ALK-positive Non-small Cell Lung Cancer Research Articles

Brigatinib in Japanese patients with anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer (NSCLC): First results from the J-ALTA tyrosine kinase inhibitor (TKI)-naive expansion cohort.

9042 Background: Brigatinib is a next-generation ALK inhibitor with demonstrated activity against ALK mutations. We report primary analysis results with brigatinib in Japanese patients with ALK-positive NSCLC who have not previously been treated with an ALK TKI in the phase 2 J-ALTA study (NCT03410108). Methods: J-ALTA, a multi-cohort study, included a TKI-naive expansion cohort. Patients in the TKI-naive cohort received brigatinib 180 mg qd with 7-day lead-in at 90 mg. Primary endpoint was 12-month progression-free survival (PFS) as assessed by an independent-review committee (IRC). Secondary endpoints included confirmed objective response rate (ORR; IRC- and investigator-assessed); IRC-assessed PFS and duration of response (DoR); overall survival (OS); intracranial PFS (iPFS by IRC); and safety. Results: A total of 104 patients were enrolled in the whole study; of these, 32 patients had TKI-naive NSCLC (median age, 60.5 y; 94% had adenocarcinoma; 22% had baseline brain metastases; 25% received prior chemotherapy). As of September 29, 2020, median follow-up was 14.2 months and 27 patients remained on treatment. IRC-assessed 12-month PFS was 93% (90% CI, 79–98). Confirmed ORR was 97% (90% CI, 84–100) by IRC, with 2 complete responses and 29 partial responses. Median DoR as assessed by the IRC was not mature; median PFS, iPFS, and OS were not reached. In the TKI-naive cohort, treatment-emergent adverse events (TEAEs) were reported in all 32 patients (most common: increased creatine phosphokinase, 81%; hypertension, 59%; diarrhea, 47%). Grade ≥3 TEAEs were reported in 91% of patients in this cohort (most common: increased creatinine phosphokinase, 44%; hypertension, 34%; increased lipase, 19%) and 75% of all patients. Three cases (9.4%) of interstitial lung disease/pneumonitis were reported in the TKI-naive cohort; all were grade 1 and occurred after day 15 of brigatinib treatment. Dose discontinuations/interruptions/reductions due to AEs in the TKI-naive cohort were 0%/94%/66%, respectively, and in the total study population were 5%/72%/41%. AE frequency and profile were similar in the TKI-naive and overall cohorts. Conclusions: In the J-ALTA TKI-naive cohort, brigatinib demonstrated substantial efficacy and manageable safety in the Japanese patient population. Brigatinib remains one of the treatment options in Japanese patients. Clinical trial information: NCT03410108.

Early circulating tumor (ct) DNA dynamics and efficacy of lorlatinib: Analysis from the CROWN study.

9011 Background: Lorlatinib, a third-generation ALK tyrosine kinase inhibitor, significantly improved progression-free survival (PFS) and overall/intracranial responses vs crizotinib in patients (pts) with previously untreated ALK-positive advanced non-small cell lung cancer (NSCLC) in the ongoing randomized Phase 3 CROWN study (NCT03052608). To identify whether additional molecular biomarker analysis correlated with efficacy, we evaluated early ctDNA dynamics compared with clinical outcomes. Methods: Plasma samples were prospectively collected at screening (SC), week 4 (cycle 2, day 1 [C2D1]), week 24 (C7D1), and end of treatment for ctDNA analysis. ctDNA was analyzed using Guardant360CDx (Guardant Health, Inc., Redwood City, CA, USA). Mean variant allele fraction (VAF) of ALK alterations (fusions and/or mutations) and overall detected alterations at each time point and longitudinal mean change (dVAF) as (VAFC2D1) – (VAFSC) were calculated; dVAF <0 indicated decreased ctDNA at week 4. Objective tumor response and PFS were evaluated according to dVAF. These analyses were repeated vs ctDNA results at week 24. Additional correlation analyses between depth of molecular response and/or ctDNA clearance and clinical outcomes are ongoing. Results: Paired samples were available at SC and week 4 from 232 of 255 pts included in the ctDNA analysis: 118/130 (90.8%) in the lorlatinib arm and 114/125 (91.2%) in the crizotinib arm. ALK alterations were detected in 122/232 (52.6%) pts at SC (62/118 [52.5%] from the lorlatinib arm) but only 19/232 (8.2%) at week 4 (8/118 [6.8%] from the lorlatinib arm). Mean VAF of ALK alterations at week 4 was significantly decreased compared with SC in both treatment arms (lorlatinib -1.54, crizotinib -1.25; both P<0.0001; P=0.4239 between arms). In the lorlatinib arm, mean VAF at week 4 was significantly decreased compared with SC in pts with a complete or partial response (dVAF -1.53; n=47; P<0.0001), or stable disease (dVAF -1.37; n=12; P=0.0304). Similar results were observed in the crizotinib arm. In pts with dVAF <0 for ALK alterations, mean percent change from screening in tumor size was -40.8% with lorlatinib (n=59) and -38.7% with crizotinib (n=58). Only 2 pts had dVAF ≥0, both from the crizotinib arm. Median PFS for pts with dVAF <0 for ALK alterations was not reached in the lorlatinib arm (n=62), and was 7.4 months (95% CI, 7.2–9.3) in the crizotinib arm (n=58). Similar response and PFS data were observed in the analysis of dVAF for ALK alterations at week 24. Conclusions: Early ctDNA dynamics may predict lorlatinib efficacy in pts with previously untreated ALK-positive NSCLC. The magnitude of reduction in ctDNA at 4 weeks may be associated with better responses and potentially longer PFS. These findings further support the utility of dynamic ctDNA monitoring in ALK-positive NSCLC. Reference: Shaw AT, et al. N Engl J Med. 2020;383:2018-2029. Clinical trial information: NCT03052608.

Stage IV ALK-Positive Lung Adenocarcinoma: 7.5-Year Complete Remission with Crizotinib

Multiple lines of Anaplastic Lymphoma Kinase (ALK) Tyrosine Kinase Inhibitors (TKIs) are recommended for the treatment of ALK-positive Non-Small Cell Lung Cancer (NSCLC). This article provides an unusual case report of a 33-year-old male patient with a 91-month Progression-Free Survival (PFS) on a first-generation TKI, crizotinib.

Impact of prior ALK-tyrosine kinase inhibitor on pemetrexed-based chemotherapy in patients with advanced ALK positive non-small cell lung cancer.

e21113 Background: In phase Ⅲ trial comparing crizotinib with chemotherapy in patients with ALK-positive non-small-cell lung cancer (NSCLC) patients, it suggests that pemetrexed is highly effective against ALK-positive NSCLC. However, it is unclear that pemetrexed-based chemotherapy is effective in patients previously treated with ALK-tyrosine kinase inhibitor (ALK-TKI) as well as ALK-TKI naïve patients. Therefore, we investigated the impact of prior ALK-TKI therapy on pemetrexed-based chemotherapy. Methods: We retrospectively reviewed 28 ALK positive NSCLC patients who had received pemetrexed-based chemotherapy at Shizuoka Cancer Center, Japan, from January 2011 to October 2020. The efficacies of pemetrexed-based chemotherapy after or before ALK-TKI was evaluated. Results: Eight patients (29 %) were treated with pemetrexed-based chemotherapy before ALK-TKI (ALK-TKI treated group), and 20 (71%) with this regimen after the failure of ALK-TKI (ALK-TKI naïve group). Patients characteristics (ALK-TKI naïve/ALK-TKI treated) were as follows: median age (range) 66 (27-72)/57 (35-73); male 100/45%; PS0-1 100/85%; adenocarcinoma 100/90%; stageⅣ 88/90%; with CNS metastasis 12/40%. The pemetrexed-based chemotherapy was administered in 5 (18%) patients as the 1st line, 11 (39%) as 2nd line, and 12 (43%) as 3rd or latter line. Twenty-five patients received the combination of platinum with pemetrexed and 3 done pemetrexed monotherapy. Regarding previous ALK-TKI, 17 patients received only alectinib and 8 patients did both alectinib and crizotinib. Progression-free survival (PFS) in ALK-TKI treated group was shorter than in ALK-TKI naïve group (median PFS 3.8 months vs 12.4 months Hazard ratio = 0.41; 95%CI 0.16-1.01 by wald test, p = 0.047 by log-rank test). In overall survivals (OS) from first line treatment between two groups, and ALK-TKI treated group tended to be shorter than ALK-TKI naïve group (median OS 29.5 months vs. 48.8 months; Hazard ratio 0.47, 95%CI 0.13-1.7, p = 0.248). OS from pemetrexed-based chemotherapy of ALK-TKI treated group was also significantly shorter than ALK-naïve group (median OS 10.1 months vs. not reached; Hazard ratio 0.20, 95%CI 0.05-0.75, p = 0.01). Overall response rate (ORR) of pemetrexed-based chemotherapy was lower in ALK-TKI treated group than ALK-TKI naïve group (35% vs 50%) and ORR of ALK-TKI was 85% vs 63%. There was no difference in PFS of pemetrexed-based chemotherapy regardless of efficacy of prior ALK-TKI (PFS ≥24 months vs < 24 months; median PFS 4.5 months vs 7.2 months, Hazard ratio 0.99, 95%CI 0.42-2.31, p = 0.99). Conclusions: Pemetrexed-based chemotherapy might be less effective in ALK-positive NSCLC patients previously treated with ALK-TKI. This retrospective study results suggested that ALK-TKI sequence can be a better treatment option in ALK-positive NSCLC patients.

Combining radiotherapy with targeted therapies in non-small cell lung cancer: focus on anti-EGFR, anti-ALK and anti-angiogenic agents.

The combination of radiotherapy (RT) with targeted agents in non-small cell lung cancer (NSCLC) has been expected to improve the therapeutic ratio and tumor control. The EGFR blockade enhances the antitumor effect of RT. The ALK inhibition elicits anti-proliferative, pro-apoptotic and antiangiogenic effects in ALK-positive NSCLC cell lines, enhanced by the exposure to RT. The antiangiogenic agents normalize pathological tumor vessels, thus decrease tumor cell hypoxia and improve radiosensitivity. To date, however, none of the targeted agents combined with RT has shown proven clinical benefit over standard chemoradiation (CRT) in locally advanced NSCLC. The risk of potential excessive toxicity related to the therapeutic combination of RT and targeted agents cannot be ignored. Well-designed clinical trials may allow development of more effective combination strategies. Another potential application of combined RT and targeted therapies in oncogene-driven NSCLC is metastatic oligoprogressive or oligopersistent disease. The use of RT in oligoprogressive oncogene-driven NSCLC, while continuing first line targeted therapy, can potentially eradicate resistant cell clones and provide survival benefit. Likewise, the consolidation of oligopersistent foci (molecularly resistant to first line targeted therapy) may potentially interfere with the natural course of the disease by avoiding or delaying progression. We discuss here the molecular and radiobiological mechanisms of combining RT and targeted agents, and summarize current clinical experience.

A retrospective study of alectinib versus ceritinib in patients with advanced non\u2013small-cell lung cancer of anaplastic lymphoma kinase fusion in whom crizotinib treatment failed

BackgroundCrizotinib is the approved treatment for advanced non-small cell lung cancers (NSCLCs) of anaplastic lymphoma kinase (ALK) fusion. Failure of crizotinib treatment frequently involves drug intolerance or resistance. Comparison of using second-generation ALK inhibitors in this setting remains lacking.MethodsSixty-five ALK-positive advanced NSCLC patients receiving second-generation ALK inhibitors following treatment failure of crizotinib were retrospectively analyzed for the therapeutic efficacy.ResultsForty-three (66.2%) and 22 (33.8%) patients received alectinib and ceritinib, respectively. Comparing alectinib to ceritinib treatment: the 12-month progression-free survival (PFS) rate (61.0% [95% confidence interval, 47.1 to 78.9%] vs. 54.5% [95% CI, 37.3 to 79.9%]); the hazard ratio (HR) for disease progression or death, 0.61 (95% CI, 0.31–1.17; p = 0.135). Multivariate Cox regression showed ECOG PS (0–1 vs. 2–3 HR 0.09 [95% CI, 0.02–0.33]; p < 0.001) and cause of crizotinib treatment failure (resistance vs. intolerance HR 2.75 [95% CI, 1.26–5.99]; p = 0.011) were the independent predictors for the PFS of second-generation ALK inhibitors. Treatment of alectinib, compared to ceritinib, was associated with a lower incidence of CNS progression (cause-specific HR, 0.10; 95% CI 0.01–0.78; p = 0.029) and a higher efficacy in patients whose cause of crizotinib treatment failure was intolerance (HR 0.29 [95% CI, 0.08–1.06]; p = 0.050). The most commonly noted adverse events were elevated AST/ALT in 10 (23.3%) patients treated with alectinib and diarrhea in 8 (36.4%) patients treated with ceritinib.ConclusionSecond-generation ALK inhibitors in crizotinib-treated patients showed a satifactory efficacy. Alectinib treatment demonstrated a CNS protection activity and a higher PFS in selected patients failing crizotinib treatment.

P84.10 The Impact of 3rd-Line ALK Inhibitors in ALK Positive NSCLC in Real-World Data

ALK inhibitors (ALKi) are the standard treatment for metastatic ALK-rearranged Non-Small Cell Lung Cancer (NSCLC) patients in the first and second line setting. We conducted a real-world multi-institutional study, aiming to compare third-line ALKi versus chemotherapy in these patients.

P84.23 The Safety and Toxicities of ALK -TKIs in ALK-Positive NSCLC: A Systematic Review and Pool Analysis

The anaplastic lymphoma kinase tyrosine kinase inhibitors (ALK-TKIs) including crizotinib, alectinib, ceritinib and brigatinib are available for the first-line treatment of patients with positive non-small cell lung cancer (NSCLC) and show a promising response. Selecting a treatment with acceptable toxicities and has a lower influence on the quality of life of the patient is essential. However, the analysis of the toxicity and safety profiles among different first line ALK TKIs is lacking. We performed a systemetic review to evaluate the safety and tolerability profiles of the first-line ALK inhibitors according to ALK -TKI type. We extracted the data from prospective clinical trials searched in database and conducted a pooled analysis of severe AEs according to the type of ALK-TKIs. All statistical analyses were performed with the SPSS software. A total of 21 studies including 3418 patients were considered eligible for analysis. The frequencies of treatment-related death and AEs due to treatment withdrawn were 0.7% (24/3418) and 7.8 % (258/3308), respectively. The frequency of severe AEs in patients treated with ceritinib was significantly higher than patients treated with crizotinib, alectinib and brigatinib. One of the most common adverse events (AEs) observed with ALK inhibitors were gastrointestinal (GI) toxicities, such as nausea,vomiting and diarrhea. The frenquency of GI toxicities grade ≥ 3 in ceritinib group is significantly higher than in crizotinib group (5.6% vs. 1.2%, OR 4.825, 95% CI 2.907–8.008, P < 0.001) alectinib cohort (5.6% vs. 0.3%, OR 22.148, 95% CI 3.038–161.462, P < 0.001) and brigatinib group (5.6% vs 0.7%, OR 8.129, 95% CI 1.956–33.782, P=0.001). Hepatotoxicity of grade≥3 was significantly more frequent in patients treated with ceritinib, occured up to 24.1%(24.1% vs. 3.7%, OR 0.122, 95% CI 0.07–0.21, P < 0.001; 24.1% vs. 1.4%, OR 21.70, 95% CI 7.98–59.05, P < 0.001; 24.1% vs. 9.6%, OR 0.34 95% CI 0.27–0.42, P < 0.001). Significant difference of fatigue of grade ≥3 between ceritinib and other TKIs were detected (4.9% vs 0.9% OR 0.176, 95% CI 0.042–0.736, P=0.007; 4.9% vs0.7% OR 7.19, 95% CI 0.978–52.872, P=0.024; 4.9% vs 2.3% OR 0.46, 95% CI 0.29–0.74, P=0.001). It is more frequently in patients treated with crizotinib that occured neutropenia than any other group (12% vs 0.6% OR 21.07, 95% CI 5.2–85.2, P< 0.001; 12% vs1.1% OR 0.08, 95% CI 0.012–0.616, P=0.002; 12% vs 0% OR 1.09, 95% CI 1.08–1.11,P<0.001). Lung toxicity of grade ≥3 occured more often in brigatinib(6.1% vs 0% OR 2.46, 95% CI 2.22–2.71, P< 0.001; 6.1% vs2.8% OR 2.26, 95% CI 1.06–4.83, P=0.031; 6.1% vs 2.6% OR 2.46, 95%CI 1.33-4.54,P=0.003). Attention should be focused on ALK inhibitor-related SAEs although ALK inhibitors have an acceptable safety profile with a low risk of treatment-related deaths. Statistically significant differences in some severe AEs among ceritinib, crizotinib alectinib and brigatinib were detected in this pool analysis.

FP07.15 Real-world ALK Testing Trends and Patterns in Patients with Advanced NSCLC in the United States

Patients whose lung cancers harbor anaplastic lymphoma kinase (ALK) rearrangements are sensitive to treatment with ALK tyrosine kinase inhibitors (TKIs). Several treatment guidelines recommend molecular testing to identify ALK-positive patients who are eligible for ALK TKI therapy. This study assessed real-world ALK testing patterns among community practices in the United States in patients with advanced non-small cell lung cancer (NSCLC) and explored treatments received prior to receiving test results in patients with ALK-positive NSCLC.

P84.08 First-line Brigatinib in Anaplastic Lymphoma Kinase-positive Non-small Cell Lung Cancer: A Network Meta-Analysis

Anaplastic Lymphoma Kinase (ALK)-targeted tyrosine kinase inhibitors have shown to be effective as first-line (1L) treatment of ALK-positive non-small cell lung cancer (NCSLC). However, head-to-head comparisons between most available ALK inhibitors are lacking. The objective of this study was to conduct a systematic literature review (SLR) and meta-analyses to estimate the relative efficacy of brigatinib compared to other approved ALK inhibitors or chemotherapy in patients with locally advanced or metastatic ALK inhibitor-naïve ALK-positive NSCLC (≤1 prior chemotherapy regimen was allowed).

The impact of baseline brain metastases on clinical benefits and progression patterns after first-line crizotinib in anaplastic lymphoma kinase-rearranged non-small cell lung cancer.

Baseline brain metastasis (BBM) commonly occurs in anaplastic lymphoma kinase (ALK)-rearranged non-small cell lung cancer. Crizotinib prolongs the survival of patients with ALK rearrangement but lacks significant effect on brain metastasis. It remains unclear whether BBM and local therapy affect therapeutic outcomes and progression patterns during crizotinib treatment.Patients with ALK-positive (immunotherapy) non-small cell lung cancer were screened from West China Hospital between May 2013 and January 2019. A total of 155 patients were enrolled in this research, with entirely recorded statistics to analyze retrospectively.Baseline brain metastasis occurred in 64 patients (55.7%). Thirty-seven patients received local therapy, while 24 patients did not. We observed higher overall response rate in patients receiving local therapy (70.2% vs. 41.7%, P = .026), but no statistical difference was found in median progression free survival (mPFS) (12.0 months vs 13.0 months, P = .633). A significantly shorter mPFS was found in patients not receiving local treatment compared with the 16.5 months mPFS of patients without BBM (P = .029). Intracranial progressions were recorded in 35 patients with BBM (71%) and 16 patients who don’t have (30%). As for extracranial progression, there is a higher occurrence rate (75.5%) in patients who had baseline extracranial metastases versus 49.0% in BBM patients. A significantly higher occurrence rate of multiple progression was noted in patients with BBM (14/49 vs. 6/53).Baseline intracranial metastasis changes the location and number of progressions after the first-line crizotinib and results in poor prognosis. There is no evidence that local treatment for brain metastasis had a protective effect on intracranial progression.

Intracranial and extracranial efficacy of lorlatinib in patients with ALK-positive non-small-cell lung cancer previously treated with second-generation ALK TKIs

Lorlatinib, a potent, brain-penetrant, third-generation anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitor (TKI), has substantial activity against ALK-positive non-small-cell lung cancer (NSCLC). This study assessed the overall, intracranial, and extracranial efficacy of lorlatinib in ALK-positive NSCLC that progressed on second-generation ALK TKIs. In the ongoing phase II study (NCT01970865), patients with ALK-positive advanced NSCLC treated with ≥1 prior second-generation ALK TKI ± chemotherapy were enrolled in expansion cohorts (EXP) based on treatment history. Overall, intracranial and extracranial antitumor activity were assessed independently per modified Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. Of the 139 patients with ≥1 prior second-generation ALK TKI (EXP3B-5), 28 received one prior second-generation ALK TKI (EXP3B), 65 two prior ALK TKIs (EXP4), and 46 three prior ALK TKIs (EXP5). In EXP3B-5, the objective response rate (ORR) [95% confidence intervals] was 39.6% (31.4-48.2), intracranial ORR (IC-ORR) was 56.1% (42.4-69.3), extracranial ORR (EC-ORR) was 36.7% (28.7-45.3), median duration of response (DOR) was 9.6months [5.6-16.7; IC-DOR, 12.4 (6.0-37.1); EC-DOR, 9.7 (6.1-33.3)], median progression-free survival was 6.6(5.4-7.4) months, and median overall survival was 20.7 months (16.1-30.3). In EXP3B, the ORR was 42.9% (24.5-62.8), the IC-ORR was 66.7% (29.9-92.5), and the EC-ORR was 32.1% (15.9-52.4). In EXP4 and EXP5, the ORR was 38.7% (29.6-48.5), the IC-ORR was 54.2% (39.2-68.6), and the EC-ORR was 37.8% (28.8-47.5). Lorlatinib had clinically meaningful intracranial and extracranial antitumor activity in the post-second-generation ALK TKI setting, with elevated intracranial versus extracranial ORR, particularly in patients with fewer lines of therapy.

Phase II, Open-label, Single-arm, Multicenter Study to Assess the Activity and Safety of Alectinib as Neoadjuvant Treatment in Surgically Resectable Stage III ALK-positive NSCLC: ALNEO Trial

BackgroundAlectinib is a potent anaplastic lymphoma kinase (ALK)-tyrosine kinase inhibitor (TKI) which is currently used in the first-line setting of advanced ALK+ non-small cell lung cancer (NSCLC). Despite favorable results in the metastatic setting, the activity of alectinib in locally-advanced ALK+ NSCLC as a neoadjuvant treatment remains to be assessed. We report the case of a patient with stage IIIA ALK+ NSCLC (cT2aN2) who received alectinib as neoadjuvant treatment, achieving major pathological response (MPR) at pathologic examination. Hence we present the treatment rationale and study design of a phase II, open-label, single-arm, multicenter clinical trial (ALNEO study, EUDRACT number 2020-003432-25). Materials and MethodsPatients with potentially resectable stage III ALK+ NSCLC (any T with N2, T4N0-1) will be registered to receive oral alectinib 600 mg twice daily for 2 cycles of 4 weeks each (8 weeks totally) during the neoadjuvant phase. After definitive surgery, patients will enter in the adjuvant setting, during which they will receive alectinib 600 mg twice daily for 24 cycles (96 weeks). The primary endpoint is MPR, defined as ≤10% residual viable tumor cells histologically detected in the resected primary tumor and all resected lymph nodes after surgery. Secondary endpoints include pathological complete response, objective response, event-free survival, disease-free survival, overall survival, adverse events. ConclusionsOur case report supports the feasibility of alectinib as neoadjuvant treatment. ALNEO study will further explore the activity and safety of this novel treatment strategy.

The effect of EML4-ALK break-apart ratio on crizotinib outcomes in non-small cell lung cancer harboring EML4-ALK rearrangement

Anaplastic lymphoma kinase (ALK) gene rearrangement exists in approximately 3-7% of non-small cell lung cancer (NSCLC) and more than 15% split or isolated red signals among 50 tumor nuclei scored in the FISH analysis defines as ALK-positive. The previous studies showed that the high EGFR mutational load related to better outcomes in EGFR mutant NSCLC. Therefore, we aimed to investigate the effect of the ALK break-apart ratio on treatment outcome in metastatic ALK-positive NSCLC. The patients (pts) who ALK-positive and treated with crizotinib were retrospectively enrolled. The 30%, 40%, 50%, 60%, and 70% break-apart ratios were determined as a threshold value, and each of these was evaluated separately. Based on the results of these analyses, we detected the optimal threshold value and also performed further investigations. A total of 70 patients were enrolled in the study. The most significant decrease in the risk of the progression or death was detected at the 50% threshold value and it was accepted as the optimal threshold. The median PFS was 17.9 vs. 7.06months (mo) in the pts with high ALK rearrangement than low (HR: 0.43, 95% CI 0.24-0.76, p 0.004). The median OS was also significant longer in high ALK rearrange group (44.6 mo vs. 16.8 mo; HR: 0.37, 95% Cl 0.1883-0.7315; p 0.004). The intracranial progression during crizotinib treatment was significantly frequent in the pts with high ALK rearrangement (62.5-32.5%, P 0.039) DISCUSSION: In this study, we found that the high break-apart ratio can predict the extent of benefit from targeted therapy in ALK-positive NSCLC patients. Based on the results of this study, the percentage of the ALK rearrangement can be used to predict treatment outcome and to choose the optimal targeted agent in the treatment of metastatic ALK-positive NSCLC.

Different clinical features between patients with ROS1-positive and ALK-positive advanced non-small cell lung cancer

ObjectiveTo compare the baseline clinical characteristics between patients with ROS1-positive and ALK-positive advanced non-small cell lung cancer (NSCLC), and the correlations of these subtypes with the distribution of metastases.MethodsWe compared the clinical characteristics and imaging features of patients with ROS1-positive and ALK-positive NSCLC using statistical methods.ResultsData for 232 patients were analyzed. Compared with ALK-positive NSCLC, ROS1-positive NSCLC was more likely to occur in women (71% vs 53%), and primary lesions ≤3 cm were more common in patients with ROS1-positive compared with ALK-positive NSCLC (58% vs 37%). There was no significant difference in the distribution of metastases between the two groups. Subgroup analysis within the ROS1-positive group showed that, compared with primary lesions >3 cm, primary lesions ≤3 cm were more likely to present as peripheral tumors (72% vs 43%) and more likely to exhibit non-solid density (44% vs 4%).ConclusionsAlthough ROS1-positive and ALK-positive NSCLCs show similar clinical features, the differences may help clinicians to identify patients requiring further genotyping at initial diagnosis.

Brigatinib: A Review in ALK-Inhibitor Naïve Advanced ALK-Positive NSCLC.

Brigatinib (Alunbrig®) is an oral, potent and selective anaplastic lymphoma kinase (ALK) and c-ros oncogene 1 (ROS1) tyrosine kinase inhibitor approved for treating adults with advanced ALK-positive non-small-cell lung cancer (NSCLC) not previously treated with an ALK inhibitor. In a multinational, phase III study (ALTA-1L) in this patient population, brigatinib significantly improved median blinded independent review committee-assessed progression-free survival (PFS), the confirmed objective response (OR) rate and the confirmed intracranial OR rate compared with crizotinib. Its tolerability profile in this study was manageable and no new safety concerns were identified. Although final analysis data are awaited with interest, brigatinib therapy extends the first-line treatment options available for standard of care in this patient population, including patients with CNS metastases.

Impact of STAT1 polymorphisms on crizotinib-induced hepatotoxicity in ALK-positive non-small cell lung cancer patients.

Crizotinib is the first-line small molecule tyrosine kinase inhibitor for ALK-positive non-small cell lung cancer. In this study, a retrospective pharmacogenomics investigation was conducted to explore the relationship between genes related to RTK downstream signaling pathways and crizotinib-induced hepatic toxicity in ALK-positive NSCLC patients. The variable importance analysis of random forest algorithm was applied to identify the significant features which contribute to the crizotinib sensitivity in Cancer Cell Line Encyclopedia (CCLE) database. The KEGG and reactome pathway enrichment analysis were conducted with EnrichR. The differential expression genes were identified with R package DESeq2 in CCLE liver derived cell lines between crizotinib sensitive and resistant groups. From 2012 to 2015, 42 NSCLC patients were enrolled in this study. 90 polymorphisms were genotyped using the Sequenom Massarray system. Sequencing of HGFR (c-Met) genes was carried out on the Ion Torrent Proton. In total, 66.7% NSCLC patients suffered from crizotinib-induced liver toxicity and 11.9% progressed to severe hepatic toxicity. The features with the top importance from classification and regression random forest model were enriched in RTK downstream signaling pathways (JAK/STAT, RAS/RAF/MAPK, PI3K/AKT pathways) and immune system-related pathways. Collagen family genes (COL1A1, COL1A2, COL6A1, COL5A1) and other extracellular matrix protein (TNC, TAGLN, TENM2, EDIL3, VCAN, CNN1, SH3BP4, TAGLN), which were closely related to MAPK-ERK signaling pathways, were significantly enriched in crizotinib resistant cell lines. In multiple logistic regression, STAT1 rs10208033 (T > C) was significantly associated with crizotinib-induced liver toxicity (OR = 6.733, 95% CI 1.406-32.24, P = 0.017). Compared with non-CC, OR is 5.5 (95% CI 1.219-24.81, P = 0.027) for STAT1 rs10208033 CC genotypeto develop crizotinib-induced liver toxicity. Further cell viability test in human fetal hepatocyte line, L-02, reveals that the STAT1 inhibitor might protect hepatocyte cells from the toxicity caused by crizotinib. Polymorphism of rs10208033 is a potential biomarker for predicting crizotinib-induced hepatotoxicity. These results suggest that STAT1 plays an important role in crizotinib-induced hepatotoxicity. Further studies are needed to confirm our finding and understand the underlying mechanisms.

MRI radiomic signature predicts intracranial progression-free survival in patients with brain metastases of ALK-positive non-small cell lung cancer.

BackgroundIntracranial progression is considered an important cause of treatment failure in anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer (NSCLC) patients. Recent advances in targeted therapy and radiomics have generated considerable interest for the exploration of prognostic imaging biomarkers to predict the clinical course. Here, we developed a magnetic resonance imaging (MRI) radiomic signature that can stratify survival and intracranial progression.MethodsWe analyzed 87 brain metastatic lesions in 24 ALK-positive NSCLC patients undergoing ALK-inhibitor ensartinib therapy and divided them into training (n=61) and validation (n=26) sets. Radiomic features were extracted and screened from contrast-enhanced MR images. Combined with these selected features, the Rad-score was calculated with multivariate logistic regression. The predictive model and Rad-score performance were assessed in the training set and validated in the validation set; decision curve analysis was performed with the combined training and validation sets to estimate Rad-score’s patient-stratification ability.ResultsThe prediction model constructed with nine selected radiomic features could predict intracranial progression within 51 weeks (AUC =0.84 and 0.85 in the training and validation sets, respectively), while clinical and regular MRI characteristics were independent of progression (P>0.05). The decision-curve analysis showed that the radiomic prediction model was clinically useful. The Kaplan-Meier analysis showed that the progression-free survival (PFS) difference between the high- and low-risk groups distinguished by the Rad-score was significant (P=0.017).ConclusionsRadiomics may provide prognostic information and improve pretreatment risk stratification in ALK-positive NSCLC patients with brain metastases undergoing ensartinib treatment, allowing follow-up and treatment to be tailored to the patient’s individual risk profile.

The Emerging Therapeutic Landscape of ALK Inhibitors in Non-Small Cell Lung Cancer.

The treatment of metastatic non-small cell lung cancer (NSCLC) has undergone a paradigm shift over the last decade. Better molecular characterization of the disease has led to the rapid improvement of personalized medicine and the prompt delivery of targeted therapies to patients with NSCLC. The discovery of the EML4-ALK fusion gene in a limited subset of patients affected by NSCLC and the subsequent clinical development of crizotinib in 2011 has been an impressive milestone in lung cancer research. Unfortunately, acquired resistances regularly develop, hence disease progression occurs. Afterward, modern tyrosine kinase inhibitors (TKIs), such as ceritinib, alectinib, brigatinib, and lorlatinib, have been approved by the Food and Drug Administration (FDA) for the management of anaplastic lymphoma kinase (ALK)-positive NSCLCs. Several compounds are currently under investigation to achieve the optimal strategy of therapy. Additionally, the results of ongoing clinical trials with novel-generation TKI will provide more evidence on the best sequence in the treatment of ALK-positive NSCLC patients. In this review, we provide a comprehensive overview of the state-of-the-art targeted therapy options in ALK-positive NSCLCs. Resistance, potential therapeutic strategies to overcome drug resistance, and future perspectives for this subset of patients are critically analyzed and summarized.

Out-of-Pocket Costs for Tyrosine Kinase Inhibitors and Patient Outcomes in EGFR- and ALK-Positive Advanced Non-Small-Cell Lung Cancer.

We investigated the association of out-of-pocket (OOP) costs for tyrosine kinase inhibitors (TKIs) with overall survival (OS) in epidermal growth factor receptor (EGFR)- and anaplastic lymphoma kinase (ALK)-positive advanced non-small-cell lung cancer (NSCLC). We secondarily investigated associations of TKI OOP costs with TKI adherence, duration of therapy (DOT), and TKI discontinuation. We used the Hutchinson Institute for Cancer Outcomes Research registry-claims database to identify patients with stage IV EGFR- or ALK-positive NSCLC; ≥ 1 claims for EGFR or ALK TKIs; and ≥ 3-month survival from TKI initiation. We estimated the average monthly TKI OOP costs per patient up to 3 months from TKI initiation, categorizing patients into quartiles of TKI OOP costs (Q1 < Q2 < Q3 < Q4). We conducted landmark analysis at 3 months from TKI initiation to compare Q1-3 v Q4 TKI OOP costs with respect to OS, TKI DOT, TKI adherence, and TKI discontinuation. Seventy-eight and twenty-seven patients comprised the Q1-3 and Q4 groups, respectively. Median monthly TKI OOP costs were $1,431 (Q1-3) v $2,888 (Q4). Compared with Q1-3, Q4 patients had inferior OS (adjusted hazard ratio [HR], 1.85; [95% CI, 1.11 to 3.10], similar TKI DOT (adjusted HR, 1.06; 95% CI, 0.53 to 2.15), decreased TKI adherence (adjusted odds ratio [OR], 0.28; 95% CI, 0.10 to 0.76), and higher TKI discontinuation rate (adjusted OR, 8.75; 95% CI, 2.59 to 29.52). Among patients with advanced EGFR- and ALK-positive NSCLC, higher TKI OOP costs are associated with decreased TKI adherence, a higher likelihood of TKI discontinuation, and inferior survival.