metastatic disease.
Treatment in dose escalation ( n = 6 ) was: concurrent Osimertinib 40 mg or 80 mg + Gefitinib 250 mg daily.
In dose expansion ( n = 21 ), the combination of Osimertinib and Gefitinib was used at the maximum tolerated dose ( MTD ).
Prior to protocol amendment 6 patients received alternating monthly cycles of TKI monotherapy and were excluded from this analysis.

The primary endpoints in the dose escalation and expansion phases were, respectively, identification of the maximum tolerated dose and feasibility, defined as receipt of combination therapy for greater than or equal to 6 four-week cycles.
Secondary endpoints included overall response rate ( ORR ), survival outcomes, plasma EGFR mutation clearance ( cell free DNA by droplet digital PCR [ ddPCR ] ), and mechanisms of acquired resistance.

From May 2017 to July 2019 27 patients were enrolled and evaluable for the primary endpoints.

The maximum tolerated dose was Osimertinib 80 mg plus Gefitinib 250 mg orally daily.

In feasibility analysis, 81.5% completed greater than or equal to 6 cycles combination therapy ( 1 patient discontinued for progression, 4 for toxicity ).

The ORR was 85.2% ( 95% CI 67.5%-94.1% ). Best response was: 85.2% partial response ( PR ), 14.8% stable disease ( SD ).

The most common treatment-related adverse effects ( TRAEs ) ( % any grade, % grade 3 ) were rash ( 96.3%, 3.7% ), diarrhea ( 85.2%, 11.1% ) and dry skin ( 70.4%, 0% ).

Plasma ddPCR ( n = 25 pts ) detected the driver EGFR mutation at baseline in 68% of patients.
In these patients, plasma EGFR cleared to undetectable at 2 weeks treatment in 82.4%.

At 14.8 months median follow up the median progression free survival was not yet reached.

In conclusions, combination therapy with Osimertinib and Gefitinib is tolerable for first-line treatment of EGFR-mutated non-small cell lung cancer and resulted in rapid plasma clearance of the EGFR mutation.
The observed ORR is consistent with previously reported first-line response rates to Osimertinib.
Analysis of survival outcomes and acquired resistance mechanisms are pending data maturity and will facilitate understanding of the role of first-line dual EGFR TKI therapy for this population. ( Xagena )

Source: American Society of Clinical Oncology ( ASCO ) Virtual Meeting, 2020

XagenaMedicine_2020



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