Combining Afatinib and Concurrent Chemotherapy, Followed by Osimertinib and Concurrent Chemotherapy, in Untreated EGFR Positive NSCLC Tumors

Osimertinib monotherapy is now the preferred treatment option in EGFR mutation positive non-small cell lung cancer (NSCLC). However, a sequential combination strategy using first line afatinib in with a short course of chemotherapy, followed by osimertinib with a short course of chemotherapy (in T790M positive tumors) could increase the targeted therapy efficacy option for these patients.
Study design: this is a single arm, open label, multicenter phase II study. A total of 21 evaluable patients are needed.
Study population: TKI-naïve advanced EGFRm+ del19/L858R NSCLC patients who are eligible for treatment with EGFR TKI and chemotherapy. Patients with CNS metastases will be excluded.

We hypothesized that treating advanced stage EGFR mutation positive NSCLC in first line with afatinib and osimertinib in second line (in T790M positive tumors) will cause an apoptotic cell death in a large part of TKI-sensitive cancer cells, resulting in a large reduction of the tumor bulk. Adding cytotoxic chemotherapy after 6 weeks of EGFR-TKI will destroy remaining TKI-resistant subclones at an early stage, when the TKI-resistance tumor volume is the smallest and most vulnerable. We will administer only 2 cycles of chemotherapy to limit toxicity, while maintaining a substantial anti-cancer effect. After progression on afatinib-chemotherapy combination, the majority of patients will develop T790M and will be able treated by osimertinib-chemotherapy combination.
So, this strategy will allow us to timely sequence the most appropriate drugs (afatinib and osimertinib with chemotherapy) to get the highest anti-cancer efficiency. In this way, we will avoid long periods of maintenance treatments with chemotherapy or anti-VEGFR treatments that are associated with toxicity, costs, and necessitate the patients to come into the ward for intravenous medication. The limited cycles of chemotherapy also allows
the treating physician to again treat the patient with the same chemotherapy regimen once progression occurs after all sensible targeted therapy options have been used.
Therefore, we hypothesize that this sequential combination strategy will be more effective than other available strategies and will improve the quality of patient care as compared to current general practice.

The primary endpoint will be evaluated at 18 months of inclusion using RECIST1.1. The secondary and explorary endpoints will be evaluated using RECIST1.1 every six weeks, survival data, molecular analysis of histologic specimen at baseline and upon progression, and blood samples dd-PCR every six weeks initially and upon progression.

This study consists of 2 parts. Part 1 is defined as a first line treatment with afatinib orally (30 mg once a day) for the first 6 weeks, followed by concurrent use of afatinib (20mg once a day, part 1B) plus 2 cycles of carboplatin and pemetrexed (21 days per cycle); followed by afatinib monotherapy (30mg once a day). Part 2 comprises a 2nd line treatment with osimertinib (80 mg once daily) after failure of part 1, only in T790M positive patients for the first 6 weeks, followed by concurrent use of osimertinib (80mg once a day) plus 2 cycles of carboplatin and pemetrexed (21 days per cycle); followed by osimertinib monotherapy (80mg once a day).