Second-line chemotherapy superior to erlotinib for EGFR wild-type NSCLC

  • August 21, 2013

Chemotherapy remains the standard of care for patients with advanced non–small cell lung cancer who have wild-type EGFR tumors, according to study findings.

“Our results unequivocally show that, although neither docetaxel nor erlotinib are magic bullets for second-line treatment of NSCLC, a cytotoxic approach to treatment of patients with NSCLC is still the best option in the absence of a clear therapeutic target,” the researchers wrote.

Although erlotinib (Tarceva; Genentech, Astellas) has been the recommended therapy for patients with NSCLC, the efficacy for treating patients with EGFR wild-type tumors is undetermined, according to background information in the study.

For this reason, researchers set out to compare the efficacy of erlotinib vs. standard second-line chemotherapy with docetaxel in 222 patients with metastatic NSCLC who had wild-type EGFR tumors and underwent prior treatment with a platinum-based chemotherapy.

Researchers randomly assigned 112 patients to 150 mg oral erlotinib daily. The other 110 patients received 75 mg/m² docetaxel IV once every 21 days or 35 mg/m² on days 1, 8 and 15 for every 28 days. OS in the intention-to-treat population served as the primary outcome measure.

Median OS was 8.2 months (95% CI, 5.8–10.9) among patients assigned docetaxel compared with 5.4 months (95% CI, 4.5–6.8) among those assigned erlotinib (adjusted HR=0.73; 95% CI, 0.53–1.0).

PFS was 2.9 months (95% CI, 2.4–3.8) with docetaxel vs. 2.4 months (95% CI, 2.1–2.6) with erlotinib (adjusted HR=0.71; 95% CI, 0.53–0.95).

The most common grade 3 and 4 adverse event was low absolute neutrophil count, which occurred in 20% of patients assigned docetaxel and no patients assigned erlotinib).

In an accompanying editorial, Jacek Jassem, MD, PhD, and Rafał Dziadziuszko, MD, PhD, both of the department of oncology and radiotherapy at the Medical University of Gdańsk in Poland, wrote: “Do the results mean that chemotherapy remains the only option for patients with wild-type EGFR disease? Not necessarily. Within the past decade, several molecular changes have been identified that drive NSCLC growth and survival, many of which are promising therapeutic targets.”

Additional molecular subtyping of wild-type EGFR tumors may help identify which patients are suitable for alternative therapies, Jassem and Dziadziuszko added.

“The clinical application of biomarker-driven therapeutic strategies will also be helped by the introduction of high-throughput multiplex genotyping, which will enable simultaneous sequencing and measuring copy numbers of hundreds of genes from only nanograms of cancer cell DNA,” they wrote.

For more information:

  • Garassino MC. Lancet Oncol. 2013;doi:10.1016/S1470-2045(13)70310-3.
  • Jassem J. Lancet Oncol. 2013;doi:10.1016/S1470-2045(13)70352-8.

Disclosure: The researchers report consulting roles with Amgen, Boehringer Ingelheim, Eli Lilly and Roche.

Perspective

Greg Otterson

  • The TAILOR trial, a comparison of erlotinib vs. docetaxel as second-line treatment of patients with advanced non–small cell lung cancer (NSCLC) with wild-type EGFR is an important study. Since 2000, there have been many published studies of second-line treatment in unselected patients (with respect to EGFR mutations) with NSCLC demonstrating benefit, leading to approval of three agents — docetaxel, pemetrexed (Alimta, Lilly) and erlotinib. As the authors point out, the initial treatment of patients with EGFR-sensitizing mutations is either erlotinib or gefitinib (Iressa, AstraZeneca), and soon perhaps afatinib (Gilotrif, Boehringer Ingelheim).

    What has not been evaluated prior to this study is the best subsequent treatment of patients with wild-type EGFR. This study demonstrates superiority of docetaxel over erlotinib in this patient population in terms of OS (8.2 months vs. 5.4 months) and PFS (2.9 months vs. 2.4 months). As expected, docetaxel had increased hematologic toxicity and asthenia, whereas erlotinib had increased dermatologic toxicity. One could argue that docetaxel performed better than expected (in the initial unselected trials by Fosella and Shepherd, median survival was between 5.5 and 7.5 months), especially considering that one would probably expect EGFR-mutant patients in the two previous studies to do better with chemotherapy than the wild-type patients. Similarly, one could suggest that erlotinib underperformed (in the BR21 study, the median OS for erlotinib was 7.9 months) though conversely, any EGFR-mutant patients in the BR21 study would have improved the results in this study compared with TAILOR.

    Additional critiques of TAILOR are that it allowed both adenocarcinomas and squamous carcinomas, and that KRAS-mutant cancers were not analyzed separately, though there seemed to be no effect from KRAS-mutant patients. Regardless, the TAILOR study should signal that the era of design and analysis of lung cancer trials without regard to molecular markers is over and that future studies in the first and second line need to include data regarding, at a minimum, EGFR, KRAS, and likely other prognostic and predictive biomarkers.
    • Greg Otterson, MD
    • Co-director of thoracic oncology
      Division of medical oncology
      The Ohio State University Comprehensive Cancer Center —
      Arthur G. James Cancer Hospital and Richard J. Solove Research Institute
      Columbus, Ohio
  • Disclosures: Otterson reports no relevant financial disclosures.
Perspective
Nathan Pennell, MD, PhD

Nathan Pennell

  • In recent years, with the broad use of pemetrexed (Alimta, Eli Lilly) as first-line therapy for patients with metastatic non-small cell lung cancer, there have been essentially two valid choices for second-line treatment of patients with NSCLC.

    Docetaxel was approved for NSCLC patients who failed first-line chemotherapy when it showed an improved OS of 2.4 months compared with placebo, with an objective response rate (ORR) of 7.1% (Shepard FA. J Clin Oncol. 2000;18:2095-2103). The other drug of choice is erlotinib, an oral tyrosine kinase inhibitor (TKI) against the epidermal growth factor receptor (EGFR). Erlotinib was approved for NSCLC patients who failed one or two prior therapies based on the BR.21 trial, which showed an improvement in OS over placebo of 2 months and a response rate of 8.9% (Shepard FA. N Engl J Med. 2005;353:123-32). There was a general consensus that they were comparably effective, and the choice of agent was usually based on the side effect profile.

    This judgment was only bolstered by the results of the INTEREST trial, which compared another EGFR TKI — gefitinib (Iressa, AstraZeneca) — with docetaxel in unselected patients with NSCLC. This enormous trial showed that the TKI was noninferior to docetaxel, with virtually identical clinical outcomes (Kim ES. Lancet. 2008;372:1809-1818).

    Into this setting comes the TAILOR trial, which also compared erlotinib with docetaxel in second-line NSCLC but differs in one key way. Patients were all tested for EGFR mutations and were confirmed to be wild-type prior to enrollment, potentially eliminating the bias of greater-than-average benefit in the small population of mutation-positive patients in an unselected trial. TAILOR indeed showed a significantly longer PFS with docetaxel compared with erlotinib in this population, although there was no significant difference in OS in the intent to treat population. The authors determined there were imbalances in the randomization and did an “adjusted” OS analysis to try to account for these, which suggested there may be an OS benefit to docetaxel.

    There are a couple of things to take away from this trial. First, the PFS with both agents was less than 3 months, so neither is particularly effective and we need better treatments for these patients. Docetaxel may be slightly more effective than erlotinib in EGFR wild-type patients, but it is questionable how clinically meaningful this is. One extra element to consider is the recent PROSE study (Lazzari C. Abstract #8005. Presented at: ASCO Annual Meeting; May 31-June 4, 2013; Chicago), which also compared chemotherapy with erlotinib but stratified all patients by their proteomic profile to define those who were unlikely to benefit from erlotinib. Patients who had a “poor” profile did significantly better with chemotherapy, whereas those with a “good” profile (about 70%) did exactly the same with either choice. Perhaps the inclusion of a large percentage of “poor”-risk patients can explain the small difference in outcomes in the TAILOR trial. For now, I think in unselected patients, both erlotinib and docetaxel are still reasonable choices for second-line treatment of NSCLC until we have something better to offer.

    • Nathan Pennell, MD, PhD
    • Staff physician
      Department of solid tumor oncology
      Cleveland Clinic Taussig Cancer Institute
  • Disclosures: Pennell reports a consulting relationship with Genentech, which makes erlotinib.