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Emerging Data Could Rearrange Frontline EGFR TKIs in NSCLC

Individualizing frontline therapy for patients with non–small cell lung cancer based on preferences and clinical experience, as well as efficacy and safety data from pivotal trials, is an appropriate method for selecting EGFR-targeted agents.

Howard L. “Jack” West, MD

Individualizing frontline therapy for patients with non—small cell lung cancer (NSCLC) based on preferences and clinical experience, as well as efficacy and safety data from pivotal trials, is an appropriate method for selecting EGFR-targeted agents, according to H. Jack West, MD, who lectured on choosing the best upfront treatment for patients with EGFR-mutant NSCLC during the 11th Annual New York Lung Cancer Symposium®.

With the current 3 EGFR tyrosine kinase inhibitors (TKIs) that are FDA approved—erlotinib (Tarceva), gefitinib (Iressa), and afatinib (Gilotrif)—West picked apart key clinical trial findings comparing the trio's efficacy to determine if one is superior to another.

Afatinib was explored in the LUX-Lung 3 and LUX-Lung 6 studies.1 In both studies, afatinib was compared with chemotherapy in patients with NSCLC and was associated with a median overall survival (OS) of 27.3 months with afatinib versus 24.3 for chemotherapy-treated patients. Specifically in patients with exon 19 deletion, there was a more significant difference; the median OS was 31.7 months with afatinib versus 20.7 months with chemotherapy (HR, 0.59; CI 95%, 0.45-0.77; P = .0001).

A head-to-head comparison of EGFR-targeted agents was observed in LUX-Lung 7 of daily gefitinib (n = 159) and afatinib (n = 160) in the first-line setting in patients with EGFR-positive disease who also harbored exon 19 or exon 21 deletions.2 Results showed that there was minimal difference in duration of response between patients with exon 19 deletions and L858R substitution. Patients treated with afatinib had an overall response rate (ORR) of 70% while afatinib’s was 50% (P = .0083). Duration of response was 10.1 and 8.4 months with afatinib and gefitinib, respectively.

In terms of safety, the most common grade 3/4 adverse events (AEs) with afatinib were diarrhea (11.9%) and rash/acne (9.4%). With gefitinib, alanine aminotransferase increase was the most common grade 3/4 AE (7.5%). Additionally, treatment-related interstitial lung disease occurred in 2.5% of patients treated with gefitinib versus 0% with afatinib.

The study also showed that serious treatment-related AEs were more frequent with afatinib (10.6%) versus gefitinib (4.4%). AEs that led to dose reductions occurred in 41.9% of patients treated with afatinib versus 1.9% with gefitinib; however, treatment discontinuation due to AEs was the same in each arm (6.3%).

Regarding adverse events, West stressed, this is an important part of distinguishing these targeted agents from one another.

“The overall summary is not that different in adverse events or discontinuation in the gefitinib and afatinib arms,” stated West, a thoracic oncologist of Swedish Cancer Institute at Swedish Medical Center. “Afatinib is a somewhat more challenging agent to deliver, but [...] when you look at the drug-related AEs, gefitinib was associated with a higher incidence of LFT abnormalities, including some grade 3 abnormalities.”

Overall, West said that as physicians balance efficacy and side effects of these EGFR TKIs to guide treatment decision-making, it is imperative to individualize patients.

Additionally, they should recognize that “efficacy might be marginally greater with afatinib and it may be a good choice for a robust and motivated patient,” West concluded. “However, the tolerability issues would favor erlotinib over gefitinib intentionally. In the United States, we generally see that erlotinib is the most commonly prescribed [treatment], while afatinib also represents a significant fraction. Gefitinib is a very fine choice for patients who are concerned specifically about toxicity issues, or their ability to tolerate a treatment.”

Promise With Combinations

An in-development 2-drug regimen including erlotinib plus bevacizumab (Avastin) is already garnering excitement in the field, and is an option West said he prefers in most cases.

While not yet available for use in the United States, the European Medicines Agency approved the combination as a frontline treatment for patients with unresectable advanced, metastatic, or recurrent EGFR-mutant NSCLC in June 2016.

The European approval was based on findings from the phase II JO25567 study, which demonstrated a 46% reduction in the risk of progression or death with erlotinib/bevacizumab versus single-agent erlotinib.3 The median PFS with bevacizumab added was 16 months compared with 9.7 months with erlotinib alone (HR, 0.54; 95% CI, 0.36-0.79; P = .0015).

Exon 19 deletions and 21 mutations played a factor in outcomes, as well. The median PFS was 18.0 months with the combination versus 10.3 months with erlotinib alone (HR, 0.41; 95% CI, 0.24-0.72; P = .0011) in the exon 19 deletion subgroup. In the exon 21 mutation group, the median PFS was 13.9 versus 7.1 months for the combination and single-agent, respectively (HR, 0.67; 95% CI, 0.38-1.18; P = .1653).

“[The combination] demonstrated a significantly better disease-control rate, and a trend toward a better response rate overall,” said West. “We have not seen the follow-up yet […] but the benefit for the combination is impressive for both of these populations.”

However, toxicities poised a challenge with this regimen, too. Grade 3/4 adverse events (AEs) occurred in 91% of patients treated with the combination compared with 53% with the single-agent. The most commonly observed grade 3/4 AEs were rash (25% vs 19%), hypertension (60% vs 10%), and proteinuria (8% vs 0%) for erlotinib/bevacizumab and erlotinib, respectively. Sixteen percent of patients in the combination arm discontinued treatment due to AEs versus 18% in the erlotinib-alone arm.

Regardless, West said the question is: “Is this something that is a standard of care? At this point, many of are in favor of adopting.”

Exploring Indications for EGFR-Resistance Therapy

Osimertinib (Tagrisso) is a third-generation EGFR TKI designed to target patients with T790M NSCLC, the most common resistance mutation for patients with EGFR-mutant disease who progress on an EGFR TKI. Currently, ongoing phase III trials are exploring the agent in frontline following tumor resection with or without adjuvant chemotherapy (NCT02511106), as well as in comparison with gefitinib or erlotinib in the frontline setting for patients with EGFR-mutant NSCLC (NCT02296125).

The advantage is that patients would get rigor activity for a long period of time of 18 to 20 months or potentially longer, and this is also a very well-tolerated therapy,” West reflected. “It gives us access to all of the patients—not just those who are T790M-positive. The disadvantage is that it may not be better than giving 1 year of first-line therapy with 9 or 12 months benefit from osimertinib to half or two-thirds of that from the other agents.”

To Use or Not to Use Immunotherapy in EGFR-Mutant NSCLC

However, West cautions that attempting to treat EGFR-mutant patients with immunotherapy is not a recommended method. In the CheckMate-057 trial, which compared the efficacy of nivolumab (Opdivo) versus docetaxel in pretreated patients with nonsquamous NSCLC, the 2-year OS rate was 29% with nivolumab versus 16% with docetaxel. However, this was not the same across all subgroups.

“The only subset that did not do well were the patients who were EGFR-positive,” West said. “The point is that [these] patients don’t seem to be big beneficiaries, at least with that drug in that setting.”

“We don’t have a lot of data yet except for the discontinuation of a trial of durvalumab and osimertinib combined, where we saw higher levels of pulmonary toxicities than were expected,” he explained. “That should give us pause about being cavalier about doing ad-hoc combinations.”

In conclusion, West said that there are similar levels of efficacy among the first-, second, and third-generation EGFR TKIs, aside from the superiority seen with afatinib in LUX Lung 7. “For afatinib, you need to ask a question of whether it is a clinically significant difference, particularly when you’re laying that against the toxicity differences.”

His strongest argument, however, is a call for individualized recommendations based on the patient preferences, tolerance, and toxicities, as well as clinical experience.

“I would consider erlotinib/bevacizumab a combination worth considering and, when offering my own perspective, it’s actually an approach that I use in most of my patients with active EGFR mutations,” concluded West. “It’s not a clear standard of care, but it is the approach I use a lot. For the patients where bevacizumab is not an appropriate choice, I use afatinib for the most robust, and erlotinib alone for the rest.”

References

  1. Sequist L, Wu Y, Schuler M, et al. Overall survival (OS) with afatinib versus chemotherapy in patients (Pts) with advanced non-small cell lung cancer (NSCLC) harboring common (Del19/L858R) epidermal growth factor receptor mutations (EGFR mut): results of LUX-Lung 3 (LL3) and LUX-Lung 6 (LL6). Presented at: 2014 Multidisciplinary Symposium in Thoracic Oncology; October 30-November 1, 2014; Chicago, IL. Abstract 9.
  2. Park K, Tan EH, O'Byrne K, et al. Afatinib versus gefitinib as first-line treatment of patients with EGFR mutation-positive non-small-cell lung cancer (LUX-Lung 7): a phase 2B, open-label, randomised controlled trial. Lancet Oncol. 2016;17(5):577-589.
  3. Seto T, Kato T, Nishio M, et al. Erlotinib alone or with bevacizumab as first-line therapy in patients with advanced non-squamous non-small-cell lung cancer harbouring EGFR mutations (JO25567): an open-label, randomised, multicentre, phase 2 study. Lancet Oncol. 2014;15(11):1236—1244.

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View more from the 2016 New York Lung Cancer Symposium

West also cautioned use of combination treatments of immunotherapies and EGFR TKIs as there is a lack of clinical data supporting efficacy and safety of them. He says to “never not do it,” but to use it as a later-line therapy rather than an available EGFR inhibitor.