ALK TKI Research Articles

EML4-ALK fusion variant V3 confers early treatment failure with first and second generation ALK TKI

EML4-ALK fusion variant V3 confers early treatment failure with first and second generation ALK TKI

PC 03.01 Crizotinib First

Crizotinib is the first ALK TKI that has demonstrated statistically superior progression-free survival over standard of platinum-based chemotherapy in treatment-naïve ALK+ NSCLC patients (PROFILE1014, PROFILE 1029). Since then next generation ALK TKI such as ceritinib (ASCEND-4) has also demonstrated statistically improved PFS over platinum-base chemotherapy (ASCEND-4) and alectinib has demonstrated statistically improved PFS over crizotinib (J-ALEX, ALEX). In ALEX, a global randomized phase 3 study comparing alectinib to crizotnib demonstrated that alectinib achieved an median PFS of 25.7 months compared to median PFS of 10.4 months for crizotinib.

P3.16-049 Surgery with Continued TKI Therapy After Acquiring Resistance to EGFR or ALK TKI

P3.16-049 Surgery with Continued TKI Therapy After Acquiring Resistance to EGFR or ALK TKI

P2.04-012 First-Line Ensartinib (X396) versus Crizotinib in Advanced ALK-Rearranged NSCLC (eXalt3): A Randomized, Open-Label, Phase 3 Study

Ensartinib (X-396) is a novel, potent ALK TKI with additional activity against MET, ABL, Axl, EPHA2, LTK, ROS1 and SLK. Its phase 1/2 study (NCT01625234) demonstrated that ensartinib is well-tolerated and induces favorable responses in both crizotinib-naïve (ORR 80%) and crizotinib-resistant ALK+ NSCLC patients (ORR 71%), as well as those with CNS metastases.

MA 07.01 Patients with ALK IHC-Positive/FISH-Negative NSCLC Benefit from ALK TKI Treatment: Response Data from the Global ALEX Trial

MA 07.01 Patients with ALK IHC-Positive/FISH-Negative NSCLC Benefit from ALK TKI Treatment: Response Data from the Global ALEX Trial

JCES 01.27 Patients with ALK IHC-Positive/FISH-Negative NSCLC Benefit from ALK TKI Treatment: Response Data from the Global ALEX Trial

JCES 01.27 Patients with ALK IHC-Positive/FISH-Negative NSCLC Benefit from ALK TKI Treatment: Response Data from the Global ALEX Trial

Abstract 3736: Characterization of tumor cells and assessment of PD-L1 expression in pleural effusions of metastatic non-small cell lung cancer patients

Abstract Introduction: Malignant pleural effusions (MPE) occur as a frequent complication of advanced non-small cell lung cancer (NSCLC), and denote a poor prognosis. Cytological evaluation of MPEs has a sensitivity of only 40-60%. The CellSearch technology (Janssen Diagnostics, LLC) is an FDA approved method of detecting rare circulating tumor cells (CTCs) in blood. Assessment of pleural fluid samples using CellSearch provides an approach to enrich often undetectable CTCs and phenotype these cells for markers of interest. PD-L1 staining of tumor tissue is essential for determining patient candidacy for checkpoint inhibitor therapy, however, tissue can often be difficult to obtain. Here, we demonstrate the feasibility of applying the CellSearch CTC enrichment platform to measure PD-L1 expression and enumerate tumor cells in MPE of NSCLC patients. Methods: This was a single center, prospective observational study of NSCLC patients with a pleural effusion. The anti-human CD274 (PD-L1) antibody (Biolegend) was used as a marker with the CellSearch CXC CTC kit and was detected in the open 4th channel of the CellTracks Analyzer. Determination of CTC PD-L1 expression was validated through peripheral blood spiking experiments. 7.5ml of pleural fluid was collected from NSCLC patients, preserved in CellSave tubes and processed within 72 hours. Identification and enumeration of CTCs was performed using the CellTracks Analyzer. We then compared CellSearch results to conventional cytological analysis. Results: Pleural effusion samples from 66 patients between the ages of 43 and 80 (median=69) were obtained following thoracentesis. The majority of patients were former (40; 60.6%) or never (21; 31.8%) smokers. At the time of effusion, 23 (34.8%) patients were on a therapeutic regimen: 10 (15.2%) were receiving chemotherapy, 9 (13.6%) were on an EGFR or ALK TKI, and 5 (7.6%) were on a checkpoint inhibitor. CTCs were detected in 63 of 66 samples using the CellSearch system. Among the 66 pleural effusions, cytological evaluation determined 40 samples were malignant and 26 were benign. CellSearch detected more CTCs in patients with a MPE (median 1798, range: 7 to 114,920) compared to patients with a benign effusion (median 8, range: 0 to 953; p=0.005). In the MPE group, 18 (45.0%) samples demonstrated >10% PD-L1 positivity with 9 (22.5%) samples showing >50% PD-L1 positivity. Conclusion: The CellSearch CTC enumeration and characterization platform can be successfully adapted for detection of CTCs in MPE of NSCLC patients. Our preliminary results suggest this approach may be a useful, non-invasive diagnostic adjunct for the determination of a MPE and assessment of PD-L1 expression in NSCLC patients. Further study is warranted to determine what role this test could play in assessing patients for checkpoint inhibitor therapy and its relationship with tissue based tests. Citation Format: Jeffrey C. Thompson, Samantha L. Savitch, Ryan Fan, Stephanie S. Yee, Christian A. Powers, Gordon Yu, Lauren Gebrian, Chandra Rao, Steve Gross, Michael Feldman, Anil Vachani, Erica L. Carpenter. Characterization of tumor cells and assessment of PD-L1 expression in pleural effusions of metastatic non-small cell lung cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3736. doi:10.1158/1538-7445.AM2017-3736

Collateral sensitivity networks reveal evolutionary instability and novel treatment strategies in ALK mutated non-small cell lung cancer

Drug resistance remains an elusive problem in cancer therapy, particularly for novel targeted therapies. Much work is focused upon the development of an arsenal of targeted therapies, towards oncogenic driver genes such as ALK-EML4, to overcome the inevitable resistance that develops over time. Currently, after failure of first line ALK TKI therapy, another ALK TKI is administered, though collateral sensitivity is not considered. To address this, we evolved resistance in an ALK rearranged non-small cell lung cancer line (H3122) to a panel of 4 ALK TKIs, and performed a collateral sensitivity analysis. All ALK inhibitor resistant cell lines displayed significant cross-resistance to all other ALK inhibitors. We then evaluated ALK-inhibitor sensitivities after drug holidays of varying length (1–21 days), and observed dynamic patterns of resistance. This unpredictability led us to an expanded search for treatment options, where we tested 6 further anti-cancer agents for collateral sensitivity among resistant cells, uncovering possibilities for further treatment, including cross-sensitivity to standard cytotoxic therapies, as well as Hsp90 inhibitors. Taken together, these results imply that resistance to targeted therapy in non-small cell lung cancer is highly dynamic, and also one where there are many opportunities to re-establish sensitivities where there was once resistance. Drug resistance in cancer inevitably emerges during treatment; particularly with novel targeted therapies, designed to inhibit specific molecules. A clinically-relevant example of this phenomenon occurs in ALK-positive non-small cell lung cancer, where targeted therapies are used to inhibit the ALK-EML4 fusion protein. A potential solution to this may lie in finding drug sensitivities in the resistant population, termed collateral sensitivities, and then using these as second-line agents. This study shows how the evolution of resistance in ALK-positive lung cancer is a dynamic process through time, one in which patterns of drug resistance and collateral sensitivity change substantially, and therefore one where temporal regimens, such as drug cycling and drug holidays may have great benefit.

Adénocarcinome bronchique avec mutation de l’EGFR et réarrangement ALK concomitants

Among patients with non-small-cell lung cancer, coexistence of EGFR mutation and ALK rearrangement is rare. We describe the clinical features of two patients with this double anomaly. A 62-year-old Caucasian non-smoking woman was diagnosed with cT4N0M0lung adenocarcinoma. Initial biopsy showed EGFR mutation and ALK rearrangement. She received cisplatin-gemcitabine, followed by 17months of gemcitabine. Owing to progression, she received erlotinib for 14months, then paclitaxel for 6months and finally crizotinib. A partial response was achieved and maintained for 24months. A 45-year-old Caucasian woman, light smoker, was diagnosed with cT2N3M0lung adenocarcinoma. Only EGFR mutation was found on initial analysis. She underwent treatment with cisplatin-gemcitabine and thoracic radiotherapy. Progression occurred after 8months and afatinbib was started. Eight months later, progression was observed with a neoplasic pleural effusion in which tumor cells expressing ALK rearrangement were found. A new FISH analysis was performed on the initial tumor but did not find this rearrangement. Despite a third line of crizotinib, the patient died one month later. The literature shows 45other cases of these two abnormalities, observed either from the start or during follow-up. EGFR's TKI were almost always given before ALK's TKI. Therapeutic strategy needs to be clarified in cases of double alteration. With regard to the second patient, appearance of ALK rearrangement may constitute a resistance mechanism to EGFR's TKI.

Liquid biopsies could be superior to tumor biopsy to provide a molecular profile in non-small cell lung cancer (NSCLC) patients

vomiting (25%), and fatigue (23%). Most AEs were Grade (G) 1-2. The G3 treatment-related AEs were rash (6 pts), fatigue (1 pt), decreased appetite (1 pt), dehydration (1 pt), pruritus (1 pt), and face edema (1 pt). In particular, no G3 treatment-related gastrointestinal toxicity or liver enzyme elevation has been reported. To date, 24 ALKþ NSCLC pts treated at doses 200 mg are evaluable for response; partial response (PR) was achieved in 16 pts (67%) and stable disease (SD) in 3 pts (13%). In the crizotinib-naive pts (n1⁄48), responses were observed in 6 pts (75%) and SD in 1 pt (13%). In the 12 pts with prior crizotinib but no other ALK TKI, 10 pts (83%) achieved PR and 1 (8%) SD. CNS responses have been observed in both crizotinib naive and crizotinib resistant pts. The median duration of treatment in the 24 evaluable ALKþ pts is 23.8þ weeks, with the longest being 112þ weeks. Conclusion: X-396 is well-tolerated and induces responses in both crizotinib-naive and crizotinib-resistant ALKþ NSCLC pts, as well as patients with CNS lesions. Enrollment is ongoing in the expansion cohorts.

SY15-4 - ALK resistance mechanism & TKI selection

SY15-4 - ALK resistance mechanism & TKI selection

Targeted Disruption of ALK Reveals a Potential Role in Hypogonadotropic Hypogonadism.

Mice lacking ALK activity have previously been reported to exhibit subtle behavioral phenotypes. In this study of ALK of loss of function mice we present data supporting a role for ALK in hypogonadotropic hypogonadism in male mice. We observed lower level of serum testosterone at P40 in ALK knock-out males, accompanied by mild disorganization of seminiferous tubules exhibiting decreased numbers of GATA4 expressing cells. These observations highlight a role for ALK in testis function and are further supported by experiments in which chemical inhibition of ALK activity with the ALK TKI crizotinib was employed. Oral administration of crizotinib resulted in a decrease of serum testosterone levels in adult wild type male mice, which reverted to normal levels after cessation of treatment. Analysis of GnRH expression in neurons of the hypothalamus revealed a significant decrease in the number of GnRH positive neurons in ALK knock-out mice at P40 when compared with control littermates. Thus, ALK appears to be involved in hypogonadotropic hypogonadism by regulating the timing of pubertal onset and testis function at the upper levels of the hypothalamic-pituitary gonadal axis.

SY14-4 - Acquired Resistance to ALK Tyrosine Kinase Inhibitors

ABSTRACT The ALK tyrosine kinase inhibitor crizotinib has demonstrated clinical efficacy in ALK-rearranged NSCLC patients and is currently under additional phase III clinical development as both initial and second-line therapy for advanced ALK-rearranged NSCLC. However, their efficacy will ultimately be limited by the development of acquired drug resistance. Recent studies have identified and studied two mechanisms of ALK TKI resistance based on evidence from a crizotinib-treated ALK-positive lung cancer patient and in a cell line generated from the resistant tumor. To date four secondary mutations, all identified from crizotinib-treated ALK-rearranged tumor patients, have been reported. These mutations either involve the ‘gatekeeper’ residue (L1196) or sites away from crizotinib binding (F1174L, L1152R and C1156Y). The mechanistic basis for how the different mutations lead to crizotinib resistance is not fully understood. The L1196 mutation may create a steric hindrance for crizotinib binding, whereas the F1174L mutation likely promotes the active conformation of ALK, thus disfavoring crizotinib binding which preferentially binds the inactive conformation of ALK. The other mechanism was activation of EGFR signaling as a bypass signaling mechanisms that contributes to ALK inhibitor resistance. Finally, we discuss the strategies that are underway to clinically overcome acquired drug resistance.