Being molecular in the molecular age
Authors: R. Raghupathy, T. Mok
Journal: Annals of Oncology (2016)

We congratulate the authors for completion of this large study, LUX Lung 5, to address an important question of the role of afatinib in combination with chemotherapy after progression of lung cancer on afatinib alone. In this phase III randomized study of patients with advanced nonsmall-cell lung cancer (NSCLC) treated with one or more lines of chemotherapy followed by an epidermal growth factor receptor tyrosine kinase inhibitor (EGFR TKI) and afatinib, the authors show that continuing afatinib beyond progression in combination with paclitaxel resulted in a 2.5-fold increase in overall response rate and a doubling of progression-free survival (PFS) compared with investigator choice chemotherapy [1.Schuler M. Yang J.C. Park K. et al.Afatinib beyond progression in patients with non-small-cell lung cancer following chemotherapy, erlotinib/gefitinib and afatinib: phase III randomized LUX-Lung 5 trial.Ann Oncol. 2016; 27: 417-423Abstract Full Text Full Text PDF PubMed Scopus (114) Google Scholar]. No significant improvement in overall survival was seen. This is a positive study that has met its primary end point of improvement in PFS. The challenge is to translate this finding into clinical practice. For this, we should ask two basic questions, ‘Who may benefit?’ and ‘Why should there be a benefit?’ Afatinib is an irreversible ErbB blocker. Preclinical data show that it is a more potent blocker of EGFR and human epidermal growth factor receptor (HER) signaling compared with the first-generation EGFR TKIs and has efficacy in lung cancer cells with resistance to EGFR TKIs due to development of the T790M exon 20 mutation or upregulation of the HER signaling pathway [2.Li D. Ambrogio L. Shimamura T. et al.BIBW2992, an irreversible EGFR/HER2 inhibitor highly effective in preclinical lung cancer models.Oncogene. 2008; 27: 4702-4711Crossref PubMed Scopus (1165) Google Scholar]. In the LUX Lung 3 and LUX Lung 6 trials, afatinib has demonstrated clinical efficacy as first-line treatment in patients with advanced NSCLC molecularly selected for activating EGFR mutation [3.Sequist L.V. Yang J.C. Yamamoto N. et al.Phase III study of afatinib or cisplatin plus pemetrexed in patients with metastatic lung adenocarcinoma with EGFR mutations.J Clin Oncol. 2013; 31: 3327-3334Crossref PubMed Scopus (2563) Google Scholar, 4.Wu Y.L. Zhou C. Hu C.P. et al.Afatinib versus cisplatin plus gemcitabine for first-line treatment of Asian patients with advanced non-small-cell lung cancer harbouring EGFR mutations (LUX-Lung 6): an open-label, randomised phase 3 trial.Lancet Oncol. 2014; 15: 213-222Abstract Full Text Full Text PDF PubMed Scopus (1583) Google Scholar]. However, its efficacy in clinically selected patients who have progressed on EGFR TKIs has been modest. In the LUX Lung 1, phase IIb/III study of advanced NSCLC patients progressing after chemotherapy and ‘clinically enriched’ for EGFR TKI response, the response rate to afatinib monotherapy was only 7%–11%. About 50% of patients had stable disease for 8 weeks [5.Miller V.A. Hirsh V. Cadranel J. et al.Afatinib versus placebo for patients with advanced, metastatic non-small-cell lung cancer after failure of erlotinib, gefitinib, or both, and one or two lines of chemotherapy (LUX-Lung 1): a phase 2b/3 randomised trial.Lancet Oncol. 2012; 13: 528-538Abstract Full Text Full Text PDF PubMed Scopus (845) Google Scholar]. Similar response rates were also seen in the phase II Lux Lung 4 trial where patients received afatinib after initial clinical benefit from EGFR TKI, although no prior chemotherapy was given [6.Katakami N. Atagi S. Goto K. et al.LUX-Lung 4: a phase II trial of afatinib in patients with advanced non-small-cell lung cancer who progressed during prior treatment with erlotinib, gefitinib, or both.J Clin Oncol. 2013; 31: 3335-3341Crossref PubMed Scopus (306) Google Scholar]. In both of these studies, as in current study (LUX Lung 5), progression after disease control for ≥12 weeks with gefitinib/erlotinib was used as a surrogate for acquired resistance to EGFR TKIs. We must understand that this ‘clinically enriched’ population is a heterogeneous group that comprises wild-type and mutated EGFR (with or without concurrent exon 20 T790M) [7.Jackman D.M. Miller V.A. Cioffredi L.A. et al.Impact of epidermal growth factor receptor and KRAS mutations on clinical outcomes in previously untreated non-small cell lung cancer patients: results of an online tumor registry of clinical trials.Clin Cancer Res. 2009; 15: 5267-5273Crossref PubMed Scopus (354) Google Scholar]. According to the TAILOR study that compared docetaxel with erlotinib in patients with wild-type EGFR, ∼30% of patients were progression-free after 12 weeks on erlotinib and these patients would have been eligible for LUX Lung 5 [8.Garassino M.C. Martelli O. Broggini M. et al.Erlotinib versus docetaxel as second-line treatment of patients with advanced non-small-cell lung cancer and wild-type EGFR tumours (TAILOR): a randomised controlled trial.Lancet Oncol. 2013; 14: 981-988Abstract Full Text Full Text PDF PubMed Scopus (432) Google Scholar]. It may not be appropriate to use the word ‘acquired resistance’ for this population as it is unlikely that these patients were having a true response to EGFR TKI [9.Jackman D. Pao W. Riely G.J. et al.Clinical definition of acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors in non-small-cell lung cancer.J Clin Oncol. 2010; 28: 357-360Crossref PubMed Scopus (682) Google Scholar]. In LUX Lung 5, the patients who met the modified ‘higher clinical enrichment criteria’ of complete remission/partial remission to EGFR TKI or ≥48 weeks of disease control were more likely, but not exclusively, to be representative of an EGFR mutant population [7.Jackman D.M. Miller V.A. Cioffredi L.A. et al.Impact of epidermal growth factor receptor and KRAS mutations on clinical outcomes in previously untreated non-small cell lung cancer patients: results of an online tumor registry of clinical trials.Clin Cancer Res. 2009; 15: 5267-5273Crossref PubMed Scopus (354) Google Scholar, 10.Mok T.S. Wu Y.L. Thongprasert S. et al.Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma.N Engl J Med. 2009; 361: 947-957Crossref PubMed Scopus (7058) Google Scholar]. The benefit of paclitaxel plus afatinib beyond progression was statistically significant for the subgroup with positive ‘higher clinical enrichment criteria’ [hazard ratio (HR): 0.56 (0.36–0.87)] while the benefit was more marginal [HR: 0.65 (0.39–1.08)] for the negative subgroup. Thus, we should explore the potential reasons for the benefit of the combination independently in both EGFR mutation-positive and -negative population. Patients with an EGFR mutation can be genuinely considered as ‘oncogene addicted’. The concept of treatment beyond RECIST progression in EGFR mutant patients with advanced NSCLC was explored in the ASPIRATION study and in the IMPRESS study [11.K Park, CJ Yu, SW Kim et al. First-line erlotinib therapy until and beyond response evaluation criteria in solid tumors progression in Asian patients with epidermal growth factor receptor mutation-positive non-small-cell lung cancer: the ASPIRATION Study. JAMA Oncol2015 Dec 30 [epub ahead of print], doi:10.1001/jamaoncol.2015.4921.Google Scholar, 12.Soria J.C. Wu Y.L. 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: 990-998Abstract Full Text Full Text PDF PubMed Scopus (323) Google Scholar]. In the ASPIRATION study, erlotinib was continued as a single agent beyond RECIST progression and showed an improvement in PFS by 3.1 months. Exploratory analyses suggested that the benefit of continuation was best seen in those with good initial response to erlotinib. The IMPRESS study showed no significant benefit of gefitinib beyond progression in combination with platinum-based chemotherapy compared with chemotherapy alone. However, subgroup analysis suggested that the combination may benefit T790M mutation-negative patients with improvement in PFS from 5.4 to 6.7 months (HR 0.67, 95% confidence interval 0.43–1.03, P = 0.0745) [13.Soria J.C. Kim S.W. Wu Y.L. et al.Gefitinib/chemotherapy vs chemotherapy.in: EGFR mutation-positive NSCLC resistant to first-line gefitinib: IMPRESS T790M subgroup analysis World Conference on Lung Cancer, 2015Google Scholar]. With the recent approval of osimertinib (third-generation EGFR TKI) for patients with T790M, there will be no role for combination of paclitaxel plus afatinib in this population. The combination, plausibly, may be worthy of consideration in the T790M-negative patients. Afatinib resistance in the T790M-negative population may be related to upregulation of the extracellular-regulated kinase and v-Akt murine thymoma viral oncogene/mammalian target of rapamycin (mTOR) signaling pathways, bypassing EGFR [14.Kim Y. Ko J. Cui Z. et al.The EGFR T790M mutation in acquired resistance to an irreversible second-generation EGFR inhibitor.Mol Cancer Ther. 2012; 11: 784-791Crossref PubMed Scopus (153) Google Scholar]. Paclitaxel, in preclinical studies, has been shown to inhibit the mTOR signaling pathway and also phosphorylate the downstream target of mTOR, p70 S6 kinase [15.Rocha G.Z. Dias M.M. Ropelle E.R. et al.Metformin amplifies chemotherapy-induced AMPK activation and antitumoral growth.Clin Cancer Res. 2011; 17: 3993-4005Crossref PubMed Scopus (248) Google Scholar, 16.Le X.F. Hittelman W.N. Liu J. et al.Paclitaxel induces inactivation of p70 S6 kinase and phosphorylation of Thr421 and Ser424 via multiple signaling pathways in mitosis.Oncogene. 2003; 22: 484-497Crossref PubMed Scopus (47) Google Scholar]. Afatinib in combination with paclitaxel has demonstrated preclinical synergy in solid tumor cell lines and xenografts and has been studied in the phase I setting. In the phase I study including different solid tumor patients, nine patients with NSCLC were treated, three obtained clinical benefit and one of these patients had a wild-type EGFR [16.Le X.F. Hittelman W.N. Liu J. et al.Paclitaxel induces inactivation of p70 S6 kinase and phosphorylation of Thr421 and Ser424 via multiple signaling pathways in mitosis.Oncogene. 2003; 22: 484-497Crossref PubMed Scopus (47) Google Scholar, 17.Suder A. Ang J.E. Kyle F. et al.A phase I study of daily afatinib, an irreversible ErbB family blocker, in combination with weekly paclitaxel in patients with advanced solid tumours.Eur J Cancer. 2015; 51: 2275-2284Abstract Full Text Full Text PDF PubMed Scopus (23) Google Scholar]. It is possible that afatinib and paclitaxel may have synergistic effect in the T790M-negative population. Potentially, authors may study the T790M status of patients from LUX Lung 5 if plasma cfDNA is available. Benefit of the combination in patients with predominantly wild-type EGFR remains a challenge to explain. PFS benefit of the afatinib paclitaxel combination was more striking in squamous cell histology [n = 17; HR: 0.15 (0.03–0.62)] compared with adenocarcinoma [n = 174; HR: 0.69 (0.49–0.99)]; in Caucasians [n = 77, HR:0.47 (0.27–0.82)] compared with East Asians [n = 82, HR: 0.67 (0.39–1.15)] and in those that had received previous taxane [n = 105; HR: 0.51 (0.32–0.80)] compared with those that had not [n = 97, HR:0.75 (0.45–1.24])]. However, the true benefit of the combination should be compared against only paclitaxel in the control arm. According to the supplementary Table S4, available at Annals of Oncology online, the median PFS of different agents in the control arm was 3.8 months for paclitaxel, 2.9 months for pemetrexed and 2.1 months for others. The difference between the combination and the paclitaxel alone subgroup was not statistically significant. It remains unclear if there is a true benefit of the combination over single-agent paclitaxel alone for patients with predominantly wild-type EGFR. The past decade of investigation has confirmed lung cancer to be a heterogeneous, molecularly diverse disease. We have learnt from LUX Lung 5 but we would have learnt a lot more if patients were selected according to molecular profile. TM is a speaker with AstraZeneca, Roche/Genentech, Pfizer, Eli Lilly, BI, MSD, Amgen, Janssen, Clovis Oncology, GSK, Novartis, BMS, and prIME Oncology. He has received honoraria from AstraZeneca, Roche/Genentech, Pfizer, Eli Lilly, BI, Merck Serono, MSD, Janssen, Clovis Oncology, BioMarin, GSK, Novartis, SFJ Pharmaceutical, ACEA Biosciences, Inc., Vertex Pharmaceuticals, BMS, AVEO & Biodesix, prIME Oncology, and Amgen. He is a major shareholder in Sanomics LTD. He is on the advisory board of AstraZeneca, Roche/Genentech, Pfizer, Eli Lilly, BI, Merck Serono, MSD, Janssen, Clovis Oncology, BioMarin, GSK, Novartis, SFJ Pharmaceutical, ACEA Biosciences, Inc., Vertex Pharmaceuticals, Aveo & Biodesix and BMS. The remaining author has declared no conflicts of interest.