ALK-positive Non-small Cell Lung Research Articles

P2.10-08 A New Prognostic Tool for Predicting the Overall Survival of ALK Positive Non-small Cell Lung Cancer with Brain Metastasis

P2.10-08 A New Prognostic Tool for Predicting the Overall Survival of ALK Positive Non-small Cell Lung Cancer with Brain Metastasis

Recommended first-line management of asymptomatic brain metastases from EGFR mutant and ALK positive non-small cell lung cancer varies significantly according to specialty: an international survey of clinical practice.

The role for radiotherapy or surgery in the upfront management of brain metastases (BrM) in epidermal growth factor receptor mutant (EGFRm) or anaplastic lymphoma kinase translocation positive (ALK+) non-small cell lung cancer (NSCLC) is uncertain because of a lack of prospective evidence supporting tyrosine kinase inhibitor (TKI) monotherapy. Further understanding of practice heterogeneity is necessary to guide collaborative efforts in establishing guideline recommendations. We conducted an international survey among medical (MO), clinical (CO), and radiation oncologists (RO), as well as neurosurgeons (NS), of treatment recommendations for asymptomatic BrM (in non-eloquent regions) EGFRm or ALK+ NSCLC patients according to specific clinical scenarios. We grouped and compared treatment recommendations according to specialty. Responses were summarized using counts and percentages and analyzed using the Fisher exact test. A total of 449 surveys were included in the final analysis: 48 CO, 85 MO, 60 NS, and 256 RO. MO and CO were significantly more likely than RO and NS to recommend first-line TKI monotherapy, regardless of the number and/or size of asymptomatic BrM (in non-eloquent regions). Radiotherapy in addition to TKI as first-line management was preferred by all specialties for patients with ≥4 BrM. NS recommended surgical resection more often than other specialties for BrM measuring >2 cm. Recommendations for the management of BrM from EGFRm or ALK+ NSCLC vary significantly according to oncology sub-specialties. Development of multidisciplinary guidelines and further research on establishing optimal treatment strategies is warranted.

382P Real-world data on treatment outcome of ALK positive non-small cell lung cancer from an Indian multi-centric cancer registry

The ALK inhibitors (ALKi) are the standard of care in metastatic NSCLC with EML4-ALK rearrangements. Different ALKi have been used in the clinics, however, not all eligible patients get to be treated with them for various reasons. We attempted to find out the real-world data on the treatment outcome in our country.

SAF-189s in advanced, ALK-positive, non–small cell lung cancer: Results from a first-in-human phase 1/2, multicenter study.

9076 Background: SAF-189s is a potent, brain-penetrant, next-generation anaplastic lymphoma kinase (ALK) inhibitor with preclinical activity against most known resistance mutations of ALK. We investigated safety, population pharmacokinetics, efficacy, and antitumor activity of SAF-189s in advanced, ALK-positive (ALK+) non-small cell lung cancer (NSCLC). Methods: In this first-in-human phase 1/2 trial (NCT04237805), patients aged ≥18 years with histologically or cytologically confirmed, advanced, ALK+ NSCLC (with or without brain metastases) and an Eastern Cooperative Oncology Group performance status of 0–2 were recruited from 41 hospitals in China. Oral SAF-189s was given in escalating doses of 20–210 mg once daily in continuous, 21-day cycles until disease progression, unacceptable toxicity, consent withdrawal, or death. Phase 1 data were presented at ASCO 2020. Here, we report updated phase 1 results and preliminary phase 2 data. Results: At a clinical cutoff date of January 18, 2022, 45 patients with prior systemic therapy enrolled in phase 1 and 150 were enrolled in phase 2. SAF-189s was well tolerated, the most common grade 3–4 treatment-related adverse events were hyperglycemia (7%), hypertension (6%) and diarrhea (3%). No treatment-related death was reported. 160 mg was chosen as the recommended phase 2 dose. In phase 1, 11 (24%) patients were ALK inhibitor (ALKi)-naive and 34 (76%) were ALKi-pretreated. Median progression-free survival (PFS) was 33.1 and 22.1 months (95% CI 6.9–not reached: 13.8–26.6) in ALKi-naive and ALKi-pretreated patients, respectively. Disease control rates (DCRs) were 100% in both ALKi-naive and ALKi-pretreated patients. Most patients in phase 2 were ALKi-naive (n=104, 69%), 26 (17%) received prior crizotinib only and 20 (12%) were pretreated with ≥1 non-crizotinib ALKi. The median duration of follow-up was 11.7 months (range 10.3–16.8), ORRs were comparable between the full analysis set and the 71 patients with brain metastases at 78.7% (95% CI 71.2–84.9) and 74.6% (95% CI 62.9–84.2) respectively. ALKi-naive patients had ORR of 92.3% (95% CI 85.4–96.6), compared to 65.4% (95% CI 44.3–82.8) in the crizotinib-pretreated group. DCR was 98.1% in ALKi-naive and 88.5% in crizotinib-pretreated patients. PFS data are not mature. Conclusions: SAF-189s showed clinical antitumor activity and was well tolerated in patients with advanced, ALK+ NSCLC, including those with brain metastases and pretreated with crizotinib. SAF-189s represents a promising, next-generation, targeted therapy for patients with ALK+ NSCLC. Clinical trial information: NCT04237805. [Table: see text]

ALK-Positive Non-Small Cell Lung Cancer; Potential Combination Drug Treatments.

Advances in chromosomally rearranged ALK positive non-small cell lung cancer have been dramatic in only the last few years. Survival times have improved dramatically due to the introduction of ever more efficacious ALK inhibitors. These improvements have been due largely to improvements in blood-brain barrier penetration and the breadth of ligand binding pocket mutations against which the drugs are effective. However, the advances maybe slow due to the frequency of cancers with compound resistance mutations are appearing, suggesting the need to develop multiple ALK inhibitors to target different compound mutations.Another research area that promises to provide further gains is the use of drug combinations, with an ALK inhibitor combined with a drug targeting a "second driver" to overcome resistance. In this review, the range of secondary targets for ALK+ lung cancer and the potential for their clinical success are reviewed.

Pathological cytomorphologic features and the percentage of ALK FISH-positive cells predict pulmonary adenocarcinoma prognosis: a prospective cohort study

BackgroundWe conducted a study to explore the relationship between pathological cytomorphologic features and the percentage of anaplastic lymphoma kinase (ALK)-positive cells to better predict pulmonary adenocarcinoma prognosis with crizotinib treatment.Patients and methodsWe investigated 60 cases of patients with ALK-positive advanced or metastatic non-small cell lung cancer (NSCLC). Immunohistochemistry was performed to screen for ALK rearrangement. Fluorescence in situ hybridization (FISH) was used to detect the percentage of ALK-positive cells. The primary objectives of the study were the progression-free survival (PFS), the 3-year overall survival, and the 3-year overall survival (OS) rates. The secondary objectives of the study were the disease control rate (DCR) and the overall response rate (ORR).ResultsWe compared the pathological cytomorphologic features of 60 cases of ALK-positive pulmonary adenocarcinoma, of which 21 cases were ALK-positive with signet ring cell cytomorphologic characteristics. There were statistical differences in the ORR (p = 0.019), DCR (p = 0.032), and PFS (p = 0.047) between the signet ring cell group and group without signet ring cells. Of these, 37 cases were ALK-positive with EML4 (echinoderm microtubule associated protein like 4)-ALK high percentage of positivity group. These cases benefited more from crizotinib treatment in the ORR (p = 0.046) and achieved a longer PFS (p = 0.036) compared to those with EML4-ALK low percentage of positivity group.ConclusionsSignet ring cell cytomorphologic characteristics of pulmonary adenocarcinoma are associated with the percentage of ALK-positive cells. Signet ring cell cytomorphologic characteristics and the percentage of ALK-positive cells might predict the prognosis of pulmonary adenocarcinoma with crizotinib treatment.Trial registrationThe study was approved by the Institutional Review Board (Medical Ethics Committee of Yantai Yuhuangding Hospital). The registration number is NO.2016[193].

1356P Cumulative incidence and baseline imaging patterns of brain metastases in advanced EGFR and ALK positive non-small cell lung cancer (NSCLC)

Up to 40% of NSCLC patients develop brain metastases (mets) during the course of their disease. We explored the impact of histology and EGFR and ALK mutations on cumulative incidence rates of brain mets and influence of brain imaging patterns.

Drug interaction profile of TKI alectinib allows effective and safe treatment of ALK+ lung cancer in the kidney transplant recipient

ALK targeting with tyrosine kinase inhibitors (TKIs) is a highly potent treatment option for the therapy of ALK positive non-small cell lung cancer (NSCLC). However, pharmacokinetics of TKIs leads to clinically significant drug interactions, and the interfering co-medication may hamper the anti-cancer therapeutic management.Here, we present for the first time a drug interaction profile of ALK-TKIs, crizotinib and alectinib, and immunosuppressive agent cyclosporine A in kidney transplant recipients diagnosed with ALK+ lung cancer. Based on therapeutic drug monitoring of cyclosporin A plasma level, the dose of cyclosporine A has been adjusted to achieve a safe and effective therapeutic level in terms of both cancer treatment and kidney transplant condition. Particularly, 15 years upon the kidney transplantation, the stage IV lung cancer patient was treated with the 1st-line chemotherapy, the 2nd-line ALK-TKI crizotinib followed by ALK-TKI alectinib. The successful therapy with ALK-TKIs has been continuing for more than 36 months, including the period when the patient was treated for COVID-19 bilateral pneumonia. Hence, the therapy of ALK+ NSCLC with ALK-TKIs in organ transplant recipients treated with cyclosporine A may be feasible and effective.

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.

Experience of targeted therapy for ALK positive non-small cell lung cancer – a clinical case

Lung cancer holds a leading position in the cancer mortality pattern worldwide. The emergence of knowledge about driver mutations heralded a new era in the targeted therapy for lung carcinomas. ALK translocation is identified in 5–7% of non-small cell lung cancer cases. ALK-positive lung adenocarcinomas are associated with specific clinical features, including no or light smoking history and younger age. Alectinib is a novel ALK inhibitor that has been granted a breakthrough therapy status by the FDA to accelerate approval as a second-line therapy after progression during crizotinib therapy.Here, the case of a patient with metastatic ALK-positive lung adenocarcinoma treated with alectinib has been discussed. Molecular genetic testing for driver mutations makes it possible to personalize approaches to anticancer drug therapy. At the same time, the custom-compounded targeted therapy is more often accompanied by significant objective responses and moderate symptoms of toxicity, which is relevant for patients in critical condition. The experience in using alectinib demonstrates the possibility of its long-term administration with high efficiency and a controlled safety profile.

A phase I, dose-escalation and expansion study of TQ-B3139, a novel ALK TKI, in Chinese ALK or ROS1 positive advanced non-small cell lung cancer (NSCLC).

9585 Background: TQ-B3139 is a novel ALK inhibitor with activity 3-7 folds higher than Crizotinib against a broad range of ALK mutations. This phase I study (NCT03099330) is to investigate the safety, and determine the recommended phase II dose (RP2D), and pharmacokinetic (PK), clinical efficacy of TQ-B3139 in Chinese NSCLC patients. Methods: Patients with advanced NSCLC and failed at least one systemic anti-cancer treatment were enrolled. TQ-B3139 was administered orally from 50mg~100mg qd and 200, 300, 400, 500, 600 and 800mg bid, using a PK-guided modified Fibonacci 3+3 dose escalation design. The dose-escalation evaluated patients in 28-day cycles, dose limited toxicities (DLTs) was observed at first cycle. Dose-expansion phase started at dose level which objective response occurs. Treatment was continued until disease progression, death or unacceptable toxicity. Results: Between July 2017 and May 2019, totally 63 patients (59 ALK+, 4 ROS1+) were enrolled. Sixteen patients had prior ALK inhibitor therapy (11 Crizotinib, 5 Ensartinib), and 23 (36.5%) with baseline brain metastasis. Totally, 62 (98.4%) patients experienced treatment-related adverse events (TRAEs), grade 3-4 TRAEs were observed in 21 (33.3%) patients. One DLT occurred in the 800mg bid dose cohort (grade 3 nausea and vomiting). Top 3 common TRAEs were nausea (all grade 87.3%; grade 3-4 3.2%), diarrhea (84.1%, 6.4%), transaminase elevation (65.1%, 4.8%). AUC and Ctrough at steady state increased proportionally from 200mg to 600mg bid. Absorption saturation was observed in 800mg bid. Base on the safety and PK results, PR2D was decided at 600mg bid. Overall ORR was 73.0% (2 CR, 44 PR); DCR was 85.7% (8 SD). Objective response was observed from dose level 200mg bid cohort, ORR and DCR at ≥200mg bid was 78.0% and 89.8%. For ALK TKI-naïve and -resistant patients, the ORR was 78.7% (37/47) and 56.3% (9/16) respectively. For patients with measurable baseline brain metastasis, the ORR for brain lesions was 80.0% (8/10). At data cut-off (23 Jan 2020), 32 events (50.8%) occurred, the median PFS for all patients was 12.1 months (95%CI 8.5-15.6), for patients at ≥200mg bid dose was 12.2 months. The median PFS was not reached for -naive patients (6 months PFS rate 74.5%, 95%CI 68.1-80.9), and 5.6months (95%CI 1.6-9.5) for ALK TKI-resistant patients. Conclusions: TQ-B3139 was well tolerated in Chinese NSCLC patients with high antitumor activity. RP2D was established at 600mg bid. A randomized phase III trial of TQ-B3139 versus Crizotinib in advanced ALK-TKI naïve NSCLC patients is underway. Clinical trial information: NCT03099330 .

Cytotoxicity of curcumin derivatives in ALK positive non-small cell lung cancer

Non-small cell lung cancer with ALK rearrangements can be targeted effectively with ALK inhibitors such as crizotinib. However, cancer progression typically occurs within a year as drug resistance develops. One strategy to overcome this drug resistance is to determine if novel cytotoxic agents retain the ability to kill lung cancer cells that have developed ALK inhibitor resistance. We therefore examined curcumin, a drug with anticancer properties, and 2 s-generation curcumin derivatives (1-methyl-3,5-bis[(E)-4-pyridyl) methylidene]-4-piperidone (RL66) and 1-isopropyl-3,5-bis[(pyridine-3-yl) methylene]piperidin-4-one (RL118)) in lung cancer cell lines. The cytotoxicity of curcumin, RL66, and RL118 were tested in both ALK+ lung cancer cells (H3122), crizotinib resistant ALK+ cells (CR-H3122) and ALK− lung cancer cells (A549), both alone and in combination with crizotinib. ALK+ cells were 2-3x more sensitive to RL66 and RL118 than ALK− cells, with the drugs’ eliciting IC50 values in the range of 0.7–1 μM in H3122 cells. Retained cytotoxic potency of the curcumin derivatives in crizotinib resistant cells indicated that mechanisms of resistance to the two drug types are independent, with resistance to ALK inhibitors not necessarily causing cross-resistance to curcumin derivatives. This was further corroborated by drug combination analysis where the effect of the drugs in combination was consistent with Bliss additivity, consistent with independent targets for crizotinib and curcumin derivatives. Results from Western blotting showed that RL118 (2 μM) inhibited p-ALK/ALK by ~50%, which was not as potent as the 90% inhibition elicited by crizotinib (0.25 μM). Since this is the primary mechanism of crizotinib cytotoxicity this provides further evidence of independent mechanisms of toxicity.

P1.16-30 Impact of Patient TKI Copayments on Insurance Expenditure in Advanced EGFR or ALK Positive Non-Small Cell Lung Cancer (NSCLC)

To influence treatment choice and control expenditures, insurance plans impose cost sharing policies for expensive oral tyrosine kinase inhibitors (TKIs). We evaluated the effect of patient TKI copayments on insurance expenditures among patients with EGFR and ALK positive advanced NSCLC receiving TKIs. We identified EGFR+ and ALK+ NSCLC patients in the Washington State SEER registry using natural language processing on registry pathology reports, followed by manual confirmation of molecular test results. We linked registry records with commercial and Medicare claims. Eligible patients had stage IV NSCLC diagnosed between 01/01/2010 and 12/31/2016, EGFR exon 19 deletions or L858R mutations, or ALK + by FISH, ≥ 12 months of insurance enrollment, survival of ≥6 months, and ≥ 1 pharmacy claims for EGFR or ALK TKIs with FDA approval in the study period. We estimated monthly TKI copayments by subtracting the drug amount paid from the amount allowed by insurance in pharmacy claims. We used claims to calculate lifetime total and drug costs from the insurance perspective. Covariates included sociodemographic characteristics, insurance type, comorbidity, mutation type, and receipt of chemotherapy and immunotherapy. We used generalized linear models with gamma family and log link to estimate the adjusted effect of TKI copayment of $0 vs. above $0 on insurer expenditures in 2016 US dollars. Of 103 eligible patients, median age was 69; 66% were female; 72% were White, median household income was $69,951; 54% had Medicare, 85% were EGFR+, and 51% received chemotherapy or immunotherapy. Mean monthly TKI copayment was $312 (range= $0 to $5,913). Mean total and drug reimbursements were $234,294 and $114,253. Table 1 shows the adjusted effect of TKI copayments on insurance expenditures. Higher TKI copayments were not associated with lower insurance expenditures. Eliminating TKI copayments would reduce patient financial burden and not adversely impact insurer spending.Table 1Effect of Patient TKI Copayments on Insurance Expenditures, Adjusted for Age, Race, Comorbidity, Insurance Type, Mutation Type, Receipt of Chemotherapy and Immunotherapy (EGFR TKIs: erlotinib, gefitinib, afatinib, osimertinib; ALK TKIs: crizotinib, alectinib, ceritinib, brigatinib).TKI Copayment (n=103)Adjusted Mean Total Expenditure (95% CI)P valueAdjusted Mean Drug Expenditure (95% CI)P value$0 (n=82)$230,989 ($188,958; $273,019)Ref.$110,171 ($88,150; $132,194)Ref.Above $0 (n=21)$264,963 ($182,424; $347,502)0.44$132,707 ($83,206; $182,208)0.38 Open table in a new tab

EP1.01-35 Concurrent Use of Low Dose Aspirin and Vitamin D in ALK, ROS and EGFR Mutant NSCLC: A Single Institution Retrospective Analysis

Tyrosine kinase inhibitors (TKI) are the backbone therapy for EGFR, ALK and ROS positive (pos) non-small cell lung cancer (NSCLC). Pre-clinical data suggest that low vitamin D level facilitates the growth of mutant EGFR NSCLC through Vitamin D receptor (VDR). VDR is highly expressed in EGFR lung cancer cells, and its interaction with activated 1,25 vitamin D3 (1,25D3) promotes epithelial differentiation and apoptosis while inhibiting cellular proliferation and angiogenesis. Thus vitamin D3 supplementation may potentially add anti-cancer activity to conventional therapy in this population. On the other hand, murine models have shown that prolonged use of aspirin reduces the incidence of distant metastases. It is postulated that biosynthesis of prostaglandins generate a permissive intravascular metastatic niche, through platelet aggregation and endothelial activation. Recent meta-analysis published by Feng et al. analyzed seventeen studies and reported statistically significant reduction in risk of lung cancer by 8% when circulating 25-VD is at 10 nmol/L, this benefit was seen in both Caucasian and Asian population. To our knowledge, there have been no studies looking at influence of concurrent vitamin D or aspirin intake on outcomes in ALK, ROS and EGFR pos NSCLC treated with tyrosine kinase inhibitors. We performed a retrospective single institution analysis to study this association. Patients (pts) with ALK, ROS EGFR pos NSCLC treated with first line TKI from January 2014 to June 2017 were included. Information on concurrent use and doses of aspirin and vitamin D supplements were studied. Patients were dichotomized based on use of these individual supportive medications. Two sample t-test was used to compare mean PFS and chi-square test to compare proportions of disease control rate (DCR) at 3 months between groups. 74 patients were included. PFS in Vitamin D supplementation (n=41, 55%) group was 11 months compared to 10.2 m in those not on Vitamin D (p = 0.21, CI 1.9). For those on aspirin (n=23, 35%), mean PFS was 16m vs 12.5 m (p = 0.7213; 95% CI -5.5812 to 3.8812). DCR for aspirin use was 50% vs 65% (p = 0.1796) and for vitamin D 48.6% vs 43.7% (p= 0.6989). Our study did not show any differences in PFS or DCR in EGFR, ROS and ALK positive NSCLC patients who were concurrently taking vitamin D or aspirin compared with those who were not. Our study was small and was not powered to pick up any significant differences. Given the strong pre-clinical background, further prospective studies would be interesting to evaluate the synergistic benefit of vitamin D and aspirin with concurrent TKI use.

Predictors of delays in initiation of oral tyrosine kinase inhibitors (TKIs) in EGFR and ALK positive advanced non-small cell lung cancer (NSCLC).

134 Background: Molecular testing practices and cost-sharing policies may result in delayed initiation of TKI therapy. We assessed predictors of delayed initiation of TKIs in metastatic EGFR+ or ALK+ NSCLC. Methods: We identified patients with EGFR+ and ALK+ NSCLC diagnosed between 01/01/2010 and 12/31/2016 in the Washington State SEER registry using validated natural language processing methods. We linked registry records to commercial and Medicare (including part D) claims. Eligible patients had stage IV NSCLC, sensitizing EGFR mutations or ALK+ by FISH, ≥ 1 pharmacy claims for EGFR or ALK TKIs, and ≥12 months of insurance enrollment post-diagnosis. Potential predictors included age, sex, race, Census-level median household income, urban status, insurance type, comorbidity, histology, mutation type, and receipt of chemotherapy prior to first TKI claim (pre-TKI chemo). We defined time to TKI initiation as the interval from diagnosis to first pharmacy claim for EGFR or ALK TKIs. We fitted Cox regression models to identify predictors of delays in TKI initiation, defining covariates with a P < 0.05 in a final multivariate model as independently associated with delays. Results: For 122 patients (median age 70; 65% female; 74% White; median income $66,580; 98% metropolitan; 35% Medicare; 80% EGFR+; 12% using pre-TKI chemo), the median time to TKI initiation was 6.7 weeks (IQR = 3.9 to 14.0). Independent predictors of TKI delays included male sex (HR = 0.51; 95%CI = 0.34; 0.76); Medicare insurance (HR = 0.32; 95% CI = 0.20; 0.53) and pre-TKI chemo (HR = 0.37; 95% CI = 0.20; 0.66). Median time to TKI initiation was 9.7 vs. 5.8; 7.8 vs. 4.1; and 16.0 vs. 6.3 weeks in male vs. female, Medicare vs. commercial insurance, and pre-TKI chemo (yes vs no), respectively. Conclusions: Male sex, Medicare insurance, and chemotherapy prior to TKI are associated with delays in TKI initiation for EGFR+ and ALK+ stage IV NSCLC patients. Possible explanations include higher prevalence of smoking in males resulting in lower priority for molecular testing, high cost-sharing policies for TKIs in Medicare patients, and prolonged time to obtain molecular test results leading patients to start chemotherapy first.

The role of low dose aspirin, vitamin D, or metformin in EGFR, ALK, and ROS positive non-small cell lung cancer: A single institution retrospective analysis.

e20656 Background: Tyrosine kinase inhibitor (TKI) is the backbone therapy for EGFR, ALK and ROS positive (pos) non-small cell lung cancer (NSCLC). Metformin has shown to sensitize EGFR resistant lung cancer cells in vitro through IL-6/STAT pathways. COX-2 overexpression triggers activation of a transcription factor that binds to EGFR that activates MAPK signaling pathway. Vitamin D receptor (VDR) has shown to directly inhibit EGFR transcriptional activity. Some studies have shown that adding metformin, aspirin and vitamin D (MAD) to chemotherapy may improve progression free survival (PFS) and overall survival (OS) in lung cancer. However, data supporting use of MAD is unknown in EGFR, ALK and ROS pos NSCLC. Methods: Patients (pts) with EGFR, ALK, ROS pos NSCLC treated with first line TKI from January 2014 to June 2017 were included. Information on concurrent use of MAD was obtained. Patients were dichotomized based on use of these individual supportive medications. Two sample t-test was used to compare mean PFS and chi-square test to compare proportions of disease control rate (DCR) at 3 months between groups. Results: 74 patients were included. Vitamin D supplementation (n = 38, 51.3%) prolonged PFS by 16 m vs 11 m (p = 0.04; 95%CI 0.23 to 9.34). For those on aspirin (n = 23, 35%), mean PFS was 16m vs 12.5 m (p = 0.72; 95% CI -5.58to 3.88). Mean PFS for pts on metformin (n = 8, 10%) was 14 months (m) vs 13.5 m for those who were not (p = 0.93, 95% CI -7.27 to 7.87). DCR for metformin use was 26.5% vs 89% (p = 0.0001); for aspirin was 50% vs 65% (p = 0.17) and for vitamin D 48.6% vs 43.7% (p = 0.69). Conclusions: To our knowledge, no data has been published regarding use of MAD in NSCLC with driver mutations. In our study, concurrent use of vitamin D with TKI prolonged PFS in these pts. However, this effect was not seen with metformin or aspirin. Our study was limited by retrospective design, possible under-reporting of medication use by patients and small patient population. Further prospective studies using these medications is important to evaluate the synergistic benefit with the approved targeted therapy.

Efficacy of tyrosine kinase inhibitors (TKIs) based on the ALK resistance mutations on amplicon-based liquid biopsy in ALK positive non-small cell lung cancer (NSCLC) patients (pts).

3055 Background: Acquired ALK resistance mutations (mut.) are the main mechanism of tyrosine kinase inhibitor (TKI) resistance (30-50%). While next-generation TKIs are more active on mut. than earlier TKIs, compound ALK resistance are associated with failure to next-generation TKIs. We evaluated the clinical utility of detecting ALK resistance mutations in blood to predict TKI efficacy. Methods: ALK positive advanced NSCLC pts were prospectively enrolled between Oct. 2015 and Aug. 2018 in 8 French institutions. Prospective samples were collected; ctDNA was analyzed by amplicon-based Inivata InVisionFirst-Lung. Results: A total of 101 pts with advanced ALK positive NSCLC were enrolled and 328 samples collected. In samples collected at TKI failure (N=74), we detected 9 single and 7 complex (≥2) ALK resistance mut. (22%), associated with EML4-ALK variant 3 (38%) vs. variant 2 (13%) vs. variant 1 (none); 30% had other somatic mut. (mainly TP53 and KRAS, PI3KCA, MET, etc.). No mutations were detected in 48% of samples (ctDNA neg). ALK mut. were more frequent after 2nd/3rd generation TKI (43% post-lorlatinib (7), 29% post-2nd gen. (31), 11% post-crizotinib (36)). ALKG1202R was the most common, as single (n=3) or complex mut. (n=4). The median overall survival (mOS) was 100.4 mo. (95% CI 41.9-158.9) and the median progression free-survival (mPFS) to subsequent line was 2.8 mo. (0.7-4.9). Patients with ctDNA neg had mOS of 105 mo. (39.3-172.1) vs. 58.5 mo. (33.1-84.0) if ≥1 ALK mut. vs. 44.1 mo. (20.0-68.2) if others ( P=0.001). Pts with the complex ALK mut. had worse OS compared to singles ALK mut. (mOS 26.9 mo. vs. 58.5 mo., P=0.001); ALK complex mut. were associated with poor efficacy to subsequent therapy (PFS <3 mo. in 57%; no cases with PFS >6 mo.) vs. single mut., with longer PFS (PFS >6 mo. in 56%). Detectable ALKG1202R mut. were associated with shorter median OS (58.3 mo.; 7.9-109.1) vs. overall population; 86% of cases developed rapid PD (PFS <3mo.) to subsequent therapy with only one durable response to lorlatinib (PFS >6mo.). Conclusions: The absence of ctDNA mutations at TKI failure was associated with prolonged OS, whereas complex ALK mutations at TKI failure may predict resistance to subsequent therapy. Larger and specifically designed studies should be performed to validate these findings.

Characteristics of EGFR, ALK, or KRAS Mutant Positive Non-Small Cell Lung Cancer (NSCLC) Patients Treated in a Single Institution

Characteristics of EGFR, ALK, or KRAS Mutant Positive Non-Small Cell Lung Cancer (NSCLC) Patients Treated in a Single Institution

A real-world survival of subsequent therapy in ALK positive non-small cell lung cancer (NSCLC) patients with crizotinib resistance.

e21093Background: Crizotinib resistance among non-small cell lung cancer(NSCLC) patients with ALK gene rearrangement has attracted more attention. Subsequent therapies beyond crizotinib resistance ...

Guidenline for diagnosis and treatment of Alk and Ros1 positive non-small cell lung cancer in China

Guidenline for diagnosis and treatment of Alk and Ros1 positive non-small cell lung cancer in China