Osimertinib: First-line or second-line therapy for EGFR M+ NSCLC? A Summary of the Debate between Dr. Peter Ellis and Dr. Barbara Melosky at CLCCO 2018

At the 2018 Canadian Lung Cancer Conference (CLCCO), Peter Ellis, Medical Oncologist at the Juravinski Hospital and Cancer Centre, Hamilton, ON, and Dr. Barbara Melosky, Medical Oncologist at the British Columbia Cancer Agency, Vancouver, BC, debated whether the third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) osimertinib should be used as first-line or second-line therapy for the treatment of EGFR mutation-positive (M+) advanced non-small cell lung cancer (NSCLC). Dr. Ellis argued that osimertinib should be used as the first-line therapy, while Dr. Melosky countered that it should be reserved for second-line treatment of patients who acquire the exon 20 T790M resistance mutation (T790M). Audience voting determined the winner of this lively debate. This article summarizes the two arguments and concludes with the results of the audience vote.

Osimertinib: First-line or second-line therapy for EGFR M+ NSCLC? First line!

Dr. Peter Ellis

Dr. Ellis began by asserting that the issue under debate was a simple one, and playfully advised the audience not to allow themselves to be misled by arguments from his opponent that might rely on, e.g., subgroup analyses from clinical trials.

For first-line treatment of patients with advanced EGFR M+ NSCLC, multiple randomized clinical trials demonstrating higher response rates and longer progression-free survival (PFS) with first- or second-generation EGFR TKIs (versus platinum-based chemotherapy) have established gefitinib, erlotinib, and afatinib as the current standards of care. Dr. Ellis noted that a key question is whether any of these drugs is superior to another, and only two trials have addressed this in patients with advanced NSCLC and a common EGFR mutation (exon 19 deletion, Del19; or exon 21 point mutation, L858R). One is LUX-Lung 7, which compared afatinib with gefitinib and reported a higher objective response rate (ORR) and longer PFS for afatinib versus gefitinib (ORR: 70% vs. 56%; median PFS: 11.0 months vs. 10.9 months).1 However, Dr. Ellis argued that the PFS advantage was not clinically meaningful and afatinib was associated with higher toxicity than gefitinib.1 Thus, neither drug was clearly superior in this comparison. The other relevant trial is ARCHER 1050, which compared second-generation EGFR TKI dacomitinib with gefitinib and reported a potentially meaningful PFS advantage for dacomitinib over gefitinib (median PFS: 14.7 months vs. 9.2 months).2 But Dr. Ellis noted that, since dacomitinib is not currently approved in Canada, any difference between the two drugs does not factor into oncologists’ daily treatment decisions and is therefore not relevant.

Dr. Ellis opted to support his case for osimertinib in the first-line setting by reviewing results from the large, well-balanced FLAURA trial, which compared the efficacy of third-generation EGFR TKI osimertinib with investigator’s choice of gefitinib or erlotinib as first-line treatment for patients with advanced NSCLC and a common EGFR mutation.3 (Figure 1) Osimertinib demonstrated an impressive and clinically meaningful advantage over gefitinib or erlotinib in the primary outcome, PFS (median: 18.9 months vs. 10.2 months) (Figure 2), that was significant even in patients who had central nervous system (CNS) metastases (median PFS: 15.2 months vs. 9.6 months).3 Furthermore, the duration of response (DoR) was dramatically longer with osimertinib (median DoR: 17.2 months vs. 8.5 months) – and its toxicity profile, while similar to that for gefitinib or erlotinib, included lower rates of rash (any grade: 58% vs. 78%) and liver toxicity (any grade: 6%–9% vs. 25%–27%).3 Dr. Ellis then presented the interim analysis of overall survival (OS), which – though immature – already shows a clear separation in the survival curves in favour of osimertinib (median OS: not reached in either arm).3 (Figure 3) He went on to conclude that the available information appears to support improved survival for EGFR M+ NSCLC patients with a strategy of upfront osimertinib treatment.

The AURA3 trial investigated the efficacy of osimertinib versus platinum-pemetrexed chemotherapy in patients with advanced EGFR M+ NSCLC who had disease progression after first-line EGFR TKI therapy and tumours expressing T790M.4 To counter the potential argument that a cross-trial comparison of PFS values from AURA3 and FLAURA (first-line osimertinib) suggests a cumulative PFS advantage for patients receiving osimertinib after progression on prior EGFR TKI therapy (versus those receiving osimertinib as first-line treatment), Dr. Ellis asserted that such cross-trial comparisons are generally known to be invalid. In this case, it is inappropriate to add median PFS values from AURA3, which excluded some patients at risk for a poor prognosis by including only those who had T790M and a World Health Organization performance status of 0 or 1 after disease progression, to PFS values from FLAURA, which included T790M– patients and assessed performance status before treatment.4,3

To close his side of the debate, Dr. Ellis reiterated key findings from the FLAURA trial that suggest osimertinib is superior to other EGFR TKIs and should be used as first-line therapy for EGFR M+ NSCLC: significant benefits for both PFS and DoR, a better toxicity profile, and promising immature survival data that imply a clinically meaningful overall survival advantage.

Figure 1. FLAURA study design

Figure 2. FLAURA study: Progression-free survival by investigator assessment

Figure 3. FLAURA study: Overall survival interim analysis

Osimertinib: First-line or second-line therapy for EGFR M+ NSCLC? Second line!

Dr. Barbara Melosky

meloskyDr. Melosky began with a brief review of the clinical data supporting her position that afatinib should be the standard of care for first-line treatment of advanced EGFR M+ NSCLC, with osimertinib reserved for second-line treatment in patients who develop T790M. She touched on the IPASS5 and EURTAC6 trials that first demonstrated the importance of treating EGFR M+ patients with EGFR TKIs in the first line, and the LUX-Lung 3 trial that achieved an encouraging first-line median PFS of 13.6 months with the second-generation TKI afatinib (versus 6.9 months with standard chemotherapy) in patients with common EGFR mutations.7 The first-line PFS benefit of afatinib was subsequently bolstered by impressive OS values, particularly in patients with Del19 (median OS: 33.3 months vs. 21.1 months, afatinib vs. chemotherapy)8 – but also in those with either common EGFR mutation in a head-to-head comparison with gefitinib (median OS: 27.9 months vs. 24.5 months).9 It was based on the strength and consistency of the LUX-Lung data, combined with her considerable clinical experience with the drug at the British Columbia Cancer Agency, that Dr. Melosky chose to adopt afatinib as her standard of care for first-line treatment of EGFR M+ NSCLC.

To highlight the appropriateness of osimertinib for the second-line treatment of the large subset (>60%) of EGFR M+ NSCLC patients who develop T790M, Dr. Melosky summarized key results from the AURA3 trial (osimertinib versus chemotherapy after disease progression on EGFR TKI therapy).4 In this setting, osimertinib demonstrated an impressive advantage in the primary endpoint, investigator-assessed PFS (10.1 months vs. 4.4 months). Equally striking were statistically and clinically significant improvements in PFS assessed by blinded independent central review (median PFS: 11.0 months vs. 4.2 months) (Figure 4) and ORR (71% vs. 31%).4 Dr. Melosky argued that this evidence of superior efficacy over chemotherapy, together with advantages like proven effectiveness in patients with or without CNS metastases and a manageable toxicity profile,4 provides strong support for osimertinib as the new standard of care for second-line treatment of EGFR T790M+ NSCLC.

Dr. Melosky next considered the available data on osimertinib in the first-line treatment of advanced EFGR M+ NSCLC. She suggested that the key trial, FLAURA,3 which compared the efficacy of osimertinib and gefitinib or erlotinib in this setting, had several important flaws that limit its usefulness. Related to design, FLAURA excluded the roughly 10% of EGFR M+ patients who do not have a common EGFR mutation. It also excluded afatinib – Dr. Melosky’s own standard of care – and failed to stratify EGFR TKI–treated patients by drug, which prevented intra-group comparisons. Regarding interpretation, drawing conclusions based on promising trends in the immature OS data reported when 75% of the trial patients were still alive is inappropriate and unhelpful. And the nearly nine-month PFS increase with first-line osimertinib, which appears to represent an impressive advantage over gefitinib or erlotinib (median PFS: 18.9 months vs. 10.2 months)3 drops to just 4–5 months when compared to values reported for the second-generation TKIs in the first line (median PFS: 13.6 months vs. 6.9 months for afatinib vs. chemotherapy; 14.7 vs. 9.2 for dacomitinib vs. gefitinib).7,2 Based on PFS values already reported for the first- and second-generation TKIs in the first-line setting and osimertinib in the second-line setting,6,2,4 Dr. Melosky reasoned that practice-changing results for first-line osimertinib would have required a median PFS exceeding about 21–26 months – far longer than the 18.9 months reported for FLAURA.3 (Figure 5)

When choosing an EGFR TKI for the first-line treatment of EGFR M+ NSCLC, one often-suggested approach is to use the strongest EGFR TKI first. So, Dr. Melosky posed the question, “Is osimertinib actually the strongest EGFR inhibitor?” To answer this question, she presented in vitro activity data illustrating that, among representative first-, second-, and third-generation EGFR TKIs, osimertinib is most effective against T790M, but is outperformed by afatinib with respect to inhibiting EGFR mutations. (Figure 6)

To underscore her position that the optimal therapeutic sequence for advanced EGFR M+ NSCLC should begin with afatinib and continue with osimertinib only after progression of T790M+ disease, Dr. Melosky drew some comparisons between the two drugs. She conceded that osimertinib is a so-called “easy” drug due to its favourable toxicity profile, but cautioned that this profile includes instances of interstitial lung disease, which are not a concern with afatinib. While toxicities like rash are more common with afatinib, we can manage these effects with simple dose adjustments that are demonstrated to improve patient quality of life while maintaining drug efficacy.10 Like osimertinib, afatinib is effective in patients with CNS metastases; but unlike osimertinib, is also effective in the roughly 10% of patients who have EGFR mutations other than Del19 or L858R. Finally, while the mechanisms of T790M resistance to first- or second-generation EGFR TKI therapies are well known – as is the appropriate response: second-line treatment with osimertinib as an effective T790M inhibitor – our understanding of acquired resistance to osimertinib via the C797S mutation is limited, and drugs to treat it are lacking.

Dr. Melosky concluded by reminding the audience that the medical oncology community has worked hard to identify the important targets in lung cancer. In the case of osimertinib, the target is T790M – not all EGFR mutations. Thus, osimertinib is appropriate as second-line treatment for patients with EGFR M+ NSCLC who are T790M+ —not as first-line treatment for the up to 40% of other patients in this population who are T790M–. She closed with this advice: “Follow the science; treat the target.”

Figure 4. AURA3 study: Progression-free survival by blinded independent central review

Figure 5. Schematic comparison of PFS values for different EGFR TKIs investigated in the first- or second-line settings for EGFR M+ advanced NSCLC

Figure 6. In vitro inhibitory effectiveness of EGFR TKIs

Conclusion

The winner of the debate was Dr. Barbara Melosky, who earned 67% of the decided vote.

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