Discontinuing epidermal growth factor receptor-tyrosine kinase inhibitor during second-line chemotherapy: is the evidence strong enough?
Commentary

Discontinuing epidermal growth factor receptor-tyrosine kinase inhibitor during second-line chemotherapy: is the evidence strong enough?

Wenhua Liang1,2, Qihua He1,2, Ying Chen1,2, Xusen Zou1,2, Lindsey Hamblin1,2, Jianxing He1,2

1Department of Thoracic Surgery and Oncology, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou 510120, China; 2Guangzhou Institute of Respiratory Disease & China State Key Laboratory of Respiratory Disease & National Clinical Research Center for Respiratory Disease, Guangzhou 510120, China

Correspondence to: Jianxing He, MD, PhD, FACS. Department of Thoracic Surgery, the First Affiliated Hospital of Guangzhou Medical University; Guangzhou Institute of Respiratory Disease & China State Key Laboratory of Respiratory Disease. No. 151, Yanjiang Rd, Guangzhou 510120, China. Email: drjianxing.he@gmail.com.

Submitted Aug 18, 2015. Accepted for publication Aug 19, 2015.

doi: 10.3978/j.issn.2305-5839.2015.08.16

Dr. Soria et al. reported an important randomized controlled trial showing that continuation of gefitinib after radiological disease progression on first-line gefitinib did not prolong progression-free survival (PFS) in patients who received pemetrexed plus cisplatin chemotherapy as subsequent line of treatment (1). This study clarified some previous controversies on the management strategy of patients who progressed after epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) treatment. However, some concerns remain.

Firstly, the regimen of the treatment arm is the combination of pemetrexed, cisplatin and gefitinib. Four previous randomized trials and in vitro experiments suggested that EGFR-TKI is antagonistic to cytotoxic agents especially cisplatin (2). However, intercalated regimen of erlotinib plus platinum-based chemotherapy in the FASTACT2 study was superior to chemotherapy alone (3). In addition, a current study showed that gefitinib in combination with single agent pemetrexed contributed a relatively longer PFS of 18 months compared to historical controls (4). The conclusion derived from IMPRESS study might be different if either a regimen of gefitinib in combination with pemetrexed alone, or the intercalated administration strategy was employed.

Secondly, although there was no statistically significant difference in PFS between the two arms, the trends did potentially favor continuing gefitinib as the survival curve of the treatment arm was consistently superior to that of the control arm. We would argue that the estimation of the benefit of continuing gefitinib was over-optimistic given that no enrichment of a specific population (e.g., patients experiencing slow progression or oligo-site progression as the authors mentioned in the discussion) was proposed. Over-estimation of the benefit could reduce the sample size, declining the power to detect the difference. In the IMPRESS study, an over-estimated PFS of 9.5 months in the experimental arm is equivalent to the actual median overall survival of concurrent chemotherapy and EGFR-TKI in the first line setting (range, 8.7-10.6 months) (5). Notably, the four previous trials (5) enrolled patients with unknown EGFR mutation status; this is actually similar in the IMPRESS study as they tested the EGFR mutation at the first line but not at the second line when the mutation status might be altered.

Thirdly, in the subgroup analyses we observed that patients with stable disease in the first line gefitinib treatment benefited much more from continuing gefitinib in the second line chemothera.py (HR: 0.59; 95% CI, 0.35-1.02) than those who experienced initial tumor remission in receiving front-line gefitinib (HR: 0.97; 95% CI, 0.70-1.34). The benefit of continuation of gefitinib is considerable in that the upper limit of the 95% CI is close to the significance margin; thus, interaction tests of the subgroups might help to determine whether or not there is a beneficial subpopulation. If indeed there is a difference between the benefits of these two subpopulations, a correlated subgroup analysis stratified by progression mode of previous EGFR-TKI treatment is warranted.

There are still many unanswered questions on this complex issue. It would be highly appreciated if the authors could address these events.

Acknowledgements

None.

Footnote

Conflicts of Interest: The authors have no conflicts of interest to declare.

References

  1. Soria JC, Wu YL, Nakagawa K, et al. Gefitinib plus chemotherapy versus placebo plus chemotherapy in EGFR-mutation-positive non-small-cell lung cancer after progression on first-line gefitinib (IMPRESS): a phase 3 randomised trial. Lancet Oncol 2015;16:990-8. [PubMed]
  2. Tsai CM, Chen JT, Stewart DJ, et al. Antagonism between gefitinib and cisplatin in non-small cell lung cancer cells: why randomized trials failed? J Thorac Oncol 2011;6:559-68. [PubMed]
  3. Wu YL, Lee JS, Thongprasert S, et al. Intercalated combination of chemotherapy and erlotinib for patients with advanced stage non-small-cell lung cancer (FASTACT-2): a randomised, double-blind trial. Lancet Oncol 2013;14:777-86. [PubMed]
  4. Yoshimura N, Kudoh S, Mitsuoka S, et al. Phase II study of a combination regimen of gefitinib and pemetrexed as first-line treatment in patients with advanced non-small cell lung cancer harboring a sensitive EGFR mutation. Lung Cancer 2015. [Epub ahead of print]. [PubMed]
  5. Pennell NA. Integration of EGFR inhibitors and conventional chemotherapy in the treatment of non-small-cell lung cancer. Clin Lung Cancer 2011;12:350-9. [PubMed]
Cite this article as: Liang W, He Q, Chen Y, Zou X, Hamblin L, He J. Discontinuing epidermal growth factor receptor-tyrosine kinase inhibitor during second-line chemotherapy: is the evidence strong enough? Ann Transl Med 2015;3(14):202. doi: 10.3978/j.issn.2305-5839.2015.08.16

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