Interview with Barbara Melosky: “The sequencing question remains”
Interview: Barbara Melosky, MD, FRCPC, University of British Columbia and British Columbia Cancer Agency, Vancouver, Canada
Afatinib has been licensed for the second-line treatment of patients with squamous-cell carcinoma of the lung. A combination trial is ongoing that is testing afatinib plus pembrolizumab. What can we expect from this regimen?
I think this is a highly interesting regimen. We know that afatinib does play a role in squamous-cell carcinoma of the lung. The LUX-Lung 8 trial has shown an improvement in PFS and OS over erlotinib [1]. Our Canadian trial demonstrated that erlotinib does have activity in squamous-cell carcinoma in the second-line setting [2]. We know that afatinib is a very useful drug, and we also know that pembrolizumab has efficacy in squamous-cell carcinoma after platinum-doublet therapy in patients whose tumours express PD-L1. Therefore, I think that combining these two agents will be very interesting. The ongoing study is a phase II trial that is looking at reduction in tumour size [3]. The combination should be well tolerated, and I hope we see an improvement in response rates.
Are there further combinations of anti-EGFR agents with other drug classes that might be worth exploring?
The addition of anti-angiogenesis to EGFR TKI treatment is certainly worth exploring. At this year’s ASCO Congress, we saw exciting data obtained with the combination of erlotinib and the anti-VEGF antibody bevacizumab [4]. This phase III study demonstrated the superiority of erlotinib plus bevacizumab over erlotinib alone, with a PFS benefit of more than 3 months.
Based on the ARCHER 1050 trial, can dacomitinib be regarded as a first-line standard option in patients with EGFR-mutation–positive NSCLC?
The ARCHER 1050 study caught us all by surprise last year. At that time, Dr. Mok presented the PFS results, demonstrating a benefit of dacomitinib over gefitinib [5]. Now the pre-specified final OS analysis of ARCHER 1050 was presented, which was positive [6]. This means that we now have the first EGFR TKI study showing an OS benefit. There was no significant OS difference in any other trial, so I think dacomitinib can be regarded as a first-line standard option in EGFR-mutant NSCLC, if the patient has no brain metastases at baseline as the ARCHER 1050 study did not include these patients.
From a clinical point of view, how do you rate the sequence of afatinib followed by osimertinib as compared to first-line osimertinib?
With the positive results of the FLAURA trial [7], oncologists will soon have to decide if they use osimertinib upfront or use it after progression in patients on first-generation or second-generation EGFR TKIs who are found to have an acquired T790 mutation. With an investigator-assessed PFS of over 18 months and a favourable toxicity profile, osimertinib might be ideal for patients whose treatment goal is not necessarily OS. FLAURA will not answer the sequencing question, as patients in the control arm were only randomised to first-generation EGFR TKIs, and crossover, although allowed, was not ideal in this design. Without the OS known for the osimertinib arm of FLAURA or the osimertinib arm of AURA3 [8], the sequencing question remains.
We now have second-generation TKIs like afatinib, which showed an impressive statistically significant OS advantage of 33 months compared to chemotherapy in patients with deletion 19 included in the LUX-Lung 3 trial [9]. At this year’s ASCO Congress, the ARCHER 1050 study illustrated a statistical OS benefit of dacomitinib compared to gefitinib [6]. There is no perfect trial. Do we start with osimertinib for all patients, or do we sequence it after first-generation or second-generation EGFR TKIs in only a subset? The question remains. We will likely use individual patient factors such as age, type of mutation, performance status, or brain metastases to make such decisions. The good news is that with debate, other questions arise and the person who most benefits is the patient.
REFERENCES
- Soria JC et al., Afatinib versus erlotinib as second-line treatment of patients with advanced squamous cell carcinoma of the lung (LUX-Lung 8): an open-label randomised controlled phase 3 trial. Lancet Oncol 2015; 16(8): 897-90
- Shepherd FA et al., Erlotinib in previously treated non-small-cell lung cancer. N Engl J Med 2005; 353: 123-132
- Levy B et al., Afatinib in combination with pembrolizumab in patients with stage IIIB/IV squamous cell carcinoma of the lung. J Clin Oncol 36, 2018 (suppl; abstr TPS9117)
- Furuya N et al., Phase III study comparing bevacizumab plus erlotinib to erlotinib in patients with untreated NSCLC harboring activating EGFR mutations: NEJ026. J Clin Oncol 36, 2018 (suppl; abstr 9006)
- Mok T et al., Dacomitinib versus gefitinib for the first-line treatment of advanced EGFR mutation positive non-small cell lung cancer (ARCHER 1050): a randomized, open-label phase III trial. J Clin Oncol 35, 2017 (suppl; abstr LBA9007)
- Mok TS et al., Improvement in overall survival in a randomized study comparing dacomitinib with gefitinib in patients with advanced non-small cell lung cancer harboring EGFR-activating mutations. J Clin Oncol 36, 2018 (suppl; abstr 9004)
- Soria JC et al., Osimertinib in untreated EGFR-mutated advanced non-small-cell lung cancer. N Engl J Med 2018; 378(2): 113-112
- Mok TS et al., Osimertinib or platinum-pemetrexed in EGFR T790M-positive lung cancer. N Engl J Med 2017; 376: 629-640
- Yang JC et al., Afatinib versus cisplatin-based chemotherapy for EGFR mutation-positive lung adenocarcinoma (LUX-Lung 3 and LUX-Lung 6): analysis of overall survival data from two randomised, phase 3 trials. Lancet Oncol 2015; 16(2): 141-151
