The management of advanced non-small cell lung cancer (NSCLC) has transitioned into an algorithm directed substantially by the presence or absence of an oncogenic mutation (where mutation refers to nucleotide substitutions, insertions, deletions, or chromosomal rearrangements or duplications) that can be effectively inhibited with a specific molecularly targeted agent. We have achieved a clear consensus that the most effective initial intervention for patients with an activating epidermal growth factor receptor (EGFR) gene mutation or anaplastic lymphoma kinase (ALK) gene rearrangement should be an EGFR tyrosine kinase inhibitor (TKI) or the ALK inhibitor crizotinib, respectively. These therapies, generally administered at the earliest opportunity as the next line of therapy after the oncogenic mutation has been identified, offer the greatest probability of a dramatic and prolonged response as compared with conventional chemotherapy. Responses to these generally well-tolerated therapies often last for a year and sometimes much longer. However, patients with these oncogenic mutations eventually demonstrate progression of their disease, a clinical setting described as acquired resistance to the previously highly effective targeted therapy.
The optimal approach to treatment of such patients remains undefined. Although clinical practice varies in how best to treat patients who experience acquired resistance, the only consensus among leading researchers is that this is not a setting analogous to second-line management of advanced NSCLC in patients with a cancer that does not have an “oncogene addiction” to a molecular signaling cascade driven by a specific oncogene. There is good reason to believe that the resistance observed in such patients is only partial, so that ongoing inhibition may prove to be beneficial. Although the practice of continuing a therapy on which a patient has demonstrated prior progression runs counter to the basic tenets of oncology, we now recognize many settings in which ongoing therapy despite prior progression with that class of therapy may be beneficial. This is presumably because a subset of cancer cells remains effectively inhibited by the targeted therapy, and/or the suppression is at least somewhat effective in a broader population of cancer cells. For example, objective clinical benefit has been established for continuing trastuzumab in patients with HER2-amplified breast cancer who have progressed on this agent1 or for pursuing additional inhibitors of BCR-ABL in patients with chronic myelogenous leukemia who have demonstrated progression on imatinib,2,3 providing a helpful heuristic model for management of acquired resistance in advanced NSCLC that has an established oncogene addiction to a specific oncogenic mutation.
HETEROGENEITY OF PRESENTATIONS WITH ACQUIRED RESISTANCE TO TARGETED THERAPY IN ADVANCED NSCLC
Compounding the challenge of defining an optimal strategy for progression in patients with advanced NSCLC and an identified oncogenic mutation is the heterogeneity in the clinical picture for patients considered as demonstrating “acquired resistance.“ Though the initial criteria offered by Jackman and colleagues4 (Table 1) provide a basic definition for acquired resistance to an EGFR TKI, others use less formal definitions or a more strict approach that may require nonprogression over 6 months or longer. In addition, patients may demonstrate a pattern of progression that is a single focus or few foci of progression against a background of still very well suppressed disease, more diffuse but still relatively indolent progression that may not be clinically significant, or a diffuse and rapidly progressing process. Progression may potentially be predicated on development of a new mutation, loss of the prior oncogenic mutation, or other changes that still remain to be defined. Although they show the promise of augmenting our understanding of this process quite substantially, repeat biopsies to clarify the underlying molecular mechanism(s) are done only infrequently and have demonstrated a wide array of mechanisms that are discussed further below.
TABLE 1. Defining Acquired Resistance (Specifically to EGFR TKI)4
1. Patient previously received treatment with an EGFR TKI
2. Either of the following:
A. Tumor known to harbor an EGFR sensitizing mutation
B. Patient demonstrated an objective clinical benefit defined by either
i. Objective response
ii. Significant and durable (≥ 6 months) clinical benefit
iii. Patient previously received treatment with an EGFR TKI
iv. Either of the following:
- Systemic progression of disease
- No intervening systematic therapy between cessation of EGFR TKI and initiation of new therapy
Although the biology of EGFR mutations and ALK rearrangements are distinct, the patterns of progression seen in the setting of acquired resistance have been similar and allow us to create some shared principles to guide the emerging principles of clinical management to follow.
ACQUIRED RESISTANCE TO EGFR TKIs
Although much has been learned over past years about first-line therapy with an EGFR TKI for EGFR-mutant lung cancer, much remains to be learned about the optimal treatment of patients after resistance develops. Most agree that chemotherapy is the current standard of care for these patients, particularly with data suggesting an increased sensitivity to chemotherapy in the first-line setting.5 However, little prospective evidence exists describing the effectiveness of chemotherapy in patients with EGFR-mutated lung cancer who experience TKI treatment failure. One arm of the TORCH trial prospectively delivered cisplatin plus gemcitabine following first-line erlotinib.6 In 13 patients with EGFR mutations who received chemotherapy after erlotinib, two objective responses were seen (15%), with a median progression-free survival of 4 months.7 Retrospective series have similarly described response rates of only 15% to 18% to chemotherapy alone after TKI resistance.8,9 Because many patients develop slow or asymptomatic progression while receiving an EGFR TKI,10 oncologists are increasingly electing to continue single-agent TKI past progression in order to delay transition to chemotherapy.11 The effectiveness of this approach for prolonging disease control is being prospectively studied in the ongoing ASPIRATION study.12
One reason oncologists avoid stopping an EGFR TKI after resistance develops is concern over a “rebound progression” or “flare” of cancer growth when the TKI is withdrawn, felt to be due to regrowth of faster-growing TKI-sensitive cells.13 In one study of patients that stopped an EGFR TKI for clinical trial accrual, 23% of patients developed severe rebound progression requiring hospitalization after a median of 8 days off TKI.14 This has led many to advocate for continuation of the initial targeted therapy up to the time that a new treatment is initiated, rather than favoring a washout period of several weeks Another option is to continue the TKI in addition to chemotherapy, an approach that augmented the effectiveness of chemotherapy in cell line models.13 The first prospective study of an EGFR TKI plus chemotherapy after TKI resistance used single-agent pemetrexed plus erlotinib or gefitinib15 and described a response rate of 26%; median progression-free survival was 7 months. A retrospective study has also shown higher response rates in this setting when chemotherapy is given with a TKI.9 In a randomized study conducted in the first-line setting, erlotinib plus chemotherapy was found to be somewhat more toxic than chemotherapy, but no antagonism was seen; efficacy was equal in patients with untreated EGFR-mutant lung cancer.16 To test whether an EGFR TKI increases the activity of chemotherapy in the acquired resistant seeing, the IMPRESS study is randomly assigning patients to chemotherapy with or without gefitinib after acquired resistance, and a study using erlotinib is planned. The general schema for these trials, and for a similar one in development with ALK-positive advanced NSCLC and acquired resistance to crizotinib, is illustrated in Fig. 1.
Several clinical trials exploring the benefit of tyrosine kinase inhibitor (TKI) continuation with the addition of chemotherapy following progression on a TKI alone are underway or proposed. The IMPRESS trial is currently accruing patients with advanced NSCLC who have EGFR-activating mutations and who have experienced disease progression on gefitinib. The trial will randomly assign patients to either cisplatin and pemetrexed alone or to cisplatin and pemetrexed with continuation of gefitinib. A similar trial in patients with EGFR+ disease who have experienced disease progression on erlotinib will randomly assign patients to cisplatin or carboplatin plus pemetrexed alone or in combination with continuation of erlotinib. This trial will allow reintroduction erlotinib in the chemotherapy arm following disease progression. The proposed SWOG study 1300 will randomly assign patients with ALK+ disease with progression on crizotinib to either pemetrexed alone or in combination with crizotinib. Reintroduction of crizotinib following disease progression on pemetrexed will be allowed within the trial.
Targeted therapies studied for use after TKI resistance have often focused on the T790M mutation, a gatekeeper mutation acquired in 49% to 68% of cancers after TKI resistance.17,18 Second-generation irreversible EGFR inhibitors such as afatinib and dacomitinib appeared to inhibit T790M in preclinical models but have generated response rates of less than 10% in prospective trials in patients who were erlotinib or gefitinib resistant.19,20 A more impressive response rate of 36% was seen when afatinib was combined with cetuximab, a monoclonal antibody against EGFR, in patients with EGFR-mutated, TKI-resistant disease. Interestingly, this rate was not dependent on the presence of T790M21; yet development of this combination has been slowed in part by toxicity. A third generation of EGFR TKIs has been identified with selective activity against T790M and minimal inhibition of wild-type EGFR,22 but these agents are very early in their clinical development.
Other trials for acquired EGFR resistance have focused on less common resistance mechanisms. Several trials are studying the combination of EGFR TKIs with MET kinase inhibitors,23 although the incidence of MET amplification in clinical specimens appears to be less than 10%.17,18 One series found PIK3CA mutations in 5% of cases of acquired resistance,18 and several trials combining EGFR TKIs with PI3K inhibitors are underway.24 The HSP90 inhibitor AUY922 has shown signs of activity in some patients with acquired resistance,25 and is also being studied in combination with erlotinib.26 The most surprising finding may be histologic transformation to small cell lung cancer, seen in 3% to 14% of cases of acquired resistance,17,18 supporting a clinical role for repeat biopsies for these patients to determine the potential utility of a chemotherapy approach for that histology.
ACQUIRED RESISTANCE TO CRIZOTINIB IN ALK-POSITIVE NSCLC
The identification of ALK gene rearrangements in patients with NSCLC has led to substantial improvements in clinical outcomes for this subset of patients. Treatment with crizotinib leads to objective response rates (ORR) of approximately 50% to 60%, progression-free survival of 7 to 10 months, and evidence of prolonged survival.27,28 Recent results also demonstrate that that crizotinib is superior to treatment with single-agent chemotherapy.29 Despite the clear benefits of crizotinib in ALK+ lung cancer, patients treated with crizotinib ultimately experience disease progression related to poor CNS penetration or because of cellular resistance.
Both in vitro and patient-based studies have yielded insights into mechanisms of crizotinib resistance in ALK+ lung cancer. One of the earliest identified mechanisms of resistance were ALK kinase domain mutations. In contrast to EGFR mutation-positive lung cancer, where the vast majority of resistance mutations are T790M, numerous ALK kinase domain mutations have been identified in patients with ALK gene rearrangements with only a slight preponderance of the gatekeeper mutation, L1196M, which is analogous to T790M in EGFR.30 Indeed, mutations have been identified in clinical tumor samples in nine different amino acid positions in exons 22, 23, and 25 of the ALK kinase domain.31 Additional mutations have been identified using in vitro studies in exons 21–25 of ALK corresponding to the kinase domain.
The increased complexity of resistance mutations has several implications for patients and physicians. First, it is more difficult to develop robust assays that can encompass and detect all known resistance mutations. Second, it is likely that tumors may harbor more than one mutation at resistance. The first published case of crizotinib-resistance demonstrated two different mutations (C1156Y and L1196M) in the same tumor sample.32 In chronic myeloid leukemia, patient samples derived at the time of dasatinib or nilotinib resistance demonstrated up to 10 different resistance mutations by mass-spectrometry, many of which were missed by direct sequencing techniques.33 Thus, samples that harbor multiple mutations may register as false-negatives by direct sequencing because of allelic dilution if there is not a dominant mutation in a large percentage of the tumor cells. Finally, many of the resistance mutations identified thus far in ALK do not seem to confer a fitness disadvantage in the absence of an ALK inhibitor as the EGFR resistance mutation, T790M, does.34-35 Thus the repeat response observed in some patients with EGFR mutations may not be as common in patients with ALK mutations who were rechallenged with crizotinib. A recent case report of an patient who was ALK+ and who showed a response at rechallenge demonstrates that this can also occur ALK+ lung cancer, although the mechanism of crizotinib for this patient was not known.36
Increase in copy number of the ALK gene fusion was initially identified in ALK+ cell lines made resistant to crizotinib.37 Evidence of copy number gain has also been identified in patient samples from patients who were resistant to crizotinib, suggesting that this may play a role in cellular resistance.34,38 In the case of a kinase domain mutation or copy number gain of the ALK gene fusion, ALK signaling would be retained and is expected that tumor cells might still harbor oncogene addiction to the ALK gene fusion. Thus, more potent second-generation ALK inhibitors might overcome these cellular resistance mechanisms. This type of resistance has been termed ALK-dominant resistance.31
The final class of resistance can be classified as ALK nondominant resistance defined by emergence of other signaling pathways to ALK signaling dependence, rendering the inhibition of ALK insufficient to inhibit cancer cell growth. Multiple alternate signaling pathways have been identified. The presence of activating mutations in EGFR or KRAS in both crizotinib-naïve and crizotinib-treated patients. In vitro studies demonstrate that EGFR and other HER family receptor tyrosine kinases can also mediate resistance through ligand-mediated activation of these receptors. Addition of an EGFR TKI was able to resensitize cancer cells to crizotinib.39-41 Additional support for this mechanism of resistance has been demonstrated in crizotinib-resistant tumor samples showing increased phosphorylated EGFR compared with precrizotinib tumor samples.38 Activation of the KIT receptor tyrosine kinase by the stem cell factor (SCF) has been shown to mediate crizotinib resistance in vitro and evidence of KIT gene amplification by fluorescence in situ hybridization testing, as well as increased stem cell factor staining by immunohistochemistry.38
Tumor heterogeneity may lead to further complexity when trying to overcome crizotinib resistance in ALK+ lung cancer. Indeed, tumor heterogeneity with respect to cellular resistance has already been observed. Two different kinase domain mutations were identified in one patient sample with some of the tumor cells showing no evidence of mutation.32 Copy number gain and mutation have been found in the same sample, although it is unclear whether both aberrations were present in the same cell.34 Finally one patient who underwent two biopsies of separate lesions showed different molecular results at each site of biopsy.34 This leads to the inevitable question of whether the molecular results on a given biopsy are representative for the entirety of the disease burden, and whether current limited molecular testing is revealing all sources of cellular resistance.
Next generation ALK inhibitors such as CH5424802 demonstrate preclinical activity against cancer cells harboring EML4-ALK gene fusions and have activity against many of the resistance mutations identified in the ALK kinase domain.38 Early preclinical data with LDK378, AP26113, and CH5424802 suggest that these drugs have activity in both crizotinib-naïve and crizotinib-resistant patients, and each drug has anecdotal data for response of brain metastases.42-44 Next generation ALK inhibitors might be the optimal choice for ALK-dominant resistance where tumors still rely predominantly on ALK signaling as the oncogenic mutation.
EML4-ALK is a client of HSP90, and several drugs in this class have shown clinical activity.45,46 Notably, AUY-922 has also shown clinical activity against EGFR+ lung cancer or tumors that are wild-type for EGFR, KRAS, and ALK, making this a potentially attractive agent to study in ALK-nondominant resistance.25 Pemetrexed-containing regimens appears to show notable activity in ALK+ lung cancer and thus represent reasonable standard of care options for patients where a clinical trial is not feasible or available29,47 Whether to continue crizotinib in the presence of chemotherapy remains an unanswered question, but a clinical trial has been proposed to help answer this question (Fig. 1). Use of local ablative therapy also seems an attractive option to extend the clinical benefit of crizotinib in cases where disease progression is limited to one or a few lesions (“oligoprogressive” disease).48
TRANSLATING EARLY RESEARCH INTO PRACTICAL MANAGEMENT
Although there are no randomized trial data to develop a clear evidence-based recommendation for clinical management of acquired resistance, there is converging evidence that supports an individualized approach based on the pattern of progression in terms of both pace and extent of progressing disease, as illustrated in Fig. 2.
Proposed algorithm for management of acquired resistance to a targeted therapy in advanced NSCLC.
A key insight into the management of acquired resistance, whether to an EGFR inhibitor, ALK inhibitor, or other oncogenic mutations that may emerge in the future, is that this resistance is often incomplete, so that a subset of the existing cancer cells remain suppressed by the targeted therapy on which progression has been demonstrated. Before any therapeutic changes are made, it is important to distinguish between detectable and clinically significant progression, since many patients with acquired resistance may demonstrate minimal, asymptomatic progression that still represents a net decrease in tumor burden compared to the status of the patient before initiation of the targeted therapy in question. Findings such as the rebound progression that are sometimes seen with discontinuation of a targeted therapy on which a patient has demonstrated recent progression, followed by improved disease control again with reintroduction of the same agent or another in the same class, highlight that continuation of the targeted therapy is often still effectively suppressing at least a subset of the disease that remains responsive to it, even as progression demonstrates that a subset of the cancer cell population has developed resistance. Moreover, this resistance may not only be partial in terms of appearing in a subset of cancer cells within a patient's overall disease burden, but also may be partial within these cells, so that these cells may still be relatively inhibited by ongoing targeted therapy, compared with withdrawal of the targeted therapy entirely.
The common finding of only one or a few areas of progression against a background of ongoing disease control elsewhere suggests the potential value of local therapy, (e.g., radiation, surgery, or radiofrequency ablation), to the very limited extent of progressive disease, while continuing the targeted therapy that is effectively controlling disease elsewhere. This practice is best established in the management of brain metastases, where local failure can be in part due to the limited penetration of systemic agents through the blood–brain barrier. Several groups have described success with continued targeted therapy after delivery of radiation to the brain. There is optimism that this approach can be generalized to instance of focal progression outside of the CNS, although experience to date is limited.
For those patients with systemic progression, the question of whether to discontinue the targeted therapy or continue it in combination with alternative systemic therapy—commonly chemotherapy-based—remains a matter of clinical judgment. In the absence of meaningful data to address this question, the authors differ in their own favored approaches and feel that this is a question that is left to the judgment of the treating oncologist. The clearest consensus is that clinical trials to address such questions are especially welcome.
There are no data to support a specific systemic therapy to initiate, although the authors favor an approach essentially identical to the decision-making strategy that guides the recommendation for first-line treatment in a patient without an identified mutation so that a platinum doublet-based chemotherapy combination is most often favored and is modified as needed by the comorbidities, performance status, and treatment preferences of the patient.
Discontinuation of the targeted therapy to which acquired resistance has developed is a particularly reasonable consideration in the subgroup of patients who demonstrate rapid and diffuse progression, suggestive that the targeted therapy is providing little or no inhibitory effect. In such patients, a repeat biopsy may reveal clinically relevant findings of changes in histology or new mutations that may potentially be treated effectively with commercially available or investigational agents.
The introduction of targeted therapies for defined populations with the relevant molecular target has transformed our expectations about what is possible in treating advanced NSCLC, but this remains limited by the essentially invariable development of acquired resistance. Although the role of a repeat biopsy at the present time may or may not yield an “actionable” result, our understanding of the mechanisms underpinning acquired resistance have been facilitated greatly by these limited efforts in recent years. By concentrating efforts on repeat biopsies and the molecular evolution of progressing lesions in patients with an identified oncogenic mutation who develop acquired resistance, we can realistically expect to confer additional clinical benefits to these patients as we gain a remarkably richer understanding of the complex biology of the molecular evolution of lung cancer that can translate to broader patient populations as well.
von Minckwitz G, du Bois A, Schmidt M, et al. Trastuzumab beyond progression in human epidermal growth factor receptor 2-positive advanced breast cancer: a German Breast Group 26/Breast International Group 03-05 study. J Clin Oncol.
Kantarjian H, Talpaz M, O'Brien S, et al. Nilotinib in imatinib-resistant CML and Philadelphia chromosome-positive ALL. N Engl J Med.
Kantarjian HM, Talpaz M, O'Brien S, et al. Dose escalation of imatinib mesylate can overcome resistance to standard-dose therapy in patients with chronic myelogenous leukemia. Blood.
Jackman D, Pao W, Riely GJ, et al. Clinical definition of acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors in non-small-cell lung cancer. J Clin Oncol.
Mok TS, Wu YL, Thongprasert S, et al. Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med.
Gridelli C, Ciardiello F, Gallo C, et al. First-line erlotinib followed by second-line cisplatin-gemcitabine chemotherapy in advanced non-small-cell lung cancer: The TORCH randomized trial. J Clin Oncol.
7. Gridelli C. Response rate 15% and median progression-free survival of 4 months with chemotherapy following erlotinib in EGFR mutation-positive patients on TORCH trial. Personal communication (GRO), 2012.
Wu JY, Shih JY, Yang CH, et al. Second-line treatments after first-line gefitinib therapy in advanced nonsmall cell lung cancer. Int J Cancer.
9. Goldberg SB, Oxnard GR, Digumarthy S, et al. Chemotherapy with erlotinib or chemotherapy alone in advanced NSCLC with acquired resistance to EGFR tyrosine kinase inhibitors (TKI). J Clin Oncol. 2012; 30:A#7524.
Oxnard GR, Arcila ME, Sima CS, et al. Acquired resistance to EGFR tyrosine kinase inhibitors in EGFR mutant lung cancer: Distinct natural history of patients with tumors harboring the T790M mutation. Clin Cancer Res.
11. Oxnard GR, Lo P, Jackman DM, et al. Delay of chemotherapy through use of post-progression erlotinib in patients with EGFR-mutant lung cancer. J Clin Oncol. 2012; 30: A#7547.
12. Park K, Tsai C-M, Ahn M-j, et al. ASPIRATION: Phase II study of continued erlotinib beyond RECIST progression in Asian patients (pts) with epidermal growth factor receptor (EGFR) mutation-positive non-small cell lung cancer (NSCLC). J Clin Oncol. 2012; 30: A#TPS7614.
Chmielecki J, Foo J, Oxnard GR, et al. Optimization of dosing for EGFR-mutant non-small cell lung cancer with evolutionary cancer modeling. Sci Transl Med.
14. Chaft JE, Oxnard GR, Miller VA, et al. Disease flare after tyrosine kinase inhibitor (TKI) discontinuation in patients with EGFR mutant lung cancer and acquired resistance. J Clin Oncol. 2011; 29:A#e18001.
Yoshimura N, Okishio K, Mitsuoka S, et al. Prospective assessment of continuation of erlotinib or gefitinib in patients with acquired resistance to erlotinib or gefitinib followed by the addition of pemetrexed. J Thorac Oncol.
Jänne PA, Wang X, Socinski MA, et al. Randomized phase II trial of erlotinib alone or with carboplatin and paclitaxel in patients who were never or light former smokers with advanced lung adenocarcinoma: CALGB 30406 Trial. J Clin Oncol.
Arcila ME, Oxnard GR, Nafa K, et al. Rebiopsy of lung cancer patients with acquired resistance to EGFR inhibitors and enhanced detection of the T790M mutation using a locked nucleic acid-based assay. Clin Cancer Res.
Sequist LV, Waltman BA, Dias-Santagata D, et al. Genotypic and Histological Evolution of Lung Cancers Acquiring Resistance to EGFR Inhibitors. Sci Transl Med.
19. Campbell A, Reckamp KL, Camidge DR, et al. PF-00299804 (PF299) patient (pt)-reported outcomes (PROs) and efficacy in adenocarcinoma (adeno) and nonadeno non-small cell lung cancer (NSCLC): A phase (P) II trial in advanced NSCLC after failure of chemotherapy (CT) and erlotinib (E). J Clin Oncol. 2010; 28: A#7596
Miller VA, 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.
21. Janjigian YY, Groen HJM, Horn L, et al. Activity and tolerability of afatinib (BIBW 2992) and cetuximab in NSCLC patients with acquired resistance to erlotinib or gefitinib. J Clin Oncol 29: 2011 (suppl; abstr 7525^)
Zhou W, Ercan D, Chen L, et al. Novel mutant-selective EGFR kinase inhibitors against EGFR T790M. Nature.
23. Wakelee HA, Gettinger SN, Engelman JA, et al. A phase Ib/II study of XL184 (BMS 907351) with and without erlotinib (E) in patients (pts) with non-small cell lung cancer (NSCLC). J Clin Oncol. 2010; 28: A#3017.
24. Cohen RB, Janne PA, Engelman JA, et al. A phase I safety and pharmacokinetic (PK) study of PI3K/TORC1/TORC2 inhibitor XL765 (SAR245409) in combination with erlotinib (E) in patients (pts) with advanced solid tumors. J Clin Oncol. 2010; 28: A#3015.
25. Garon EB, Moran T, Barlesi F, et al. Phase II study of the HSP90 inhibitor AUY922 in patients with previously treated, advanced non-small cell lung cancer (NSCLC). J Clin Oncol. 2012; 30: A#7543.
Johnson ML, Yu HA, Hart EM, Worden R, Rademaker A, Gupta R, et al. A phase I dose-escalation study of the HSP90 inhibitor AUY922 and erlotinib for patients with EGFR-mutant lung cancer with acquired resistance (AR) to EGFR tyrosine kinase inhibitors (EGFR TKIs). J Clin Oncol.
2012; 30: A#3083.CrossRef
Camidge DR, Bang YJ, Kwak EL, et al. Activity and safety of crizotinib in patients with ALK-positive non-small-cell lung cancer: Updated results from a phase 1 study. Lancet Oncol.
Shaw AT, Yeap BY, Solomon BJ, et al. Effect of crizotinib on overall survival in patients with advanced non-small-cell lung cancer harbouring ALK gene rearrangement: A retrospective analysis. Lancet Oncol.
29. Shaw AT, Kim DW, Nakagawa K, et al. Phase III study of crizotinib versus pemetrexed or docetaxel chemotherapy in patients with advanced ALK-positive non-small cell lung cancer (NSCLC) (PROFILE 1007). ESMO Congress 2012, A#LBA1_PR. 2012.
Lovly CM, Pao W. Escaping ALK Inhibition: Mechanisms of and Strategies to Overcome Resistance. Sci Transl Med.
Camidge DR, Doebele RC. Treating ALK-positive lung cancer-early successes and future challenges. Nature Rev Clin Oncol.
Choi YL, Soda M, Yamashita Y, et al. EML4-ALK mutations in lung cancer that confer resistance to ALK inhibitors. N Engl J Med.
Parker WT, Lawrence RM, Ho M, et al. Sensitive detection of BCR-ABL1 mutations in patients with chronic myeloid leukemia after imatinib resistance is predictive of outcome during subsequent therapy. J Clin Oncol.
Doebele RC, Pilling AB, Aisner DL, et al. Mechanisms of resistance to crizotinib in patients with ALK gene rearranged non-small cell lung cancer. Clin Cancer Res.
35. Sasaki T, Koivunen J, Ogino A, et al. A novel ALK secondary mutation and EGFR signaling cause resistance to ALK kinase inhibitors. Cancer Res. 2011;71:6151-6160.
36. Browning ET, Weickhardt AJ, Camidge DR. Response to crizotinib rechallenge after initial progression and intervening chemotherapy in ALK+ lung cancer. J Thorac Oncol. In press.
Katayama R, Khan TM, Benes C, et al. Therapeutic strategies to overcome crizotinib resistance in non-small cell lung cancers harboring the fusion oncogene EML4-ALK. Proc Nat Acad of Sci USA.
Katayama R, Shaw AT, Khan TM, et al. Mechanisms of acquired crizotinib resistance in ALK-rearranged lung Cancers. Sci Transl Med.
Koivunen JP, Mermel C, Zejnullahu K, et al. EML4-ALK fusion gene and efficacy of an ALK kinase inhibitor in lung cancer. Clin Cancer Res.
Sasaki T, Koivunen J, Ogino A, et al. A novel ALK secondary mutation and EGFR signaling cause resistance to ALK kinase inhibitors. Cancer Res.
Tanizaki J, Okamoto I, Okabe T, et al. Activation of HER family signaling as a mechanism of acquired resistance to ALK inhibitors in EML4-ALK-positive non-small cell lung cancer. Clin Cancer Res.
42. Shaw AT, Camidge DR, Felip E, et al. Results of a first-in-human phase I study of the ALK inhibitor LDK378 in advanced solid tumors. Ann Oncol. 2012; 23: A#ix153.
43. Nishio M, Kiura K, Nakagawa K, et al. A phase I/II study of ALK inhibitor CH5424802 in patient s with ALK-positive NSCLC: Safety and efficacy interim results of the phase II portion. Ann Oncol. 2012; 23: A#ix153.
44. Gettinger S, Weiss GJ, Salgia R, et al. A first-in-human dose-finding study of the ALK/EGFR inhibitor AP26113 in patients with advanced malignancies. Ann Oncol. 2012; 23: A#ix152.
Normant E, Paez G, West KA, et al. The Hsp90 inhibitor IPI-504 rapidly lowers EML4-ALK levels and induces tumor regression in ALK-driven NSCLC models. Oncogene.
Sequist LV, Gettinger S, Senzer NN, et al. Activity of IPI-504, a novel heat-shock protein 90 inhibitor, in patients with molecularly defined non-small-cell lung cancer. J Clin Oncol.
47. Camidge DR, Kono SA, Lu X, et al. Anaplastic lymphoma kinase gene rearrangements in non-small cell lung cancer are associated with prolonged progression-free survival on pemetrexed. J Clin Oncol. 2011;6:774-80.
Weickhardt AJ, Scheier B, Burke JM, et al. Local ablative therapy of oligoprogressive disease prolongs disease control by tyrosine kinase inhibitors in oncogene-addicted non-small-cell lung cancer. J Thorac Oncol.