By Julien Mazieres, MD, PhD
The standard of care for patients postresection for lung cancer is adjuvant chemotherapy, usually a platinum-based regimen.1 The deciphering of lung oncogenesis has led to the routine use of targeted therapy in metastatic lung cancer but, to date, the use of these agents in the adjuvant setting is controversial and not recommended. A recent phase III trial specifically addressed this issue. The phase III ADJUVANT trial was the first randomized trial to compare gefitinib (250 mg per day for 24 months) with standard vinorelbine plus cisplatin (4 cycles) in 222 patients with completely resected stage II-IIIA (N1-N2) nonsmall cell lung cancer (NSCLC) with confirmed EGFR-activating mutations. The primary endpoint was disease-free survival (DFS) in the intent-to-treat population. Briefly, the authors have reported a significantly longer DFS in the gefitinib arm, but no significant improvement in overall survival.2
An optimistic view is that a subset of patients with resected stage NSCLC can benefit from EGFR inhibitors with fewer side effects than chemotherapy. A more realistic analysis suggests that 24 months of oral treatment can postpone recurrence, but does not improve survival.
Thus, this trial will not change the practice patterns as we aim in this setting to cure patients and not just delay disease recurrence. This trial underscores the limits of targeted therapies in NSCLC and suggests that EGFR TKIs are not able to definitively eradicate EGFR-mutated tumors. Thus, oncogenic addiction is probably more a dogma than a biological reality, and acquisition of resistance is invariably associated with targeted therapies.
In metastatic EGFR-mutated NSCLC, targeted therapy is used as first-line treatment as it provides a clear advantage compared to standard chemotherapy. However, virtually all patients will eventually develop resistance within a median of 12 months. Recent in vitro findings suggest that resistance can occur through two nonexclusive mechanisms: (i) by selection of pre-existing mutated clones, and (ii) through an adaptive mechanism during the early stage of treatment. We will focus on this latter mechanism.
Across multiple cell lines, in response to a variety of strong drug challenges, small subpopulations of cells have been reported to survive by initially entering a drug-tolerant, so-called persister state (drug-tolerant persisters) in which there is little to no population growth.3 Crucially, after long-term treatment without appreciable cell growth, a fraction of persisters gain the ability to expand despite the presence of the inhibitor, and acquire genetic resistance to form drug-tolerant expanded persisters (DTEP). It has been hypothesized that survival and expansion through a drugtolerant state could be part of an initial strategy that mediates the acquisition of bona fide, genetically driven, resistance mechanisms.4 However, the diversity of resistance mechanisms compatible with evolution through a persister bottleneck is unclear.
The results of this phase III trial suggest that gefitinib is able to reduce micro-metastasis for a certain period of time, but is not able to eradicate these micro-metastases probably due to the induction of adaptive resistance in most of the patients. My perspective is that we need to overcome this resistance through novel therapeutic strategies. Immunotherapy, which is currently being tested in many perioperative trials, will probably help to improve the outcome of these patients. ✦
1. Arriagada R, Bergman B, Dunant A, et al. Cisplatin-based adjuvant chemotherapy in patients with completely resected non-small cell lung cancer. N Engl J Med. 2004;350:351-360.
2. Wu Y-L, Zhong W, Wang Q, et al. Gefitinib (G) versus vinorelbine+cisplatin (VP) as adjuvant treatment in stage II-IIIA (N1-N2) non-smallcell lung cancer (NSCLC) with EGFR-activating mutation (ADJUVANT): a randomized, phase III trial (CTONG 1104). J Clin Oncol. 2017 (suppl; abstr 8500). http://abstracts.asco.org/199/ AbstView_199_188666.html. Accessed June 26, 2017.
3. Ramirez M, Rajaram S, Steininger RJ, et al. Diverse drug-resistance mechanisms can emerge from drug-tolerant cancer persister cells. Nat Commun. 2016; 19;7:10690. doi: 10.1038/ncomms10690.
4. Sharma SV, Lee DY, Li B, et al. A chromatinmediated reversible drug-tolerant state in cancer cell subpopulations. Cell. 2010;141:69-80.