Introduction
Established first-line treatment options for patients with non-small cell lung cancer (NSCLC) and activating epidermal growth factor receptor (
EGFR) mutations include: the first-generation reversible EGFR-targeting tyrosine kinase inhibitors (TKIs), gefitinib (European Medicines Agency
2018a; US Food and Drug Administration
2015a) and erlotinib (European Medicines Agency
2018b; US Food and Drug Administration
2010); the second-generation irreversible ErbB family blocker afatinib (European Medicines Agency
2018c; US Food and Drug Administration
2013) and the irreversible EGFR TKI dacomitinib (US Food and Drug Administration
2018); and the third-generation
EGFR wild-type sparing, irreversible EGFR/T790M inhibitor, osimertinib (European Medicines Agency
2018d; US Food and Drug Administration
2015b). Until recently, there was a lack of prospective head-to-head comparisons of these agents.
The randomized phase IIb LUX-Lung 7 trial is, to the best of our knowledge, the first study to compare the irreversible ErbB family blocker (second-generation EGFR-targeting agent) with a reversible, first-generation EGFR TKI: in this case, afatinib was compared with gefitinib in treatment-naïve patients with advanced NSCLC harboring a common
EGFR mutation (exon 19 deletion/L858R) (Park et al.
2016). The primary analysis of LUX-Lung 7 demonstrated that afatinib significantly improved the co-primary end points of progression-free survival [PFS; median 11.0 vs 10.9 months, hazard ratio (HR) = 0.73, 95% confidence interval (CI) 0.57–0.95;
P = 0.017] and time-to-treatment failure (TTF; defined as the time from randomization to the time of treatment discontinuation for any reason; median 13.7 vs 11.5 months, HR = 0.73, 95% CI 0.58–0.92;
P = 0.007) vs gefitinib (data cutoff: August 21, 2015) (Park et al.
2016). Analysis of overall survival (OS) demonstrated no significant difference in OS between the treatment groups [median 27.9 vs 24.5 months, HR = 0.86, 95% CI 0.66–1.12;
P = 0.258 on April 08, 2016 (Paz-Ares et al.
2017) and HR = 0.85, 95% CI 0.66–1.09;
P = 0.195 on December 05, 2016] (Corral et al.
2017).
The adverse event (AE) profiles for both afatinib and gefitinib in LUX-Lung 7 were consistent with previous experience, with no unexpected safety findings. As expected, diarrhea (afatinib vs gefitinib, all grades: 90.0% vs 61.0%; grade ≥ 3: 12.5% vs 1.3%) and rash/acne (all grades: 88.8% vs 81.1%; grade ≥ 3: 9.4% vs 3.1%) were more frequent with afatinib than gefitinib (Park et al.
2016), which is also consistent with observations with another irreversible second-generation EGFR TKI, dacomitinib (Wu et al.
2017). Increased alanine transaminase/aspartate transaminase (all grades: 24.5% vs 10.0%; grade ≥ 3: 8.8% vs 0%) was more frequent with gefitinib than afatinib (Park et al.
2016).
While the primary results of LUX-Lung 7 favored afatinib over gefitinib in a clinical trial setting, it is essential to consider factors that are likely to contribute toward treatment decisions in ‘real-world’ clinical practice. Regarding afatinib, a pertinent question is how should AEs, in particular diarrhea, be managed so that patients can remain on treatment for as long as they derive clinical benefit? Furthermore, is AE management with afatinib sufficiently effective in facilitating the ‘real-world’ clinical practice of continuing EGFR TKIs beyond radiological progression, in the absence of clinical deterioration? This is an important option for physicians and is recognized in current treatment guidelines (Novello et al.
2016), as it appears to reduce the risk of ‘disease flare’ (sudden increases in tumor growth and disease-related symptoms) in
EGFR mutation-positive NSCLC patients with slow progressive disease (PD) (Chaft et al.
2011; Riely et al.
2007; Yap et al.
2017). In LUX-Lung 7, 35.0% of afatinib-treated and 29.6% of gefitinib-treated patients continued the assigned study treatment beyond radiological progression. For these patients, median duration of treatment beyond initial progression was 2.7 months (95% CI 1.9–4.3) and 2.0 months (95% CI 1.5–3.0), respectively (Park et al.
2016).
Previous studies have demonstrated that a well-established tolerability-guided afatinib dose adjustment protocol, which is facilitated by the availability of several dose strengths (European Medicines Agency
2018c; US Food and Drug Administration
2013), effectively mitigates afatinib-related AEs without impacting efficacy outcomes (Yang et al.
2016). Therefore, treatment discontinuation due to afatinib-related AEs is rare in clinical trials (6–8%) (Park et al.
2016; Sequist et al.
2013; Wu et al.
2014). Indeed, the effectiveness of tolerability-guided dose adjustment for AE management may also be reflected in the improvements in TTF observed with afatinib vs gefitinib in LUX-Lung 7 (Park et al.
2016).
In this sub-analysis of LUX-Lung 7, we further assessed the impact of tolerability-guided dose adjustment of afatinib with respect to AE management, patient-reported outcomes (PROs) and efficacy of treatment. We also evaluated the clinical characteristics of patients who continued afatinib or gefitinib treatment beyond initial radiological progression, to assess the potential for maximizing time on treatment for as long as patients derive clinical benefit.
Discussion
Effective management of AEs is an important aspect of the overall treatment strategy for patients with advanced NSCLC, with the goal of maximizing therapy exposure, and thus achieving optimal clinical benefit. Consistent with findings from other LUX-Lung studies (Yang et al.
2016), tolerability-guided dose reduction of afatinib in the LUX-Lung 7 trial led to decreases in the incidence and severity of key treatment-related AEs, particularly diarrhea and rash/acne.
The majority of afatinib dose reductions occurred within the first 6 months of treatment and were more common in females and non-Asian patients, even taking into account imbalances between gender and race in the ITT populations. In an analysis of afatinib dose reduction in the LUX-Lung 3 and 6 trials, afatinib plasma concentrations, which may vary among distinct subgroups of patients (e.g., based on gender) (Freiwald et al.
2014), were correlated with the incidence of dose reduction (Yang et al.
2016). Mean afatinib trough plasma concentration at the approved starting dose of 40 mg was higher in patients who had subsequent dose reduction, compared with patients who did not require dose reduction. Further, afatinib plasma concentrations for those who had dose reduction to 30 mg were similar to those who remained on the 40 mg dose (Yang et al.
2016). Although pharmacokinetic analyses were not conducted in the LUX-Lung 7 trial, the analyses from LUX-Lung 3 and 6, which consisted of a similar patient population and treatment setting, suggest that reducing the dose of afatinib in some patients may serve to mitigate excessive afatinib plasma exposure and thus reduce the burden of common treatment-related AEs. Given that gefitinib is only approved for administration in one dose formulation (European Medicines Agency
2018a; US Food and Drug Administration
2015a), no dose-reduction schemes were implemented for gefitinib in LUX-Lung 7, although dose interruptions were permitted for various reasons. It was not possible to identify AEs that led to a dose interruption due to an oversight in the design of the electronic case record form.
In LUX-Lung 7, there was no evidence of a statistically significant difference in median PFS with afatinib between patients who had a dose reduction to < 40 mg during the first 6 months of treatment vs those who remained on ≥ 40 mg during this time. Due to the inherent confounding in this analysis, as patients with early PD are unlikely to have been given the opportunity to reduce dose, some care should be taken in the interpretation of these results. There was no clinically meaningful difference in PROs for patients who received a dose reduction to < 40 mg during the first 6 months of treatment vs those who did not. Combined with the findings from the LUX-Lung 3 and 6 trials (Yang et al.
2016), these data indicate that dose reduction of afatinib is an effective strategy for the management of key treatment-related AEs, without negatively impacting the efficacy in patients with
EGFR mutation-positive NSCLC. In the context of these data, it is important to note that there are currently no clinical data to support adaptation of the approved afatinib starting dose based on patient clinical characteristics, and underdosing at initiation of treatment may negatively affect the achievable clinical benefit with afatinib. Thus, the approved afatinib dose of 40 mg/day is recommended at treatment start and should only be modified based on individual patient tolerability. During the patient’s first few months of treatment, there should be frequent, vigilant follow-up and monitoring to ensure timely and appropriate dose adjustments.
Approximately, one-third of patients who were experiencing clinical benefit with afatinib or gefitinib continued their assigned treatments beyond investigator-assessed radiological progression (Park et al.
2016). The median duration of the assigned study treatment beyond PD in these patients was 2.7 months with afatinib and 2.0 months with gefitinib, which may suggest some benefit in continuing EGFR TKI treatment beyond radiological progression, with a numerically longer duration of treatment observed in the afatinib vs gefitinib treatment arm (Park et al.
2016). Around half of the patients who continued treatment beyond initial progression had no documented PD in target lesions, but instead had PD in non-target lesions and/or the occurrence of a new lesion, the latter of which might be controlled by localized therapies. At the time of initial progression, 42.9% of afatinib-treated and 19.1% of gefitinib-treated patients who continued treatment beyond progression had either a CR or PR in target lesions. Based on these data, from a clinical perspective it seems that progression in non-target lesions and/or the occurrence of a new lesion, especially in conjunction with responses in target lesions, may not impact a patient’s overall clinical disease control in a way that would justify a change of systemic therapy, with an uncertain efficacy of next-line treatment.
Those patients who continued afatinib or gefitinib treatment beyond initial radiological progression in target lesions demonstrated what might be viewed as a ‘slow progression’. In general, a gradual increase in the sum of diameters of target lesions over a median of 6–7 months between the time of the nadir and initial PD was observed. Around 70% of these patients demonstrated responses (CR/PR) or non-CR/non-PD in non-target lesions, which may suggest that progression in target lesions alone may not be the only factor requiring treatment discontinuation, because patients may still be able to derive clinical benefit from continued EGFR TKI treatment. Patients who continued their assigned treatment beyond progression in target lesions tended to demonstrate either a pronounced response in target lesions at the nadir, or a long time to progression and/or a less pronounced increase in the sum of target lesion diameters from the nadir to initial PD. Investigators deemed it possible for all patients who continued treatment beyond RECIST-defined progression in target lesions to derive further clinical benefit from continued treatment and may define these patients as ‘slow-progressors’, particularly those with a longer time to progression and/or less pronounced increase in target lesion size from the nadir to initial PD. The characteristics of patients who continued treatment beyond progression were similar in both the afatinib and gefitinib treatment arms, with regard to baseline characteristics and reason for PD (PD in target and/or non-target lesions, or occurrence of new lesions) (Park et al.
2016).
These findings from the LUX-Lung 7 study provide further support that tolerability-guided dose adjustment of afatinib reduces the incidence and severity of treatment-related AEs without affecting the efficacy or diminishing the effects of afatinib on PROs in patients with advanced EGFR mutation-positive NSCLC. Our further findings suggest that treatment beyond progression may allow patients who are deriving clinical benefit, for example, those with ‘slow progression’ or less clinically relevant new lesions in conjunction with a response in target lesions at the time of initial progression, to maximize time on EGFR TKI treatment. In conclusion, protocol-defined dose adjustment of afatinib may ultimately allow patients to remain on treatment longer, thus maximizing the clinical benefit, even in the presence of radiological disease progression.
Compliance with ethical standards
Conflict of interest
Dr. O’Byrne has received advisory board fees, speaker bureau fees and travel grants from BMS, MSD, Lilly Oncology, Boehringer Ingelheim, Pfizer, Novartis, Roche-Genentech, Teva and AstraZeneca. Dr. Boyer reports grants from Boehringer Ingelheim, during the conduct of the study, grants from Pfizer, grants and non-financial support from Roche and AstraZeneca, outside the submitted work. Dr. Hirsh is a member of the Boehringer Ingelheim advisory board. Dr. Kim D-W reports travel support for advisory meeting from Novartis, outside the submitted work. Dr Märten reports employment from Boehringer Ingelheim, outside the submitted work. Dr. Massey reports employment from Boehringer Ingelheim, outside the submitted work. Dr. Mok reports grants and personal fees from AstraZeneca, Roche/Genentech, BMS, Boehringer Ingelheim, Novartis, MSD, Pfizer, Clovis Oncology, SFJ Pharmaceuticals, Takeda and Taiho, personal fees from Eli Lilly, Merck Serono, Janssen, Vertex, Celgene, ACEA Biosciences, Oncogenex, Ignyta Inc, OrigiMed, Fishawack Facilitate Ltd, Hengrui Therapeutics, Sanofi-Aventis R&D and Yuhan Corporation, non-financial support from geneDecode, grants from Eisai, personal fees and other from Hutchison ChiMed, grants from XCovery and other from Sanomics, outside the submitted work. Dr. Park reports personal fees from Boehringer Ingelheim for an advisory and consultancy role. Dr. Paz-Ares reports personal fees from Novartis, MSD, BMS, Boehringer Ingelheim, AstraZeneca, Pfizer, Roche, Lilly, Amgen and Clovis, outside the submitted work. Dr. Schuler reports grants and personal fees from Boehringer Ingelheim, during the conduct of the study, grants and personal fees from AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb and Novartis and personal fees from Roche, Abbvie, Alexion, Celgene, Lilly, MSD and Pierre Fabre, outside the submitted work. Dr. Yang reports personal fees from Boehringer Ingelheim, Eli Lilly, Roche/Genentech, Chugai, Astellas, MSD, Merck Serono, Pfizer, Novartis, Celgene, Merrimack, Yuhan Pharmaceuticals, BMS, Ono Pharmaceuticals, Daiichi Sankyo, AstraZeneca, Hansoh Pharmaceuticals and Takeda Pharmaceuticals, outside the submitted work. Dr. Zhang reports grants from Pfizer, BMS and AstraZeneca, outside the submitted work. The remaining authors declare no conflict of interest.
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