Review
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Emerging paradigms in targeted treatments for Asian patients with NSCLC 1.
Introduction
2.
EGFR
3.
ALK and ROS1
4.
Overcoming AR
5.
Adjuvant and neoadjuvant therapy
6.
Conclusions
7.
Expert opinion
E-E Ke, Qing Zhou & Yi-Long Wu† †
Guangdong Lung Cancer Institute, Guangdong General Hospital and Guangdong Academy of Medical Sciences, Guangdong, PR China
Introduction: EGFR-targeted drugs have been successfully approved in many countries and have demonstrated higher efficacy and lower toxicity than chemotherapy in molecularly defined subgroups of patients. Significant advances in clinical trials and studies focusing on targeted therapies have rapidly developed in Asia. Areas covered: In the present review article, all of the published data or meeting abstracts on completed or ongoing trials of targeted treatment for Asian patients with NSCLC were collected and analyzed. Expert opinion: Routine molecular testing has been used clinically to identify mutations/fusions and guide patient selection for targeted therapies. Based on the evidence presented, we provided up-to-date treatment recommendations for Asian patients with advanced NSCLC. Future directions, including dividing Del19 and L858R patients into two distinct populations, will optimize therapeutic strategies for L858R patients and may inform rational trial design by considering the proportion of type of sensitive EGFR mutation as a stratification factor. Another important aspect to consider involves how to monitor resistance to TKIs, which will improve the outcome for lung cancer patients with driver gene mutations. Keywords: Asian population, clinical trials, NSCLC, targeted therapy Expert Opin. Pharmacother. (2015) 16(8):1167-1176
1.
Introduction
Lung cancer is the leading cause of cancer-related mortality, both worldwide and in Asia [1]. NSCLC comprises > 80% of all lung tumors. Approximately 70 -- 80% of NSCLC patients present with locally advanced or metastatic disease, with a median survival of < 12 months with cytotoxic chemotherapy [2]. Improvements were made at a modest pace until the development of targeted therapies, which include the discovery of oncogenic drivers, therapies specific for these drivers, and new strategies to improve response or overcome acquired resistance (AR). This evolving division of NSCLC into distinct subtypes with actionable driver oncogenes has spurred the development of small-molecule tyrosine kinase inhibitors (TKIs) that are currently either clinically available or are in clinical trials for treating advanced NSCLC. Selective kinase inhibitors, such as gefitinib, erlotinib, and afatinib, which target the TK domain of the EGFR, and crizotinib, which targets anaplastic lymphoma kinase (ALK), have been approved in many countries, and demonstrate higher efficacy and lower toxicity for particular cancers than conventional chemotherapy in molecularly defined subgroups of patients [3]. During the past decade, there have been significant advances in clinical trials and studies on targeted therapies for lung cancer in Asia, which have globally changed the clinical practice guidelines for the treatment of this disease.
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combined modality therapies give a fresh impetus to the campaign to better manage this disease.
Article highlights. . .
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. .
Routine molecular testing has been recommended to guide patient selection for targeted therapies. The superiority in OS reported in EGFR Del19 patients strongly suggests that the two most common mutations (Del19 and L858R) might represent two distinct subclasses of non-small cell lung cancer. To extend the duration of EGFR-TKI therapy outcomes, the optimal therapy for EGFR mutation-positive NSCLC patients may involve a combination of multiple drugs. There is growing evidence that standard chemotherapy is significantly superior to EGFR-TKIs in treating patients with EGFR wild-type NSCLC. Next-generation TKIs are emerging with promising clinical activity while overcoming acquired resistance. Encouraging evidence may be provided in the application of EGFR-TKIs in adjuvant and neoadjuvant settings in the near future.
This box summarizes key points contained in the article.
The objectives of the present review were to summarize recent promising data on targeted therapies approved for the treatment of NSCLC, with an emphasis on targeted drugs currently used in the clinic of Asia, from Phase III development onwards. 2.
EGFR
Eight large randomized controlled trials clearly established first-generation/second-generation EGFR-TKIs as the preferred first-line therapy for advanced NSCLC patients with tumors harboring EGFR mutations [4-11]. When first-line treatment fails, several trials have shown that both gefitinib and erlotinib produce similar survival outcomes as standard second-line chemotherapy irrespective of any clinical or biological characteristics [12,13], resulting in a recommendation for EGFR-TKIs monotherapy in this setting. Icotinib, the single target EGFR-TKI approved in China for the clinical treatment of advanced NSCLC after the pivotal Phase III ICOGEN study, was comparable to gefitinib in terms of progression-free survival (PFS) when used as a second-line or third-line therapy [14]. In sequential subgroup analyses, patients with EGFR mutations seemed to have longer overall survival (OS) than patients with wild-type EGFR when receiving second-line EGFR-TKI treatments. Genetic testing prior to treatment is now considered essential to allow the best treatment option to be selected. According to current data, ~ 50% of Asian patients with advanced NSCLC of adenocarcinoma histology had tumors that harbored EGFR mutations, with the frequency less comparable in a broad white population (~ 20%) [15-17]. EGFR mutation-positive lung cancers are now recognized as a distinguished disease entity that is dissimilar to EGFR wild-type lung cancer or lung cancer defined by another oncogenic driver. Stratification analysis of EGFR mutation and potential 1168
Stratification analysis of EGFR mutations Previous findings from individual studies comparing first-line EGFR-TKIs with standard chemotherapies have suggested that patients with EGFR mutant tumors have improved responses, PFS, and quality of life, although no improvements in OS have been reported. A combined analysis of the LUX-Lung 3 and LUX-Lung 6 trials demonstrated that first-line afatinib (a second-generation EGFR-TKI) improved OS in patients harboring EGFR 19 deletions, which is a key advancement for NSCLC treatments [18]. Mutation-based stratification analysis indicated an OS benefit of 11 months individually in a subgroup of NSCLC patients with the EGFR Del19 mutation, but no significant difference was observed in the OS of patients with the L858R mutation. For patients with L858R mutations, first-line afatinib even had an inferior role in number (22.1 vs 26.9 months, hazard ratio [HR]: 1.25, p = 0.16) [15]. As interpreted by the investigators themselves, the clinically meaningful difference in median OS observed with afatinib compared to chemotherapy in patients with EGFR Del19-positive tumors could be attributed to a mechanistic difference between the irreversible ErbB family blocker afatinib and first-generation reversible EGFR TKIs. This was the first indication that patients harboring Del19 and L858R mutations might be two distinct populations and should be studied separately in the future. The stratification analysis of EGFR mutations is expected in dacomitinib trials, which is another second-generation EGFR-TKI, similar to afatinib. Here, we summarize the clinical outcomes of first-line EGFR-TKIs in Del19 and L858R patients in seven Phase III randomized controlled trials (Table 1). Although a head-tohead comparison was not performed, patients with the EGFR Del19 mutation appeared to have a superior benefit than those with the L858R mutation. In addition, a newly published meta-analysis of these trials revealed that patients with Del19 had superior PFS after receiving first-line EGFR-TKIs compared to those with the L858R mutation [19]. The superior benefits showed similar trends among different generation EGFR-TKIs (gefitinib, erlotinib and afatinib) that approached statistical significance, suggesting that the discrepancy between EGFR Del19 and L858R may also exist in patients receiving first-generation EGFR-TKIs. 2.1
Optimal arrangement of EGFR-TKIs in clinical trials
2.2
To extend the duration of EGFR-TKI therapy for those patients, several potential combined modality therapies have been studied in Asian countries. For example, the FASTACT-2 (First-line Asian Sequential Tarceva And Chemotherapy Trial) study, a randomized double-blind trial comparing chemotherapy (gemcitabine plus cisplatin/carboplatin)
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Emerging paradigms in targeted treatments for Asian patients with NSCLC
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Table 1. Stratification analysis of EGFR mutation in six phase III RCTs comparing first-line EGFR-TKIs with standard chemotherapy. Trials (year)
Race
EGFRTKIs
IPASS [4] (2009) NEJ002 [6] (2010) WJTOG3405 [7] (2010) OPTIMAL [8] (2011) EURTAC [9] (2012) LUX-Lung 3 [10] (2013)
East Asian East Asian East Asian East Asian Caucasian
Gefitinib Del19 L858R Gefitinib Del19 L858R Gefitinib Del19 L858R Erlotinib Del19 L858R Erlotinib Del19 L858R Afatinib Del19 L858R
LUX-Lung 6 [11] (2014)
EGFR Sample size mutation (TKI/chemo)
East Asian, Caucasian East Afatinib Del19 Asian L858R
Median PFS HR* for PFS (months) (95% CI) (0.26 (0.35 (0.23 (0.20 (0.27 (0.29 (0.07 (0.14 (0.18 (0.29 (0.18 (0.46
-------------
Median OS (months) 0.56) 0.87) 0.52) 0.50) 0.77) 0.90) 0.25) 0.49) 0.50) 1.02) 0.44) 1.17)
27.2 18.7 NA NA 35.5 32.2 27.0 21.5 30.4 17.7 33.3 27.6
HR* for OS (95% CI)
vs 20.6 0.79 vs 24.6 1.43 0.78 0.96 NA NA vs 31.5 1.52 vs 18.3 0.92 0.94 0.99 vs 21.1 0.54 vs 40.3 1.30
(0.54 (0.90 (0.47 (0.54
-----
1.14) 2.30) 1.30) 1.70)
(0.91 (0.55 (0.58 (0.56 (0.36 (0.80
-------
2.52) 1.54) 1.54) 1.75) 0.79) 2.11)
140 (66/74) 111 (64/47) 117 (58/59) 97 (49/48) 87 (50/37) 85 (36/49) 82 (43/39) 72 (39/33) 115 (57/58) 58 (29/29) 170 (113/57) 138 (92/46)
11.0 9.2 11.5 10.8 9.1 9.7 NA NA 11.0 vs 4.6 8.4 vs 6.0 13.7 11.0
0.38 0.55 0.35 0.32 0.45 0.51 0.13 0.26 0.30 0.55 0.28 0.73
186 (124/62) 138 (92/46)
13.7 9.6
0.20 (0.13 -- 0.33) 31.4 vs 18.4 0.64 (0.44 -- 0.94) 0.32 (0.19 -- 0.52) 19.6 vs 24.3 1.22 (0.81 -- 1.83)
* EGFR-TKI vs chemotherapy. HR: Hazard ratio; NA: Not available; OS: Overall survival; PFS: Progression-free survival.
to the intercalated combination of chemotherapy and erlotinib in untreated patients with advanced NSCLC, met its primary endpoint of PFS (median PFS, 7.6 vs 6.0 months, HR: 0.57; p < 0.0001) [20]. A treatment benefit was seen in patients with an activating EGFR mutation (median PFS, 16.8 vs 6.9 months; p < 0.0001; median OS, 31.4 vs 20.6 months; p = 0.0092), whereas no significant difference in PFS and OS was noted in patients with wild-type EGFR. The results revealed that the intercalated combination of chemotherapy and an EGFR-TKI could be a reasonable first-line option for EGFR mutation-positive patients with NSCLC or for patients with an unknown mutation status in whom clinical parameters such as female and non-smokers are suggestive of a high incidence of EGFR mutations. Strong preclinical evidence points to important cross communication between activated EGFR pathways and angiogenesis in tumors. Therefore, the simultaneous inhibition of VEGF/EGFR pathways is logical and may lead to synergistic anti-tumor activity [21]. A small single-arm, Phase II study investigating the efficacy and safety of gefitinib when combined with bevacizumab as a first-line treatment in patients with advanced NSCLC harboring EGFR mutations was conducted in Japan [22]. Forty-two patients with PS 0 to 2 were enrolled and received 250 mg gefitinib daily and 15 mg/kg bevacizumab every 3 weeks). The 1-year PFS rate was 56.7%, which did not meet the primary endpoint. The median PFS was 14.4 months with a significant difference between patients with Del19 and L858R mutations (18.0 vs 9.4 months; p = 0.006). The objective response rate (ORR) and disease control rate (DCR) were 73.8% and 97.6%, respectively. Another trial in Japan (JO25567), which was presented at the 2014 ASCO annual meeting, was the first prospective randomized trial to investigate erlotinib plus
bevacizumab as a first-line treatment in patients with EGFR mutation-positive non-squamous NSCLC [23]. The addition of bevacizumab demonstrated the significant prolongation of median PFS to 16.0 months compared to 9.7 months with erlotinib alone. The HR was 0.54 (95% CI: 0.36 -- 0.79; p = 0.0015), the ORR was 69%, and the DCR was 99% in the combination arm. No new safety signals were identified. The addition of bevacizumab did not significantly impact the quality of life. EGFR-TKIs in combination with bevacizumab as a first-line therapy seemed to be a favorable and well-tolerated for selected EGFR mutation-positive patients, especially those with exon 19 deletions. However, these results are from Phase II studies in a small group of individuals from one country. Treating patients with EGFR wild-type NSCLC Based on promising data from the BR.21 study, in which erlotinib significantly prolonged OS (6.7 vs 4.7 months) in NSCLC patients compared to placebo [24], erlotinib was recommended as a second-line or third-line treatment for advanced NSCLC [25,26]. However, a subsequent biomarker analysis in BR.21 showed that erlotinib provided no significant benefit compared to placebo in EGFR wild-type patients [27]. To date, two clinical trials, the DELTA (Docetaxel and Erlotinib Lung Cancer Trial) study from Japan, and the Chinese Thoracic Oncology Group (CTONG) 0806 study from China, have demonstrated that EGFRTKIs are inferior to chemotherapy in the second-line setting in EGFR wild-type NSCLC [28,29]. The DELTA study was conducted to compare the efficacies of erlotinib with docetaxel in patients who had previously been treated with chemotherapy. The primary analyses revealed that patients with EGFR wild-type tumors achieved 2.3
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significantly longer PFS in the docetaxel arm than in the erlotinib arm (median PFS, 2.9 vs 1.3 months; p = 0.013), although the difference did not translate into OS (median OS, 9.0 months vs 9.2 months; p = 0.914) [28]. The CTONG0806 compared pemetrexed with gefitinib as second-line treatment for non-squamous NSCLC patients with wild-type EGFR. The PFS was 1.7 months versus 5.6 months (HR, 0.53; p < 0.001), the ORR was 12.3% versus 14.5% (p = 0.695), and the DCR was 30.8% versus 61.9% (p < 0.001) for the gefitinib and pemetrexed arms, respectively [29]. In that study, 108 patients with sufficient DNA samples were tested for EGFR mutations using the Scorpion amplification refractory mutation system (ARMS). Results showed that pemetrexed was superior to gefitinib in EGFR wild-type patients as confirmed by ARMS (HR for PFS 0.44; p = 0.001). Thus, patients who test negative for EGFR mutations by sequencing, but test positive by ARMS could benefit from EGFR-TKI treatment. It should be noted, however, that in the BEYOND trial, bevacizumab proved efficacious in extending PFS when added to platinum-doublet chemotherapy as a first-line treatment for advanced non-squamous NSCLC, regardless of EGFR mutation status [30]. The median PFS was 9.2 months with the carboplatin/paclitaxel plus bevacizumab treatment compared to 6.5 months in the placebo arms (HR, 0.40; p < 0.0001). Biomarker analyses showed that VEGF-A and VEGFR-2 biomarkers had no correlation with bevacizumab treatment efficacy, and EGFR mutation-positive status appeared to be prognostic for outcome, but not predictive of bevacizumab efficacy. HR was 0.27 in mutation-bearing patients and 0.33 in the wild-type group. These results indicate that EGFR wild-type patients benefited from the combination of bevacizumab and platinum-based chemotherapy. Based on these data, new issues on treatment of EGFR mutant cases need to be reconsidered in clinical practice. For patients with Del19, EGFR-TKIs, especially afatinib, should be the choice for first-line treatment. For patients with L858R mutations, first-line EGFR-TKIs are considered as optional. For unselected or EGFR wild-type cases in a second-line setting, the efficacy of EGFR-TKIs seems to contribute to EGFR mutants or false-negative patients tested for EGFR mutations. EGFR-TKIs might not work on EGFR wild-type patients at any point in treatment. ARMS should become the new standard technique method for the identification of EGFR mutations. 3.
ALK and ROS1
Fusions of ALK with an upstream gene, echinoderm microtubule-associated protein-like 4 (EML4), were identified in NSCLC patients in 2007 [31]. This genetic rearrangement accounts for 4 -- 11.6% of unselected Asian patients with early-stage NSCLC, occurring predominantly in younger individuals with adenocarcinoma who never smoked or light smokers [32-35]. Crizotinib is an oral small-molecule 1170
tyrosine kinase inhibitor of ALK, ROS1, and another tyrosine kinase MET. It has been most widely applied for the treatment of NSCLC with ALK gene rearrangements after marked activity was noted in this patient population in the Phase I trial [36]. In August 2011, only 4 years after the discovery of ALK gene rearrangements in NSCLC, the FDA granted accelerated approval to crizotinib for patients with ALK-positive NSCLC. The PROFILE 1007 Phase III trial was the first trial that clearly demonstrated crizotinib superiority over standard second-line chemotherapy in ALK-positive NSCLC patients [37]. Patients in the crizotinib arm had a 51% relative reduction in the risk of progression compared to those receiving standard chemotherapy (7.7 vs 3.0 months, HR: 0.49; p < 0.001), higher RR (65 vs 20%; p < 0.001), and a better toxicity profile. Of the 347 randomized patients, 45% were of Asian ethnicity (crizotinib, n = 79, chemotherapy, n = 78). Consistent with the results in the overall study population, crizotinib treatment resulted in a significantly greater improvement in PFS, ORR, and patient-reported outcome compared to chemotherapy in a sub-analysis of Asian patients, confirming the utility of crizotinib in this population [38]. The efficacy of crizotinib as a first-line treatment for advanced ALK-positive NSCLC was demonstrated in the PROFILE 1014 trial [39]. First-line crizotinib treatment showed significant improvements in PFS (10.9 vs 7.0 months; HR: 0.454; p < 0.0001) and ORR (74 vs 45%; p < 0.0001) compared to pemetrexed/platinum chemotherapy while maintaining an acceptable safety profile. ROS1 rearrangement defines a second molecular subgroup of NSCLC for which crizotinib is highly active. ROS1 fusion partners include CD74, SLC34A2, and SDC4, all of which lead to oncogenic transformation in vitro and/or in vivo. It occurs in ~ 1% of patients with NSCLC [40]. Recently, Shaw et al. [41] reported the results of a Phase I study that enrolled 50 ROS1-positive NSCLC patients exposed to crizotinib. The ORR was 72%, with 3 complete responses and 33 partial responses. The median duration of response was 17.6 months and the median PFS was 19.2 months. A Phase II ROS1 trial focusing on the Asian population is presently ongoing. 4.
Overcoming AR
Although TKIs have reshaped treatment approaches in oncogene-driven NSCLC, these therapies have been universally limited by the development of AR. Novel agents and strategies were explored for overcoming TKI resistance. Considering a biopsy at the time of progression after the initial EGFR-TKI treatment is an emerging standard for EGFR mutants. Both EGFR-mutant and ALK-rearranged lung cancers highlight common principles of resistance, such as the development of secondary mutations in the target kinase, target gene amplification, and activation of bypass tracts (Figure 1) [42,43]. Rebiopsy during disease progression in patients treated by TKI provides insight into different
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Emerging paradigms in targeted treatments for Asian patients with NSCLC
A. Mechanisms of EGFR-TKI resistance
T790M mutation (50%) EGFR amplification (8%) Bypass signaling tracts (20%) Phenotypic alterations (3–14%) Unknown (~15%)
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B. Mechanisms of ALK TKI resistance
ALK secondary mutations (~35%) ALK gene amplification (~15%) Bypass signaling tracts (~30%) Unknown (~20%)
Figure 1. Major mechanisms of EGFR-TKI/ALK TKI acquired resistance.
resistance mechanisms, with potential consequences for therapeutic decision-making. TKI Continuation beyond progression The diversity of EGFR-TKI failure was retrospectively categorized into three modes according to specific criteria derived from clinical factors: dramatic progression, gradual progression, and local progression [44]. Further analysis showed that continuous EGFR-TKI treatment had better results than switching to chemotherapy in the gradual progression cohort, whereas patients in the dramatic progression group demonstrated better OS with switching to chemotherapeutic regimens. The IMPRESS study was the first and only randomized Phase III study to confirm that continuation of EGFRTKIs in addition to chemotherapy would be of no clinical benefit for patients with AR to gefitinib [45]. There was no statistically significant improvement in PFS with continuation of gefitinib (HR 0.86; p = 0.273; median PFS, 5.4 months each), and OS increased even in the placebo arm (HR 1.62; p = 0.029, median OS, 14.8 vs 17.2 months). No treatment differences were found in ORR/DCR in the two groups. The study failed to achieve its primary objective, but nevertheless the results appear to impact clinical practice. 4.1
Next-generation TKIs Initial strategies to combat AR have centered on using nextgeneration TKIs. Preclinical research data have indicated that the second-generation EGFR-TKIs such as afatinib and dacomitinib had a high level of activity against T790M in vitro [46]. There was great hope that second-generation 4.2
EGFR-TKIs would be highly effective for patients with AR when they were developed. Nevertheless, clinical trials of these drugs have been rather disappointing in patients with AR, probably as a result of dose limitations from toxicity caused by inhibiting wild-type EGFR simultaneously [47,48]. Recently, third-generation EGFR inhibitors such as AZD9291, CO-1686, and HM61713, which may be more effective for patients with T790M, have been recommended. The results of clinical studies of third-generation EGFRTKIs have been reported and appear to be promising in patients who have previously progressed on approved EGFRTKI therapies [49-51]. The efficacy was greater in patients with T790M+ (ORR, 29--65%) than in patients with T790M(ORR, 12--22%) EFGR-TKI-resistant NSCLC. Additional studies will identify the relative benefits of these three agents, as well as their role in the initial treatment of EGFR mutation-positive patients where they are likely to gain a prominent role. Similarly, next-generation TKIs are also being investigated in ALK-positive patients. Two of these next-generation ALK inhibitors, ceritinib and alectinib, were associated with high ORRs in the Phase I trials of ALK-positive patients with crizotinib resistance (Table 2) [52,53]. In contrast to third-generation EGFR-TKIs displaying efficacy in certain T790M mutant populations, ceritinib was active in the majority of patients with ALK-rearranged NSCLC who had previously received crizotinib. Confirmed responses were seen in 6 of 7 patients with ALK gene amplification or mutation, and in 7 of 12 patients without ALK change, suggesting that the activity of ceritinib in patients whose tumors had progressed during crizotinib treatment may be independent of the underlying mechanism of AR. Moreover, both agents also demonstrated activity against brain metastases. This raises the possibility that next-generation ALK inhibitors may control disease in the central nervous system, which is among the most common sites of relapse among patients undergoing treatment with crizotinib. As resistance to TKIs is inevitable, it is important issue to understand when and how resistance is developed. A second biopsy is essential for monitoring and discovering resistance, but may not always be possible. If sensitivity and specificity are resolved, serial liquid biopsies could play an important role due to its non-invasive nature and convenience. 5.
Adjuvant and neoadjuvant therapy
The first randomized adjuvant trial with an EGFR-targeted agent, BR.19 [54], was closed prematurely with only 503 patients of a planned total of 1,242, secondary to negative Phase III results with gefitinib in the advanced setting, with a median follow-up of 4.7 years and a median of < 5 months of treatment. The results are thus inconclusive, but failed to show any benefıt with this approach, even in the small number of patients whose tumors harbored an EGFR-activating mutation. Results from the randomized RADIANT trial [55]
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Table 2. Clinical activity of crizotinib and next-generation ALK inhibitors.
Crizotinib-naive population ORR (95% CI) PFS (95% CI, m) Crizotinib-resistant population ORR(95% CI) PFS (95% CI, m)
Crizotinib [39]
Ceritinib [52]
Alectinib [53]
74% (67 -- 81%) 10.9 (8.3 -- 13.9)
62% (21/34, 44 -- 78%) 10.4 (4.6 -- )
-
-
56% (45/80, 47 -- 67%) 6.9 (5.3 -- 8.8)
55% (24/44) -
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m: Months; ORR: Objective response rate; PFS: Progression-free survival.
of adjuvant erlotinib in patients with tumors with EGFR expression, as determined by immunohistochemistry or FISH, came to light at the ASCO 2014 meeting. Unfortunately, in this trial, adjuvant erlotinib did not prolong DFS in patients with early-stage resected EGFR expressing NSCLC. Exploratory analyses conducted to examine the prognosis of EGFR mutations in NSCLC showed that no significant prognostic effect with EGFR mutation status was observed, but conclusions are limited because of the small sample size, and EGFR mutation status may be associated with a higher disease stage and other variables. Despite the negative results in the BR.19 and RADIANT studies, there is enthusiasm to re-evaluate the role of EGFR-TKIs in the adjuvant and neoadjuvant settings in a selected patient population that is sensitive to this treatment. Several studies were initiated in Asia, focusing on certain populations harboring EGFR-activating mutations and staging II-IIIA with lymph node metastasis at a high risk for recurrence. Patients recruited for the CTONG1104 trial (NCT01405079, www.clinicaltrials.gov) were randomized to receive gefitinib for 24 months or vinorelbine plus platinum for four cycles after surgery. The recruiting process is complete, and the results will be available soon. A similar trial in Japan (WJOG6401L) is presently ongoing. Pool analysis of both CTONG1104 and WJOG6401L would give stronger evidence to potentially support the use of EGFR-TKIs in the adjuvant setting. CTONG1103 (NCT01407822, www.clinicaltrials.gov) is a Phase II study of a new treatment strategy for stage IIIA-N2 NSCLC patients with EGFR-activating mutations. Patients randomized to the erlotinib arm took erlotinib orally for 6 weeks in the neoadjuvant treatment phase and for 1 year or until disease progression or unacceptable toxicity in the post-surgery phase, whereas patients in the chemotherapy arm received gemcitabine/cisplatin for two cycles in each treatment phase. 6.
Conclusions
NSCLC provides an instructive conceptual framework for examining kinase-directed therapies. Decision making by now is characterized by selecting a specific therapeutic regimen based on not only the histology type but also the genotype of tumors. New approaches, including the stratification 1172
analysis of EGFR mutation and potential combined modality therapies, are likely to maximize the duration of disease control and further improve long-term outcomes. In addition, a paradigm shift in favor of chemotherapy for patients with EGFR wild-type has gained strength from recent data. AR to first-/second-generation EGFR-TKIs is a universal phenomenon that continues to be studied. Continuing EGFR-TKIs beyond progression are recommended in patients with clinical benefits; however, for patients with symptomatic progression, a platinum-based doublet is the standard treatment, and EGFR-TKIs should be terminated with no hesitation. It is important to re-biopsy patients when their tumors progress after treatment with TKIs to understand the mechanism that underlies the resistance. Third-generation EGFR-TKIs (known as T790M inhibitors) and next-generation ALK inhibitors are showing promising responses in early clinical trials. Moreover, the higher incidence of the EGFR mutation in Asian populations optimized the feasibility of prospective randomized trials comparing adjuvant EGFR-TKIs with standard chemotherapy. Encouraging evidence may be provided with regard to the application of EGFR-TKIs in adjuvant and neoadjuvant settings in the near future. 7.
Expert opinion
Currently, TKIs are the best option for use as a front-line therapy in EGFR+/ALK+ NSCLC, but they have limited efficacy for wild-type NSCLC patients. Another novel and promising targeted approach involves the use of crizotinib in patients with ROS1 rearrangement. Routine molecular testing such as DNA sequencing or fragment analysis following PCR, and evaluation of copy number and gene positioning by FISH, have been developed and used clinically to identify mutations/fusions. Developments in technology, such as whole-genomic sequencing or whole-exome sequencing, which can detect whole exons of several genes with the same amount of tissue used in single-gene tests, have resulted in breakthroughs in the care of lung cancer patients and compel the transition from one-gene-at-a-time analysis to multiplex approaches. Already, new treatments targeting genetic alterations in other, rare driver oncogenes (BRAF V660E, RET, etc.) are being evaluated in lung cancer, and testing for these may be addressed in future versions of guidelines.
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Expert Opin. Pharmacother. (2015) 16(8)
• Wild type
• Chemo D (Level 3)
• Crizotinib (Level 1)
• Chemo D (Level 3)
Chemo S (Level 2)
• Test driver genes then join trials (Level 2)
• Chemo D (Level 2)
Chemo S (Level 2)
• Chemo S (Level 3)
• Crizotinib (Level 1)
Chemo D (Level 2)
• Chemo S (Level 3)
• Crizotinib (Level 1)
• Chemo D (Level3)
Chemo S (Level 2)
Chemo S (Level 2)
Crizotinib (Level 1)
• Chemo S (Level 2)
Bev: Bevazucimab; D: Doublet; FASTACT model: Intercalated combination of chemo and an EGFR-TKI; S: Single.
Test MET then join trials (Level 2)
• Local progression: EGFR-TKI + local intervention (Level 2)
• Gradual progression: Continuation of EGFR-TKI (Level 2)
Chemo S (Level 2)
*For unselected patients, targeted therapies are limitedly recommended without the information of genetic testing
Level 3: mildly recommended
Level 2: recommended
Level 1: highly recommended
Ceritinib/Alectinib (Level 1)
• Ceritinib/Alectinib (Level 1)
• Chemo S (Level 2)
• Ceritinib/Alectinib (Level 1)
Chemo D or S (Level 2)
• Dramatic progression: Chemo D or S (Level 2)
• Chemo D or S (Level 3)
• 3rd EGFR-TKI (Level 1)
Chemo S (Level 2)
Without T790M
With T790M
Chemo D or S (Level 2)
Progression Re-biopsy
• Ceritinib/Alectinib (Level 1)
• 1st EGFR-TKI + Bev (Level 3)
• Chemo D + Bev (Level 1)
• ROS1 rearranged
• ALK rearranged
1st /2nd EGFR-TKI (Level 2)
• FASTACT model (Level 3)
• Crizotinib (Level 1)
L858R
• Chemo D
• 1st /2nd-generation EGFR-TKI (Level 1)
1st /2nd-generation EGFR-TKI (Level 1)
Figure 2. New paradigms for overall management of Asian patients with advanced NSCLC.
NSCLC*
Genetic testing
EGFR mutant
Del19
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Emerging paradigms in targeted treatments for Asian patients with NSCLC
1173
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Based on the evidence presented, we have provided these up-to-date treatment recommendations for Asian patients with advanced NSCLC (Figure 2). First-line EGFR-TKIs should be highly recommended as the standard care for either EGFR Del 19 or L858R patients, but remains some confusion for EGFR L858R patients. A re-biopsy is needed for all EGFR mutant patients acquiring resistance to first-/second-generation EGFR-TKIs to identify the presence of a secondary T790M mutation, because novel third-generation EGFRTKIs are simply recommended for patients with T790M, whereas the next-generation ALK inhibitors could be applied for the majority of crizotinib-resistant patients. Future directions including division of Del19 and L858R patients into two distinct populations will optimize therapeutic strategies for L858R patients and may inform rational trial design by Bibliography
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Declaration of interest The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.
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Affiliation
E-E Ke1,2, Qing Zhou2 & Yi-Long Wu†2 † Author for correspondence 1 Southern Medical University, Guangzhou, Guangdong 510515, PR China 2 Guangdong Lung Cancer Institute, Guangdong General Hospital and Guangdong Academy of Medical Sciences, Guangzhou, Guangdong 510080 PR China Tel: +86 20 83877855; Fax: +86 20 83827712; E-mail: [email protected]
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Emerging paradigms in targeted treatments for Asian patients with NSCLC 1.
Introduction
2.
EGFR
3.
ALK and ROS1
4.
Overcoming AR
5.
Adjuvant and neoadjuvant therapy
6.
Conclusions
7.
Expert opinion
E-E Ke, Qing Zhou & Yi-Long Wu† †
Guangdong Lung Cancer Institute, Guangdong General Hospital and Guangdong Academy of Medical Sciences, Guangdong, PR China
Introduction: EGFR-targeted drugs have been successfully approved in many countries and have demonstrated higher efficacy and lower toxicity than chemotherapy in molecularly defined subgroups of patients. Significant advances in clinical trials and studies focusing on targeted therapies have rapidly developed in Asia. Areas covered: In the present review article, all of the published data or meeting abstracts on completed or ongoing trials of targeted treatment for Asian patients with NSCLC were collected and analyzed. Expert opinion: Routine molecular testing has been used clinically to identify mutations/fusions and guide patient selection for targeted therapies. Based on the evidence presented, we provided up-to-date treatment recommendations for Asian patients with advanced NSCLC. Future directions, including dividing Del19 and L858R patients into two distinct populations, will optimize therapeutic strategies for L858R patients and may inform rational trial design by considering the proportion of type of sensitive EGFR mutation as a stratification factor. Another important aspect to consider involves how to monitor resistance to TKIs, which will improve the outcome for lung cancer patients with driver gene mutations. Keywords: Asian population, clinical trials, NSCLC, targeted therapy Expert Opin. Pharmacother. (2015) 16(8):1167-1176
1.
Introduction
Lung cancer is the leading cause of cancer-related mortality, both worldwide and in Asia [1]. NSCLC comprises > 80% of all lung tumors. Approximately 70 -- 80% of NSCLC patients present with locally advanced or metastatic disease, with a median survival of < 12 months with cytotoxic chemotherapy [2]. Improvements were made at a modest pace until the development of targeted therapies, which include the discovery of oncogenic drivers, therapies specific for these drivers, and new strategies to improve response or overcome acquired resistance (AR). This evolving division of NSCLC into distinct subtypes with actionable driver oncogenes has spurred the development of small-molecule tyrosine kinase inhibitors (TKIs) that are currently either clinically available or are in clinical trials for treating advanced NSCLC. Selective kinase inhibitors, such as gefitinib, erlotinib, and afatinib, which target the TK domain of the EGFR, and crizotinib, which targets anaplastic lymphoma kinase (ALK), have been approved in many countries, and demonstrate higher efficacy and lower toxicity for particular cancers than conventional chemotherapy in molecularly defined subgroups of patients [3]. During the past decade, there have been significant advances in clinical trials and studies on targeted therapies for lung cancer in Asia, which have globally changed the clinical practice guidelines for the treatment of this disease.
10.1517/14656566.2015.1040391 © 2015 Informa UK, Ltd. ISSN 1465-6566, e-ISSN 1744-7666 All rights reserved: reproduction in whole or in part not permitted
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combined modality therapies give a fresh impetus to the campaign to better manage this disease.
Article highlights. . .
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. .
Routine molecular testing has been recommended to guide patient selection for targeted therapies. The superiority in OS reported in EGFR Del19 patients strongly suggests that the two most common mutations (Del19 and L858R) might represent two distinct subclasses of non-small cell lung cancer. To extend the duration of EGFR-TKI therapy outcomes, the optimal therapy for EGFR mutation-positive NSCLC patients may involve a combination of multiple drugs. There is growing evidence that standard chemotherapy is significantly superior to EGFR-TKIs in treating patients with EGFR wild-type NSCLC. Next-generation TKIs are emerging with promising clinical activity while overcoming acquired resistance. Encouraging evidence may be provided in the application of EGFR-TKIs in adjuvant and neoadjuvant settings in the near future.
This box summarizes key points contained in the article.
The objectives of the present review were to summarize recent promising data on targeted therapies approved for the treatment of NSCLC, with an emphasis on targeted drugs currently used in the clinic of Asia, from Phase III development onwards. 2.
EGFR
Eight large randomized controlled trials clearly established first-generation/second-generation EGFR-TKIs as the preferred first-line therapy for advanced NSCLC patients with tumors harboring EGFR mutations [4-11]. When first-line treatment fails, several trials have shown that both gefitinib and erlotinib produce similar survival outcomes as standard second-line chemotherapy irrespective of any clinical or biological characteristics [12,13], resulting in a recommendation for EGFR-TKIs monotherapy in this setting. Icotinib, the single target EGFR-TKI approved in China for the clinical treatment of advanced NSCLC after the pivotal Phase III ICOGEN study, was comparable to gefitinib in terms of progression-free survival (PFS) when used as a second-line or third-line therapy [14]. In sequential subgroup analyses, patients with EGFR mutations seemed to have longer overall survival (OS) than patients with wild-type EGFR when receiving second-line EGFR-TKI treatments. Genetic testing prior to treatment is now considered essential to allow the best treatment option to be selected. According to current data, ~ 50% of Asian patients with advanced NSCLC of adenocarcinoma histology had tumors that harbored EGFR mutations, with the frequency less comparable in a broad white population (~ 20%) [15-17]. EGFR mutation-positive lung cancers are now recognized as a distinguished disease entity that is dissimilar to EGFR wild-type lung cancer or lung cancer defined by another oncogenic driver. Stratification analysis of EGFR mutation and potential 1168
Stratification analysis of EGFR mutations Previous findings from individual studies comparing first-line EGFR-TKIs with standard chemotherapies have suggested that patients with EGFR mutant tumors have improved responses, PFS, and quality of life, although no improvements in OS have been reported. A combined analysis of the LUX-Lung 3 and LUX-Lung 6 trials demonstrated that first-line afatinib (a second-generation EGFR-TKI) improved OS in patients harboring EGFR 19 deletions, which is a key advancement for NSCLC treatments [18]. Mutation-based stratification analysis indicated an OS benefit of 11 months individually in a subgroup of NSCLC patients with the EGFR Del19 mutation, but no significant difference was observed in the OS of patients with the L858R mutation. For patients with L858R mutations, first-line afatinib even had an inferior role in number (22.1 vs 26.9 months, hazard ratio [HR]: 1.25, p = 0.16) [15]. As interpreted by the investigators themselves, the clinically meaningful difference in median OS observed with afatinib compared to chemotherapy in patients with EGFR Del19-positive tumors could be attributed to a mechanistic difference between the irreversible ErbB family blocker afatinib and first-generation reversible EGFR TKIs. This was the first indication that patients harboring Del19 and L858R mutations might be two distinct populations and should be studied separately in the future. The stratification analysis of EGFR mutations is expected in dacomitinib trials, which is another second-generation EGFR-TKI, similar to afatinib. Here, we summarize the clinical outcomes of first-line EGFR-TKIs in Del19 and L858R patients in seven Phase III randomized controlled trials (Table 1). Although a head-tohead comparison was not performed, patients with the EGFR Del19 mutation appeared to have a superior benefit than those with the L858R mutation. In addition, a newly published meta-analysis of these trials revealed that patients with Del19 had superior PFS after receiving first-line EGFR-TKIs compared to those with the L858R mutation [19]. The superior benefits showed similar trends among different generation EGFR-TKIs (gefitinib, erlotinib and afatinib) that approached statistical significance, suggesting that the discrepancy between EGFR Del19 and L858R may also exist in patients receiving first-generation EGFR-TKIs. 2.1
Optimal arrangement of EGFR-TKIs in clinical trials
2.2
To extend the duration of EGFR-TKI therapy for those patients, several potential combined modality therapies have been studied in Asian countries. For example, the FASTACT-2 (First-line Asian Sequential Tarceva And Chemotherapy Trial) study, a randomized double-blind trial comparing chemotherapy (gemcitabine plus cisplatin/carboplatin)
Expert Opin. Pharmacother. (2015) 16(8)
Emerging paradigms in targeted treatments for Asian patients with NSCLC
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Table 1. Stratification analysis of EGFR mutation in six phase III RCTs comparing first-line EGFR-TKIs with standard chemotherapy. Trials (year)
Race
EGFRTKIs
IPASS [4] (2009) NEJ002 [6] (2010) WJTOG3405 [7] (2010) OPTIMAL [8] (2011) EURTAC [9] (2012) LUX-Lung 3 [10] (2013)
East Asian East Asian East Asian East Asian Caucasian
Gefitinib Del19 L858R Gefitinib Del19 L858R Gefitinib Del19 L858R Erlotinib Del19 L858R Erlotinib Del19 L858R Afatinib Del19 L858R
LUX-Lung 6 [11] (2014)
EGFR Sample size mutation (TKI/chemo)
East Asian, Caucasian East Afatinib Del19 Asian L858R
Median PFS HR* for PFS (months) (95% CI) (0.26 (0.35 (0.23 (0.20 (0.27 (0.29 (0.07 (0.14 (0.18 (0.29 (0.18 (0.46
-------------
Median OS (months) 0.56) 0.87) 0.52) 0.50) 0.77) 0.90) 0.25) 0.49) 0.50) 1.02) 0.44) 1.17)
27.2 18.7 NA NA 35.5 32.2 27.0 21.5 30.4 17.7 33.3 27.6
HR* for OS (95% CI)
vs 20.6 0.79 vs 24.6 1.43 0.78 0.96 NA NA vs 31.5 1.52 vs 18.3 0.92 0.94 0.99 vs 21.1 0.54 vs 40.3 1.30
(0.54 (0.90 (0.47 (0.54
-----
1.14) 2.30) 1.30) 1.70)
(0.91 (0.55 (0.58 (0.56 (0.36 (0.80
-------
2.52) 1.54) 1.54) 1.75) 0.79) 2.11)
140 (66/74) 111 (64/47) 117 (58/59) 97 (49/48) 87 (50/37) 85 (36/49) 82 (43/39) 72 (39/33) 115 (57/58) 58 (29/29) 170 (113/57) 138 (92/46)
11.0 9.2 11.5 10.8 9.1 9.7 NA NA 11.0 vs 4.6 8.4 vs 6.0 13.7 11.0
0.38 0.55 0.35 0.32 0.45 0.51 0.13 0.26 0.30 0.55 0.28 0.73
186 (124/62) 138 (92/46)
13.7 9.6
0.20 (0.13 -- 0.33) 31.4 vs 18.4 0.64 (0.44 -- 0.94) 0.32 (0.19 -- 0.52) 19.6 vs 24.3 1.22 (0.81 -- 1.83)
* EGFR-TKI vs chemotherapy. HR: Hazard ratio; NA: Not available; OS: Overall survival; PFS: Progression-free survival.
to the intercalated combination of chemotherapy and erlotinib in untreated patients with advanced NSCLC, met its primary endpoint of PFS (median PFS, 7.6 vs 6.0 months, HR: 0.57; p < 0.0001) [20]. A treatment benefit was seen in patients with an activating EGFR mutation (median PFS, 16.8 vs 6.9 months; p < 0.0001; median OS, 31.4 vs 20.6 months; p = 0.0092), whereas no significant difference in PFS and OS was noted in patients with wild-type EGFR. The results revealed that the intercalated combination of chemotherapy and an EGFR-TKI could be a reasonable first-line option for EGFR mutation-positive patients with NSCLC or for patients with an unknown mutation status in whom clinical parameters such as female and non-smokers are suggestive of a high incidence of EGFR mutations. Strong preclinical evidence points to important cross communication between activated EGFR pathways and angiogenesis in tumors. Therefore, the simultaneous inhibition of VEGF/EGFR pathways is logical and may lead to synergistic anti-tumor activity [21]. A small single-arm, Phase II study investigating the efficacy and safety of gefitinib when combined with bevacizumab as a first-line treatment in patients with advanced NSCLC harboring EGFR mutations was conducted in Japan [22]. Forty-two patients with PS 0 to 2 were enrolled and received 250 mg gefitinib daily and 15 mg/kg bevacizumab every 3 weeks). The 1-year PFS rate was 56.7%, which did not meet the primary endpoint. The median PFS was 14.4 months with a significant difference between patients with Del19 and L858R mutations (18.0 vs 9.4 months; p = 0.006). The objective response rate (ORR) and disease control rate (DCR) were 73.8% and 97.6%, respectively. Another trial in Japan (JO25567), which was presented at the 2014 ASCO annual meeting, was the first prospective randomized trial to investigate erlotinib plus
bevacizumab as a first-line treatment in patients with EGFR mutation-positive non-squamous NSCLC [23]. The addition of bevacizumab demonstrated the significant prolongation of median PFS to 16.0 months compared to 9.7 months with erlotinib alone. The HR was 0.54 (95% CI: 0.36 -- 0.79; p = 0.0015), the ORR was 69%, and the DCR was 99% in the combination arm. No new safety signals were identified. The addition of bevacizumab did not significantly impact the quality of life. EGFR-TKIs in combination with bevacizumab as a first-line therapy seemed to be a favorable and well-tolerated for selected EGFR mutation-positive patients, especially those with exon 19 deletions. However, these results are from Phase II studies in a small group of individuals from one country. Treating patients with EGFR wild-type NSCLC Based on promising data from the BR.21 study, in which erlotinib significantly prolonged OS (6.7 vs 4.7 months) in NSCLC patients compared to placebo [24], erlotinib was recommended as a second-line or third-line treatment for advanced NSCLC [25,26]. However, a subsequent biomarker analysis in BR.21 showed that erlotinib provided no significant benefit compared to placebo in EGFR wild-type patients [27]. To date, two clinical trials, the DELTA (Docetaxel and Erlotinib Lung Cancer Trial) study from Japan, and the Chinese Thoracic Oncology Group (CTONG) 0806 study from China, have demonstrated that EGFRTKIs are inferior to chemotherapy in the second-line setting in EGFR wild-type NSCLC [28,29]. The DELTA study was conducted to compare the efficacies of erlotinib with docetaxel in patients who had previously been treated with chemotherapy. The primary analyses revealed that patients with EGFR wild-type tumors achieved 2.3
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significantly longer PFS in the docetaxel arm than in the erlotinib arm (median PFS, 2.9 vs 1.3 months; p = 0.013), although the difference did not translate into OS (median OS, 9.0 months vs 9.2 months; p = 0.914) [28]. The CTONG0806 compared pemetrexed with gefitinib as second-line treatment for non-squamous NSCLC patients with wild-type EGFR. The PFS was 1.7 months versus 5.6 months (HR, 0.53; p < 0.001), the ORR was 12.3% versus 14.5% (p = 0.695), and the DCR was 30.8% versus 61.9% (p < 0.001) for the gefitinib and pemetrexed arms, respectively [29]. In that study, 108 patients with sufficient DNA samples were tested for EGFR mutations using the Scorpion amplification refractory mutation system (ARMS). Results showed that pemetrexed was superior to gefitinib in EGFR wild-type patients as confirmed by ARMS (HR for PFS 0.44; p = 0.001). Thus, patients who test negative for EGFR mutations by sequencing, but test positive by ARMS could benefit from EGFR-TKI treatment. It should be noted, however, that in the BEYOND trial, bevacizumab proved efficacious in extending PFS when added to platinum-doublet chemotherapy as a first-line treatment for advanced non-squamous NSCLC, regardless of EGFR mutation status [30]. The median PFS was 9.2 months with the carboplatin/paclitaxel plus bevacizumab treatment compared to 6.5 months in the placebo arms (HR, 0.40; p < 0.0001). Biomarker analyses showed that VEGF-A and VEGFR-2 biomarkers had no correlation with bevacizumab treatment efficacy, and EGFR mutation-positive status appeared to be prognostic for outcome, but not predictive of bevacizumab efficacy. HR was 0.27 in mutation-bearing patients and 0.33 in the wild-type group. These results indicate that EGFR wild-type patients benefited from the combination of bevacizumab and platinum-based chemotherapy. Based on these data, new issues on treatment of EGFR mutant cases need to be reconsidered in clinical practice. For patients with Del19, EGFR-TKIs, especially afatinib, should be the choice for first-line treatment. For patients with L858R mutations, first-line EGFR-TKIs are considered as optional. For unselected or EGFR wild-type cases in a second-line setting, the efficacy of EGFR-TKIs seems to contribute to EGFR mutants or false-negative patients tested for EGFR mutations. EGFR-TKIs might not work on EGFR wild-type patients at any point in treatment. ARMS should become the new standard technique method for the identification of EGFR mutations. 3.
ALK and ROS1
Fusions of ALK with an upstream gene, echinoderm microtubule-associated protein-like 4 (EML4), were identified in NSCLC patients in 2007 [31]. This genetic rearrangement accounts for 4 -- 11.6% of unselected Asian patients with early-stage NSCLC, occurring predominantly in younger individuals with adenocarcinoma who never smoked or light smokers [32-35]. Crizotinib is an oral small-molecule 1170
tyrosine kinase inhibitor of ALK, ROS1, and another tyrosine kinase MET. It has been most widely applied for the treatment of NSCLC with ALK gene rearrangements after marked activity was noted in this patient population in the Phase I trial [36]. In August 2011, only 4 years after the discovery of ALK gene rearrangements in NSCLC, the FDA granted accelerated approval to crizotinib for patients with ALK-positive NSCLC. The PROFILE 1007 Phase III trial was the first trial that clearly demonstrated crizotinib superiority over standard second-line chemotherapy in ALK-positive NSCLC patients [37]. Patients in the crizotinib arm had a 51% relative reduction in the risk of progression compared to those receiving standard chemotherapy (7.7 vs 3.0 months, HR: 0.49; p < 0.001), higher RR (65 vs 20%; p < 0.001), and a better toxicity profile. Of the 347 randomized patients, 45% were of Asian ethnicity (crizotinib, n = 79, chemotherapy, n = 78). Consistent with the results in the overall study population, crizotinib treatment resulted in a significantly greater improvement in PFS, ORR, and patient-reported outcome compared to chemotherapy in a sub-analysis of Asian patients, confirming the utility of crizotinib in this population [38]. The efficacy of crizotinib as a first-line treatment for advanced ALK-positive NSCLC was demonstrated in the PROFILE 1014 trial [39]. First-line crizotinib treatment showed significant improvements in PFS (10.9 vs 7.0 months; HR: 0.454; p < 0.0001) and ORR (74 vs 45%; p < 0.0001) compared to pemetrexed/platinum chemotherapy while maintaining an acceptable safety profile. ROS1 rearrangement defines a second molecular subgroup of NSCLC for which crizotinib is highly active. ROS1 fusion partners include CD74, SLC34A2, and SDC4, all of which lead to oncogenic transformation in vitro and/or in vivo. It occurs in ~ 1% of patients with NSCLC [40]. Recently, Shaw et al. [41] reported the results of a Phase I study that enrolled 50 ROS1-positive NSCLC patients exposed to crizotinib. The ORR was 72%, with 3 complete responses and 33 partial responses. The median duration of response was 17.6 months and the median PFS was 19.2 months. A Phase II ROS1 trial focusing on the Asian population is presently ongoing. 4.
Overcoming AR
Although TKIs have reshaped treatment approaches in oncogene-driven NSCLC, these therapies have been universally limited by the development of AR. Novel agents and strategies were explored for overcoming TKI resistance. Considering a biopsy at the time of progression after the initial EGFR-TKI treatment is an emerging standard for EGFR mutants. Both EGFR-mutant and ALK-rearranged lung cancers highlight common principles of resistance, such as the development of secondary mutations in the target kinase, target gene amplification, and activation of bypass tracts (Figure 1) [42,43]. Rebiopsy during disease progression in patients treated by TKI provides insight into different
Expert Opin. Pharmacother. (2015) 16(8)
Emerging paradigms in targeted treatments for Asian patients with NSCLC
A. Mechanisms of EGFR-TKI resistance
T790M mutation (50%) EGFR amplification (8%) Bypass signaling tracts (20%) Phenotypic alterations (3–14%) Unknown (~15%)
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B. Mechanisms of ALK TKI resistance
ALK secondary mutations (~35%) ALK gene amplification (~15%) Bypass signaling tracts (~30%) Unknown (~20%)
Figure 1. Major mechanisms of EGFR-TKI/ALK TKI acquired resistance.
resistance mechanisms, with potential consequences for therapeutic decision-making. TKI Continuation beyond progression The diversity of EGFR-TKI failure was retrospectively categorized into three modes according to specific criteria derived from clinical factors: dramatic progression, gradual progression, and local progression [44]. Further analysis showed that continuous EGFR-TKI treatment had better results than switching to chemotherapy in the gradual progression cohort, whereas patients in the dramatic progression group demonstrated better OS with switching to chemotherapeutic regimens. The IMPRESS study was the first and only randomized Phase III study to confirm that continuation of EGFRTKIs in addition to chemotherapy would be of no clinical benefit for patients with AR to gefitinib [45]. There was no statistically significant improvement in PFS with continuation of gefitinib (HR 0.86; p = 0.273; median PFS, 5.4 months each), and OS increased even in the placebo arm (HR 1.62; p = 0.029, median OS, 14.8 vs 17.2 months). No treatment differences were found in ORR/DCR in the two groups. The study failed to achieve its primary objective, but nevertheless the results appear to impact clinical practice. 4.1
Next-generation TKIs Initial strategies to combat AR have centered on using nextgeneration TKIs. Preclinical research data have indicated that the second-generation EGFR-TKIs such as afatinib and dacomitinib had a high level of activity against T790M in vitro [46]. There was great hope that second-generation 4.2
EGFR-TKIs would be highly effective for patients with AR when they were developed. Nevertheless, clinical trials of these drugs have been rather disappointing in patients with AR, probably as a result of dose limitations from toxicity caused by inhibiting wild-type EGFR simultaneously [47,48]. Recently, third-generation EGFR inhibitors such as AZD9291, CO-1686, and HM61713, which may be more effective for patients with T790M, have been recommended. The results of clinical studies of third-generation EGFRTKIs have been reported and appear to be promising in patients who have previously progressed on approved EGFRTKI therapies [49-51]. The efficacy was greater in patients with T790M+ (ORR, 29--65%) than in patients with T790M(ORR, 12--22%) EFGR-TKI-resistant NSCLC. Additional studies will identify the relative benefits of these three agents, as well as their role in the initial treatment of EGFR mutation-positive patients where they are likely to gain a prominent role. Similarly, next-generation TKIs are also being investigated in ALK-positive patients. Two of these next-generation ALK inhibitors, ceritinib and alectinib, were associated with high ORRs in the Phase I trials of ALK-positive patients with crizotinib resistance (Table 2) [52,53]. In contrast to third-generation EGFR-TKIs displaying efficacy in certain T790M mutant populations, ceritinib was active in the majority of patients with ALK-rearranged NSCLC who had previously received crizotinib. Confirmed responses were seen in 6 of 7 patients with ALK gene amplification or mutation, and in 7 of 12 patients without ALK change, suggesting that the activity of ceritinib in patients whose tumors had progressed during crizotinib treatment may be independent of the underlying mechanism of AR. Moreover, both agents also demonstrated activity against brain metastases. This raises the possibility that next-generation ALK inhibitors may control disease in the central nervous system, which is among the most common sites of relapse among patients undergoing treatment with crizotinib. As resistance to TKIs is inevitable, it is important issue to understand when and how resistance is developed. A second biopsy is essential for monitoring and discovering resistance, but may not always be possible. If sensitivity and specificity are resolved, serial liquid biopsies could play an important role due to its non-invasive nature and convenience. 5.
Adjuvant and neoadjuvant therapy
The first randomized adjuvant trial with an EGFR-targeted agent, BR.19 [54], was closed prematurely with only 503 patients of a planned total of 1,242, secondary to negative Phase III results with gefitinib in the advanced setting, with a median follow-up of 4.7 years and a median of < 5 months of treatment. The results are thus inconclusive, but failed to show any benefıt with this approach, even in the small number of patients whose tumors harbored an EGFR-activating mutation. Results from the randomized RADIANT trial [55]
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Table 2. Clinical activity of crizotinib and next-generation ALK inhibitors.
Crizotinib-naive population ORR (95% CI) PFS (95% CI, m) Crizotinib-resistant population ORR(95% CI) PFS (95% CI, m)
Crizotinib [39]
Ceritinib [52]
Alectinib [53]
74% (67 -- 81%) 10.9 (8.3 -- 13.9)
62% (21/34, 44 -- 78%) 10.4 (4.6 -- )
-
-
56% (45/80, 47 -- 67%) 6.9 (5.3 -- 8.8)
55% (24/44) -
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m: Months; ORR: Objective response rate; PFS: Progression-free survival.
of adjuvant erlotinib in patients with tumors with EGFR expression, as determined by immunohistochemistry or FISH, came to light at the ASCO 2014 meeting. Unfortunately, in this trial, adjuvant erlotinib did not prolong DFS in patients with early-stage resected EGFR expressing NSCLC. Exploratory analyses conducted to examine the prognosis of EGFR mutations in NSCLC showed that no significant prognostic effect with EGFR mutation status was observed, but conclusions are limited because of the small sample size, and EGFR mutation status may be associated with a higher disease stage and other variables. Despite the negative results in the BR.19 and RADIANT studies, there is enthusiasm to re-evaluate the role of EGFR-TKIs in the adjuvant and neoadjuvant settings in a selected patient population that is sensitive to this treatment. Several studies were initiated in Asia, focusing on certain populations harboring EGFR-activating mutations and staging II-IIIA with lymph node metastasis at a high risk for recurrence. Patients recruited for the CTONG1104 trial (NCT01405079, www.clinicaltrials.gov) were randomized to receive gefitinib for 24 months or vinorelbine plus platinum for four cycles after surgery. The recruiting process is complete, and the results will be available soon. A similar trial in Japan (WJOG6401L) is presently ongoing. Pool analysis of both CTONG1104 and WJOG6401L would give stronger evidence to potentially support the use of EGFR-TKIs in the adjuvant setting. CTONG1103 (NCT01407822, www.clinicaltrials.gov) is a Phase II study of a new treatment strategy for stage IIIA-N2 NSCLC patients with EGFR-activating mutations. Patients randomized to the erlotinib arm took erlotinib orally for 6 weeks in the neoadjuvant treatment phase and for 1 year or until disease progression or unacceptable toxicity in the post-surgery phase, whereas patients in the chemotherapy arm received gemcitabine/cisplatin for two cycles in each treatment phase. 6.
Conclusions
NSCLC provides an instructive conceptual framework for examining kinase-directed therapies. Decision making by now is characterized by selecting a specific therapeutic regimen based on not only the histology type but also the genotype of tumors. New approaches, including the stratification 1172
analysis of EGFR mutation and potential combined modality therapies, are likely to maximize the duration of disease control and further improve long-term outcomes. In addition, a paradigm shift in favor of chemotherapy for patients with EGFR wild-type has gained strength from recent data. AR to first-/second-generation EGFR-TKIs is a universal phenomenon that continues to be studied. Continuing EGFR-TKIs beyond progression are recommended in patients with clinical benefits; however, for patients with symptomatic progression, a platinum-based doublet is the standard treatment, and EGFR-TKIs should be terminated with no hesitation. It is important to re-biopsy patients when their tumors progress after treatment with TKIs to understand the mechanism that underlies the resistance. Third-generation EGFR-TKIs (known as T790M inhibitors) and next-generation ALK inhibitors are showing promising responses in early clinical trials. Moreover, the higher incidence of the EGFR mutation in Asian populations optimized the feasibility of prospective randomized trials comparing adjuvant EGFR-TKIs with standard chemotherapy. Encouraging evidence may be provided with regard to the application of EGFR-TKIs in adjuvant and neoadjuvant settings in the near future. 7.
Expert opinion
Currently, TKIs are the best option for use as a front-line therapy in EGFR+/ALK+ NSCLC, but they have limited efficacy for wild-type NSCLC patients. Another novel and promising targeted approach involves the use of crizotinib in patients with ROS1 rearrangement. Routine molecular testing such as DNA sequencing or fragment analysis following PCR, and evaluation of copy number and gene positioning by FISH, have been developed and used clinically to identify mutations/fusions. Developments in technology, such as whole-genomic sequencing or whole-exome sequencing, which can detect whole exons of several genes with the same amount of tissue used in single-gene tests, have resulted in breakthroughs in the care of lung cancer patients and compel the transition from one-gene-at-a-time analysis to multiplex approaches. Already, new treatments targeting genetic alterations in other, rare driver oncogenes (BRAF V660E, RET, etc.) are being evaluated in lung cancer, and testing for these may be addressed in future versions of guidelines.
Expert Opin. Pharmacother. (2015) 16(8)
Expert Opin. Pharmacother. (2015) 16(8)
• Wild type
• Chemo D (Level 3)
• Crizotinib (Level 1)
• Chemo D (Level 3)
Chemo S (Level 2)
• Test driver genes then join trials (Level 2)
• Chemo D (Level 2)
Chemo S (Level 2)
• Chemo S (Level 3)
• Crizotinib (Level 1)
Chemo D (Level 2)
• Chemo S (Level 3)
• Crizotinib (Level 1)
• Chemo D (Level3)
Chemo S (Level 2)
Chemo S (Level 2)
Crizotinib (Level 1)
• Chemo S (Level 2)
Bev: Bevazucimab; D: Doublet; FASTACT model: Intercalated combination of chemo and an EGFR-TKI; S: Single.
Test MET then join trials (Level 2)
• Local progression: EGFR-TKI + local intervention (Level 2)
• Gradual progression: Continuation of EGFR-TKI (Level 2)
Chemo S (Level 2)
*For unselected patients, targeted therapies are limitedly recommended without the information of genetic testing
Level 3: mildly recommended
Level 2: recommended
Level 1: highly recommended
Ceritinib/Alectinib (Level 1)
• Ceritinib/Alectinib (Level 1)
• Chemo S (Level 2)
• Ceritinib/Alectinib (Level 1)
Chemo D or S (Level 2)
• Dramatic progression: Chemo D or S (Level 2)
• Chemo D or S (Level 3)
• 3rd EGFR-TKI (Level 1)
Chemo S (Level 2)
Without T790M
With T790M
Chemo D or S (Level 2)
Progression Re-biopsy
• Ceritinib/Alectinib (Level 1)
• 1st EGFR-TKI + Bev (Level 3)
• Chemo D + Bev (Level 1)
• ROS1 rearranged
• ALK rearranged
1st /2nd EGFR-TKI (Level 2)
• FASTACT model (Level 3)
• Crizotinib (Level 1)
L858R
• Chemo D
• 1st /2nd-generation EGFR-TKI (Level 1)
1st /2nd-generation EGFR-TKI (Level 1)
Figure 2. New paradigms for overall management of Asian patients with advanced NSCLC.
NSCLC*
Genetic testing
EGFR mutant
Del19
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Based on the evidence presented, we have provided these up-to-date treatment recommendations for Asian patients with advanced NSCLC (Figure 2). First-line EGFR-TKIs should be highly recommended as the standard care for either EGFR Del 19 or L858R patients, but remains some confusion for EGFR L858R patients. A re-biopsy is needed for all EGFR mutant patients acquiring resistance to first-/second-generation EGFR-TKIs to identify the presence of a secondary T790M mutation, because novel third-generation EGFRTKIs are simply recommended for patients with T790M, whereas the next-generation ALK inhibitors could be applied for the majority of crizotinib-resistant patients. Future directions including division of Del19 and L858R patients into two distinct populations will optimize therapeutic strategies for L858R patients and may inform rational trial design by Bibliography
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Declaration of interest The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.
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Expert Opin. Pharmacother. (2015) 16(8)
Affiliation
E-E Ke1,2, Qing Zhou2 & Yi-Long Wu†2 † Author for correspondence 1 Southern Medical University, Guangzhou, Guangdong 510515, PR China 2 Guangdong Lung Cancer Institute, Guangdong General Hospital and Guangdong Academy of Medical Sciences, Guangzhou, Guangdong 510080 PR China Tel: +86 20 83877855; Fax: +86 20 83827712; E-mail: [email protected]
