February 2013, Vol 2, No 1
Resistance to Targeted Molecular Therapies in NSCLCLung Cancer
Over the past decade, there has been enormous progress in our understanding of the molecular pathogenesis of non–small cell lung cancer (NSCLC), in particular among patients with lung adenocarcinoma. Approximately 60% of these patients’ tumors will be oncogene addicted.1 Those with mutated EGFR and ALK rearrangements can be treated with targeted inhibitors of the offending oncogene. While the success of the tyrosine kinase inhibitors (TKIs) – erlotinib and gefitinib directed against the epidermal growth factor receptor (EGFR) and crizotinib targeting the anaplastic lymphoma kinase (ALK) – has catalyzed significant changes in the treatment of patients with NSCLC, it has also introduced a new challenge: resistance that develops after TKI treatment (acquired resistance). Here, we review current understanding of EGFR- and ALK-driven lung adenocarcinoma, the mechanisms of acquired resistance in both groups of patients, and newer therapies being investigated for patients after the development of acquired resistance.
EGFR Mutations and EGFR-Targeted Therapies
EGFR is a receptor tyrosine kinase (RTK) that stimulates cellular growth, proliferation, and survival mediated by PI3K-AKT-mTOR and RAS-RAF-MEK-ERK pathways (Figure).2-5 Aberrant expression of EGFR is a well-established mechanism causing development of NSCLC tumors, in particular for the 10% to 15% of patients with activating mutations in the kinase domain of EGFR.6-9 The EGFR-TKIs gefitinib and erlotinib inhibit tumor growth by competing for the ATP- binding site of the kinase domain of EGFR.2 Although EGFR-TKIs have demonstrated modest antitumor activity in unselected patients with advanced NSCLC harboring EGFR mutations (response rates [RRs] 8%-9%10,11), these agents are capable of producing far greater responses (RRs 55%-91%, as reviewed by Pao and Chmielecki12 and Nguyen et al13). Female patients, never-smokers, and patients of East Asian ethnicity are more likely to respond to gefitinib or erlotinib, as discovered in early studies, and were subsequently found to be more likely to harbor activating mutations in EGFR.14-16
The IPASS study was the first randomized phase 3 trial to demonstrate gefitinib to be superior to standard platinum chemotherapy in East Asian, never- or light-smoker patients with advanced adenocarcinoma of the lung.17 Preplanned subgroup analysis showed that patients with EGFR mutations had longer progression-free survival (PFS) when treated with gefitinib (hazard ratio [HR] 0.48; P<.001), while those patients whose tumors were EGFR wild-type had shorter PFS when treated with gefitinib (HR 2.85; P<.001). First-SIGNAL, a second study of gefitinib in never-smoker patients conducted in Korea, demonstrated similar results to IPASS, where the presence of an EGFR mutation was predictive of higher overall RRs (84.6% [22/26] vs 25.9% [7/27]; P<.001) and longer PFS (HR; 0.377; 95% CI, 0.210-0.674; P<.001) among patients who received gefitinib.18 In addition to IPASS and First-SIGNAL, 2 phase 3 trials confirmed the superior efficacy of gefitinib versus chemotherapy in selected Japanese patients with lung adenocarcinoma and EGFR mutations (NEJ002 and WJTPG3405),19,20 and a third study verified the same results using erlotinib in Chinese patients (OPTIMAL).21 The EURTAC trial confirmed erlotinib was better than standard chemotherapy in a European Caucasian population with EGFR mutations (HR 0.37; P<.001).22 Erlotinib has been adopted into both the National Comprehensive Cancer Network and the American Society of Clinical Oncology guidelines for initial treatment of patients with EGFR-mutated lung cancer.23,24
Acquired Resistance to EGFR-TKIs
Acquired resistance occurs after initial favorable response to EGFR-TKI therapy and develops despite active treatment with erlotinib or gefitinib. Jackman and colleagues have defined criteria to help identify acquired resistance to TKIs.25 These criteria require an initial objective clinical benefit – either disease shrinkage or stable disease for at least 6 months – followed by progressive disease despite continuous TKI therapy within the last 30 days prior to development of progression. Using cell lines and mouse models with EGFR mutations treated with continuous EGFR-TKIs, several mechanisms of acquired resistance have been elucidated in the laboratory. Below we focus our discussion on those that have also been encountered clinically in patient specimens after rebiopsy.
T790M “Gatekeeper” Mutations
The most common mechanism of acquired resistance to EGFR-TKIs is a secondary mutation in exon 20 of EGFR, a single amino acid substitution at position 790 (methionine for threonine), first reported in 2005 in patients with advanced NSCLC previously treated with gefitinib or erlotinib.26,27 Analogous to the “gatekeeper” mutations that develop in other oncogene-addicted cancers (Table), the T790M mutation confers drug resistance by altering drug binding within the ATP-binding pocket of EGFR; this mechanism accounts for roughly 50% of patients with acquired resistance to EGFR-TKIs.26,27,33 While other single-site mutations in EGFR, such as D761Y, L747S, and T854A, have also been identified as causing TKI resistance, they occur in less than 5% of patients. The mechanisms of resistance for these mutations remain unclear, but in vitro studies demonstrate that, unlike T790M, these less common mutations may exhibit weaker resistance that may be overcome with increasing doses of EGFR-TKIs.13
Despite developing resistance to TKI therapy, patients harboring T790M appear to have indolent, less aggressive clinical courses (19 months postprogression survival compared with 12 months in patients without T790M; P=.036) and seem more likely to progress within an existing site of disease rather than progressing to a new metastatic site.34 In a cohort of patients with acquired resistance who underwent repeat biopsies and molecular analysis (n=37), Sequist and colleagues reported 18 patients (49%) with T790M mutations, and a subset of these (n=3) were reported to have overamplification of EGFR, specifically the T790M allele.35
A second mechanism causing acquired resistance to EGFR-TKIs is the upregulation of an alternative signaling pathway, or “bypass track,” capable of activating the same intracellular pathways as EGFR.36,37 For example, upregulation of MET, an alternative RTK capable of activating the PI3K pathway and downstream effectors including AKT, provides the tumor an alternative means of signaling despite suppression of EGFR by EGFR-TKIs. MET amplification in combination with EGFR T790M occurs in 20% of EGFR-driven NSCLC with acquired resistance, but in isolation of the gatekeeper mutation, only about 5% of acquired resistance cases have MET amplification alone35,38 Insulin-like growth factor-1 receptor may be another RTK able to create a bypass track in the setting of acquired resistance to EGFR-TKIs, although this has only been suggested by preclinical data.39
Approximately 5% of patients with acquired resistance develop secondary mutations in PI3KCA.35 PI3KCA mutations were also reported in 2% of patients whose tumors were genotyped as part of the Lung Cancer Mutation Consortium, but these patients had not received prior EGFR-TKIs.1 PI3KCA mutations have been reported in another small cohort of TKI-naive patients to coexist with other driver mutations besides EGFR, such as KRAS and ALK, and predict inferior patient outcomes when expressed concurrently with one of these oncogenes.40
Rarely, patients whose tumors have acquired resistance to EGFR-TKIs will exhibit histologic transformation of their primary tumor from adenocarcinoma to small cell or neuroendocrine differentiation, although the original EGFR mutation is preserved. This phenomenon has been observed in patient samples with a frequency ranging from 2% to 14%.35,38 Interestingly, these patients can be treated with small cell lung cancer chemotherapy regimens with favorable responses. The mechanism that triggers this change in histology is unclear but may be explained by a hypothesis that proposes that a pluripotent cancer stem cell underlies EGFR-mutant lung cancer development and resistance.35,41
Strategies for Overcoming EGFR-TKI Resistance
There is no standard treatment for patients once resistance to erlotinib or gefitinib develops, despite exhaustive attempts to identify an effective second-generation EGFR inhibitor (as reviewed by Oxnard et al42). One of the most heralded agents is afatinib, an irreversible inhibitor that forms a covalent bond in the ATP- binding site of EGFR, allowing inhibition of EGFR even in the presence of a secondary T790M resistance mutation. Gefitinib-resistant NSCLC cell lines are sensitive to afatinib in vitro and result in reduced EGFR pathway signaling and increased cellular apoptosis.43,44 This finding launched a series of clinical trials, named the LUX-Lung studies, to evaluate the efficacy of afatinib in EGFR-driven lung cancers. In the LUX-Lung 1 study, patients with advanced NSCLC and prior treatment with chemotherapy and EGFR-TKIs were found to have an improved PFS when treated with afatinib compared with those who received best supportive care (HR 0.38; P<.0001),45 although RRs were only 7% and there was no improvement in overall survival (OS), the primary end point. While outcomes for patients with EGFR mutations and T790M-mediated resistance were not available, 34% of enrolled patients did meet Jackman criteria for acquired resistance.45
Importantly, afatinib and other quinazoline inhibitors of EGFR, such as erlotinib, bind wild-type and mutant EGFR, thereby causing well-known toxicities of skin rash and diarrhea. These dose-limiting toxicities may prevent afatinib and other irreversible EGFR-TKIs from reaching concentrations necessary to effectively inhibit T790M-mediated resistance. The discovery of novel covalent pyrimidine EGFR inhibitors that are more potent against EGFR T790M, and up to 100-fold less potent against wild-type EGFR, has led to an exciting new area of investigation against secondary resistance to EGFR-TKIs using mutant-selective inhibitors that do not cause the expected toxicities.46 One such “third-generation” EGFR-TKI, CO-1686, is currently being studied in a phase 1/2 clinical trial for patients previously treated with EGFR-mutant NSCLC (NCT01526928).
AP26113 is another novel TKI with potent activity against both mutated EGFR and EGFR T790M without affecting wild-type EGFR. AP26113 also inhibits NSCLC tumors driven by ALK rearrangements (described below). Preliminary results from a phase 1/2 study of AP26113 demonstrated it to be well tolerated with favorable antitumor activity.47 The ongoing phase 2 study is enrolling 4 cohorts: patients with NSCLC and acquired resistance to EGFR-TKIs, patients with ALK-rearranged NSCLC who are either treatment naive or have developed acquired resistance to ALK-targeted therapy, and patients with other cancers with ALK-rearrangements (NCT01449461).
Cetuximab and Afatinib
Studies evaluating the EGFR-directed monoclonal antibody cetuximab have shown mixed results in NSCLC – meager improvements in OS when combined with first-line chemotherapy (11.3 months vs 10.1 months; HR 0.871; P=.044), and RRs of only 5% when used as a single agent.48-50 In addition, the combination of erlotinib and cetuximab failed to lead to significant radiographic responses in patients with acquired resistance.51 However, preclinical mouse models of lung adenocarcinoma harboring T790M mutations have shown surprisingly potent synergy when combining cetuximab with the irreversible EGFR inhibitor afatinib.52 Early results of a phase 1b multicenter international trial testing this combination presented in 2011 showed a 31% confirmed partial response (PR) rate and 94% clinical benefit rate in patients with T790M-mutated NSCLC who had clinically defined acquired resistance to first-generation TKIs.53 Because of these promising results, enrollment was expanded to patients in a phase 2 study, which has recently closed to accrual (NCT01090011).
Direct targeting of MET is another possible therapeutic approach for overcoming resistance to
EGFR-TKIs. Preclinical data suggest that inhibition of MET signaling in cell lines with EGFR resistance and MET amplification may restore sensitivity to EGFR inhibitors.37 Tivantinib (ARQ 197) and MetMAb have been combined with erlotinib and studied in large numbers of unselected patients. These data suggest that such a combination can be safely given, but there have been no tests of MET inhibitors with or without erlotinib in acquired resistance to EGFR-TKIs.54,55
There is extensive preclinical rationale for the use of HSP90 inhibitors in acquired resistance to EGFR-TKIs. HSP90 chaperone proteins stabilize many oncoproteins important in NSCLC, including EGFR and MET, and when lung cancer cell lines are treated with HSP90 inhibitors, mutated EGFR can be effectively degraded.56 Mouse models harboring EGFR L858R and T790M mutations also undergo tumor regression when treated with HSP90 inhibitors.52
Two HSP90 inhibitors (IPI-504 and STA-9090) have been evaluated in phase 2 trials that included patients with EGFR mutations previously treated with erlotinib. In both of these studies, response rates were low among patients with EGFR mutations, although patients whose tumors were EGFR wild-type had impressive tumor shrinkage and were found retrospectively to harbor ALK rearrangements (described in more detail below).57,58
However, 2 additional studies investigating a third HSP90 inhibitor, AUY922, have recently been presented with more promising results for patients with EGFR mutations. Garon and colleagues reported the results of a single-agent phase 2 study evaluating AUY922 in previously treated patients with advanced NSCLC stratified by mutation subtype. Of 33 patients with EGFR mutations, 6 sustained a PR (18%).59 We reported the preliminary results of a phase 1 trial designed specifically for patients with acquired resistance to EGFR-TKIs in which patients were treated with the combination of AUY922 and erlotinib (to avoid disease flare associated with discontinuation of erlotinib in patients who develop acquired resistance).60 This drug combination was well tolerated, and 1 patient treated at the highest dose level achieved a PR. A phase 2 study evaluating the efficacy of erlotinib and AUY922 is ongoing.
ALK and Crizotinib
Gene rearrangements involving ALK, most often with the echinoderm microtubule-associated protein-like 4, are found in 3% to 5% of patients with NSCLC. In these fusion genes, ALK is constitutively activated and drives tumor development through upregulation of cell survival pathways including PI3K-AKT and MEK-ERK (Figure).61,62 Patients harboring ALK rearrangements in their lung cancer tumors tend to be younger, never or light smokers with adenocarcinoma histology.63
ALK is the second molecular target to be validated in NSCLC64 and is targeted with crizotinib, a TKI with RRs of approximately 60% and a disease control rate of 80% in ALK-positive tumors.31,63 Based on phase 1 and 2 studies, the FDA granted crizotinib accelerated approval for the treatment of patients with NSCLC and ALK rearrangements in August 2011. Although most patients with ALK rearranged lung cancers will initially respond to crizotinib, a few cases of primary resistance have also been reported.65 Nevertheless, all patients develop acquired resistance at a median of 9 months,31 similar to EGFR-mutant lung cancer.26
Acquired Resistance to Crizotinib
Several groups have reported molecular analysis of posttreatment tumors obtained from patients after development of acquired resistance to crizotinib,65-68 revealing multiple mechanisms of resistance including secondary mutations in ALK, increased ALK copy number gain, upregulation of parallel signaling pathways including EGFR and KIT, and acquisition of secondary oncogene mutations.
Choi and colleagues66 identified an acquired L1196M point mutation within ALK, analogous to gatekeeper mutations described in EGFR and BCR-ABL (Table). In addition to the L1196M point mutation, a second mutation, C1156Y, was also identified in the same patient’s sample. In the 2 largest series of postbiopsy specimen obtained from patients treated with crizotinib, additional mutations in the ALK kinase were reported. Katayama and colleagues observed 3 missense mutations (L1196M, G1202R, and S1206Y) and 1 insertion mutation (1151Tins) in 4 of 18 patients with acquired resistance to crizotinib; all of these were associated with crizotinib resistance in vivo.68 Doebele and colleagues identified 2 L1196M and 2 G1269A point mutations in 4 of 11 patients.65 All secondary mutations in ALK reported in these 2 series were noted to be located within or near the binding pocket for ATP and crizotinib. In contrast to the T790M gatekeeper mutation, which accounts for the vast majority of secondary resistance mutations in EGFR, the varied secondary mutations reported in ALK all occur at a relatively low prevalence (22%-36%).
ALK Copy Number Gain
ALK copy number gain, defined as a more than 2-fold increase in the mean of the rearranged gene per cell, has been identified as a mechanism of acquired resistance to crizotinib. Two of 11 patients in the series reported by Doebele et al exhibited a marked increase in both the number of the ALK rearrangements per cell as well as the number of cells with EML4-ALK rearrangements. One patient demonstrated ALK copy number gain in addition to an ALK mutation, while the second patient had only ALK copy number gain, suggesting that ALK copy number gain may be the primary event in developing resistance, followed by the accumulation of mutations within the ALK kinase.65
Analogous to the development of MET amplification in EGFR-resistant tumors, parallel signaling pathways that activate effectors downstream of ALK in the presence of crizotinib can also lead to the development of acquired resistance in ALK-positive patients.32 Upregulation of EGFR and KIT signaling have been identified as 2 potential bypass track signaling pathways.67,68 Using a cell line created from a patient with acquired resistance to crizotinib due to an acquired L1152R point mutation, tumor cells were found to secrete the EGFR ligand amphiregulin, indicating that dependence on EGFR signaling had developed in the setting of resistance to crizotinib.67 When comparing matched samples pretreatment and posttreatment with crizotinib, Katayama et al reported that increased EGFR expression measured by immunohistochemical staining was observed in 4 of 9 patients with ALK rearrangements, although no activating EGFR mutations were found.68 One of these patients had a secondary mutation in ALK in addition to increased EGFR activation. In the same study, marked KIT amplification by fluorescence in situ hybridization was measured in another patient’s tumor, suggesting a second avenue by which bypass signaling might develop. Finally, 1 additional patient was found to have both focal KIT amplification and a secondary ALK mutation, illustrating once again that multiple mechanisms of resistance may be encountered in a single patient’s tumor specimen.68
Methods for Overcoming Crizotinib Resistance
Several second-generation ALK inhibitors are currently in clinical development for use in patients with acquired resistance to crizotinib, including CH5424802 (Chugai Pharmaceutical), LDK378 (Novartis), and AP26113 (ARIAD). Preliminary results from the phase 1 study of CH5424802 in ALK-positive NSCLC patients who were ALK inhibitor naive were recently reported.69 Although the phase 1 portion did not identify a maximum tolerated dose (MTD), at dose levels of 240 mg twice daily or higher, all 15 patients (100%) with measurable disease had a PR to treatment. The phase 2 study will enroll patients who are crizotinib resistant and ALK inhibitor naive to separate arms (NCT01588028).
Interim results from the phase 1 trial of LDK378 in patients with ALK-positive NSCLC and prior exposure to crizotinib have also been reported.70 The MTD was determined to be 750 mg orally daily. In patients who received doses greater than 400 mg daily, 21 of 26 (81%) had PRs to treatment, and responses within the central nervous system were reported in patients treated with 750 mg daily. The phase 2 portion of this study will enroll several cohorts, including patients who are crizotinib naive, patients with acquired resistance to crizotinib, and patients with other ALK-positive solid tumors (NCT01283516).
Preliminary results from a phase 1/2 clinical trial of AP26113, a dual inhibitor with activity in ALK-positive patients with acquired resistance to crizotinib as well as patients with resistance to EGFR-TKIs, were also recently reported. Of 11 patients with ALK rearrangements, 8 achieved a PR to treatment with AP26113, including 6 with acquired resistance to prior crizotinib.47 As described above, expansion of the phase 2 portion into 4 distinct molecular cohorts is ongoing (NCT01449461).
In addition to ALK inhibitors, HSP90 inhibitors are another drug class to show preferential activity in patients with ALK-rearranged NSCLC. Relevant HSP90 client proteins including KIT, EGFR, BRAF, AKT, and MET are key effectors of signaling pathways that may be upregulated in acquired resistance to crizotinib.71,72 A phase 2 trial investigating HSP90 inhibitor IPI-504 in patients with previously treated advanced NSCLC showed that the patients with the highest responses rates and longest PFS outcomes harbored ALK rearrangements in their tumors.57 Subsequent preclinical studies verified HSP90 inhibitors to be effective against ALK-positive NSCLC cell lines and mouse models, and perhaps more potent inhibitors against ALK-positive NSCLC than EGFR-mutant lung cancers.73 In another phase 2 trial evaluating HSP90 inhibitor STA-9090 in advanced NSCLC, responses were seen in 7 of 8 ALK-positive patients, with confirmed objective responses in 4 of 8 ALK-positive patients.58 HSP90 inhibitors have been shown effective in several models of crizotinib-mediated acquired resistance, and the combination of crizotinib and HSP90 inhibitors has synergistic antitumor activity in vitro.62,67,68 A trial of crizotinib and STA-9090 in the first-line setting is ongoing (NCT01579994).
While the discovery of oncogenes such as EGFR and ALK has allowed important therapeutic advances for patients with lung adenocarcinoma, it has also catalyzed the development of tumor-mediated treatment resistance. Reversing acquired resistance, or preventing its development, has become the focus of research efforts, first to identify the variable mechanisms by which TKI resistance begins, and subsequently to identify novel small-molecule inhibitors capable of circumventing this phenomenon. Combination therapies, for example those that block both oncogene and bypass track signaling pathways, may prove to be effective for treating acquired resistance in NSCLC.
Dr Johnson: research funding (Novartis); consultant (Genentech); spouse contracted employee as Governmental Affairs lobbyist (Astellas). Dr Gentzler: no disclosures. Dr Yu: no disclosures. Dr Riely: research funding (Pfizer, Chugai 2012); consultant (Novartis, Daiichi Sankyo, Tragara, Chugai 2011, ARIAD, Celgene, Foundation Medicine, Abbott Molecular).
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