Journal of Thoracic Oncology:
A Nice Problem to Have: When ALK Inhibitor Therapy Works Better Than Expected
Doebele, Robert C. MD, PhD
Division of Medical Oncology, Department of Medicine, University of Colorado School of Medicine and the University of Colorado Cancer Center, Aurora, Colorado.
Disclosure: Dr. Doebele received research grants from Pfizer and Eli Lilly, Advisory board for Pfizer.
Address for correspondence: Robert C. Doebele, MD, PhD, Division of Medical Oncology, Department of Medicine, University of Colorado School of Medicine and the University of Colorado Cancer Center, MS 8117, 12801 E. 17th Avenue, Aurora, CO 80045. E-mail: firstname.lastname@example.org
The use of crizotinib in non–small-cell lung cancer (NSCLC) patients harboring anaplastic lymphoma kinase (ALK) gene fusions is associated with significant clinical benefit and is superior to standard second-line chemotherapy.1 Despite the high response rate and durable progression-free survival, crizotinib benefit is limited by eventual tumor progression. Analysis of tumor specimens obtained from ALK+ NSCLC patients following disease progression on crizotinib has revealed multiple mechanisms of cellular resistance.2–6 These include multiple secondary ALK kinase domain mutations that confer resistance to crizotinib. Copy number gain (CNG) of the ALK fusion gene compared with pretreatment levels has also been observed in both preclinical studies and clinical tumor specimens.2,3,5,7 Collectively, these two forms of resistance—ALK kinase mutations and ALK fusion CNG—have been termed ALK-dominant mechanisms of resistance because tumors harboring these mechanisms presumably preserve ALK signaling despite the presence of crizotinib and are still dependent on that pathway for survival. Consequently, use of a more potent second-generation ALK inhibitor may be sufficient to reestablish control of the cancer. In contrast, bypass signaling, by v-Kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog (KIT) or epidermal growth factor receptor (EGFR), has also been described as a mechanism of resistance to crizotinib in ALK+ NSCLC.2,3 In these ALK nondominant tumors, a second-generation ALK inhibitor is predicted to be ineffective given the additional requirement of inhibiting the bypass signaling mechanisms.
Multiple different ALK kinase domain mutations have been observed in post-crizotinib tumor samples, including F1174V and G1202R, the two mutations noted in a post-ALK inhibitor tumor specimens by Ou et al in this issue.8 In total, ALK kinase domain mutations are estimated to comprise approximately 27% (19 of 70 patients) based on results from four studies.4–6,9 ALK fusion CNG has been observed in approximately 14% (7 of 51) of postcrizotinib specimens, although this mechanism has been observed in tumor samples with simultaneous ALK kinase domain mutations in some cases.2,7 Thus, at most, only approximately 40% of patients seem to have an ALK-dominant mechanism of resistance that might predict for benefit from a second-generation ALK inhibitor. Specific ALK mutations, such as G1202R and D1203N, may not respond to these new ALK inhibitors,9,10 as seen in the case described by Ou et al.8 Given that only a proportion of tumor shrinkage cases result in objective response criteria per Response Evaluation Criteria in Solid Tumors, one might therefore predict objective response rates to second-generation ALK inhibitors of 20% to 30%. Nevertheless, data from several second-generation ALK inhibitors demonstrate response rates of 55% to 60% in crizotinib-resistant, ALK+ NSCLC patients with observed or predicted disease control rates of approximately 90%.11–13 This raises the question of why, when we have good rebiopsy-based translational data supported by similar observed mechanisms in preclinical models, there is an apparent disconnect with the clinical data, that is, why do these inhibitors work so well in what is predicted to be a challenging acquired resistance setting?
Several potential explanations may underlie this fortuitous discrepancy (Fig. 1). The small numbers of tumor samples available for analysis in rebiopsy series means that the confidence intervals around the observed frequencies of the different resistance mechanisms will be correspondingly wide. Consequently, the true frequency of kinase domain mutations or CNG may be higher (or lower) than our initial estimates. It is hoped that larger proposed series of crizotinib-resistant, ALK+ tumor samples will address this in the near future. In addition, some of these mechanisms may exist in tumor samples but are missed by current analytic techniques. For example, direct sequencing suffers a high false-negative rate due to allelic dilution.14 Nevertheless, at least one next-generation sequencing study failed to detect higher mutation rates.4 Different definitions of CNG may generate an underestimate of this mechanism of resistance. Mechanisms other than CNG may lead to higher protein expression of echinoderm microtubule associated protein like 4 (EML4)-ALK and hence increased signaling in the presence of a static dose of crizotinib. Loss of hypothetical negative regulators of ALK activity might also lead to improved ALK signaling despite the continued presence of crizotinib. Serendipitous targeting of another kinase responsible for bypass signaling involved in acquired resistance could also explain additional responses to therapy. One such potential pathway is IGF1R. Increased insulin-like growth factor 1 receptor (IGF1R) activity has been observed in ALK+ cell lines with induced crizotinib resistance, and some of the second-generation ALK inhibitors, such as ceritinib (LDK378) and AP26113, also target IGF1R.15–17 Re-response to crizotinib after progression on this drug and subsequent, intervening chemotherapy has been observed in two cases and could account for additional cases of response to second-generation inhibitors, although the frequency or mechanism of re-response is not yet known.18,19 Finally, one could speculate on a non–cancer cell intrinsic mechanism that could account for a re-response to a new ALK inhibitor following initial crizotinib response and then disease progression, such as decreased crizotinib exposure over time. No long-term pharmacokinetic data have been published on ALK+ patients receiving crizotinib. Increased liver metabolism or other host-specific factors could decrease drug exposure over time.
If we hope to delay or minimalize drug resistance to crizotinib or next-generation ALK inhibitors, it will be critical to understand the mechanisms underlying both our failures and successes.
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