Real-world And Translational Research For ALK Positive Non-small Cell Lung Cancer In The Era Of Second-generation Of ALK-TKIs

Background:Data about efficacy and safety of first-line alectinib and sequential therapy of crizotinib followed by alectinib in real-world setting for Chinese population are limited.Methods:Patients diagnosed of ALK positive NSCLC treated with first-line alectinib or sequential therapy of first-line crizotinib followed by alectinib(sequential treatment cohort)were collected in 8 hospitals in China.Patients with symptomatic CNS metastases could also be included.Continuation of targeted agent in company with other therapy was permitted after local or gradual progression based on clinician’s option.The reason for treatment failure could be disease progression,death,toxicity and patient’s preference.C-TTF was defined as the period from the start of crizotinib to the completely discontinuation of alectinib due to any cause.Results:105 and 61 patients were respectively included in these two cohorts.With median follow-up of 19.2 months(range 3.9-42.6m),1-year PFS for first-line alectinib cohort was 83.9%(95%CI:75.1-89.8%),estimated 2-year PFS was 80.1%(95%CI:70.4-80.9%).With median follow-up of 39.7 months(range 11.6-93.3m),3-year OS for sequential treatment cohort was 83.9%(95%CI:71.3-93.1%),estimated 4-year and 5-year OS was 75.1%(95%CI:59.3-85.5%)and 70.1%(95%CI:51.7-82.5%).At the time of data cut-off,there was no significant difference in ORR(first-line alectinib:87.8%vs first-line crizotinib:88.1%,p=l),tumor shrinkage rate(the percentage of patients whose tumor shrinkage rate over 50%,first-line alectinib:68.3%vs first-line crizotinib:54.8%,the percentage of patients whose tumor shrinkage rate over 75%,first-line alectinib:25.6%vs first-line crizotinib:16.7%),TTF(TTF for first line alectinib:NR vs c-TTF for sequential treatment cohort:39.8 months,p=0.2,HR=0.68,95%CI:0.38-1.2)and OS(NR vs NR,p=0.899,HR=1.06,95%CI:0.43-2.6)between first-line alectinib cohort and sequential treatment cohort.2,7,2 patients completely discontinued the treatment due to toxicity during the stage of first-line alectinib,first-line crizotinib and sequential treatment of alectinib.5.6%and 12.3%patients treated with alectinib and crizotinib experienced ≥grade 3 adverse events.Conclusions:First-line alectinib and sequential therapy of crizotinib followed by alectinib demonstrated potent efficacy in real-world setting.At the time of data cut-off,there was no significant difference between these two cohorts in TTF and OS,alectinib seemed to have better treatment tolerability compared with crizotinib.Clinical outcomes and long-term survival for these two cohorts are still in need of longer follow-up.Background:CNS metastases in patients with ALK-positive NSCLC are a cause of substantial morbidity and mortality.Although alectinib had demonstrated promising intracranial efficacy in several clinical trials,data were limited on its CNS activity in real-world settings.Methods:In this retrospective study,ALK-positive NSCLC patients with brain metastases(BM)or leptomeningeal metastases(LM)from six hospitals in China were divided into three cohorts based on the treatment history before the administration of alectinib.ALK-TKI-naive patients were enrolled in Cohort 1,Cohort 2 included patients who experienced intracranial progression after the treatment with crizotinib,and Cohort 3 included patients who developed progression in CNS following the treatment with other second-generation ALK-TKIs.The definition and evaluation of intracranial and extracranial lesions were based on Response Evaluation Criteria in Solid Tumors version 1.1.Results:Seventy-one patients were eligible and included in our study(Cohort 1:26,Cohort 2:32,Cohort 3:13).For overall population and patients with uncontrolled CNS metastases,similar intracranial response in CNS target lesions was observed:Cohort 1:88.2%and 87.5%;Cohort 2:76.5%and 86.7%;Cohort 3:42.8%and 33.3%.For patients in these three cohorts,83.3%(10/12),78.6%(11/14),and 83.3%(5/6)were reported to have significant improvement in CNS-related symptoms respectively.The number of patients who were in need of mannitol or corticosteroids decreased remarkably after the treatment of alectinib(65.6%→9.4%,p<0.001),and there was also a steep fall-over in the number of patients with ECOG≥2 points before and after the administration of alectinib(65.6%→21.9%,p=0.001).All patients(9/9)diagnosed with LM±BM experienced substantial alleviation in CNS-related symptoms.In Cohort 1 and Cohort 2,no significant difference in CNS-time to progression was found between patients with symptomatic or asymptomatic BM when treated with alectinib alone(Cohort 1:NR vs NR,p=0.603,HR=2.0,95%CI:0.1-38.8,Cohort 2:21.1m vs NR,p=0.09,HR=2.74,95%CI:0.85-8.8).Conclusions:Our study substantiated the potent CNS activity of alectinib in real-world settings.Patients with symptomatic and asymptomatic BM could benefit from alectinib comparatively,which indicated that alectinib alone might defer the timing of local treatment.However,our results should be treated cautiously owing to limited sample size.Background:Scholars have made much progress on the investigation about efficacy and resistance mechanism of ALK inhibitors in different ALK variants,however,these studies have reached inconsistent conclusions.We conducted this research with relatively larger sample size to make a more comprehensive analysis.Methods:Medical records of patients with identified information about ALK variants who received first-line alectinib or crizotinib were retrospectively collected in two centers.Status of TP53 was also recorded for patients with baseline result of NGS.Shorter EML4 variants included EML4 fusions up to exon 6 and longer EML4 variants contained EML4 fusions at least exon 13.Results:102 patients were included in our research(alectinib cohort:n=49,crizotinib cohort:n=53).In alectinib cohort,shorter variants were associated with significantly unfavorable PFS compared with longer variants(24.2m vs NR,p=0.025,HR=3.9),longer variants with TP53 wild-type enjoyed the most favorable prognosis compared with longer variants with TP53 mutation(PFS:NR vs NR,p=0.028,HR=0.07),shorter variants with TP53 mutation(PFS:NR vs 24.2m,p=0.006,HR=0.03)and shorter variants with TP53 wild-type(PFS:NR vs NR,p=0.04,HR=0.05).However,this was not the case in patients treated with first-line crizotinib(PFS:shorter variants 11.9m vs longer variants 12.9m,p=0.23,HR=1.4).Alectinib demonstrated superior efficacy in shorter(PFS:24.2m vs 11.9m,p=0.034,HR=0.46)and longer variants(PFS:NR vs 11.9m,p<0.001,HR=0.18)compared with crizotinib,however,the separation of PFS curves was much later in shorter variants(approximately 12 months),which indicated that alectinib showed moderate performances in early resistance of shorter variants.Higher frequency of ALK secondary mutation(76.5%vs 33.3%,p=0.029)and G1202R(64.7%vs 0%,p<0.001)was reported in shorter variants.Conclusions:Our study indicated that shorter and longer EML4-variants demonstrated different response to ALK inhibitors and resistance mechanism,therefore,more pertinent treatment strategy merits further exploration for different ALK variants.Furthermore,more intensive treatment strategy was needed for patients with longer variants with TP53 mutation and shorter variants with or without TP53 mutation.Background:In real-world setting,data about progression pattern,resistance mechanism and subsequent therapy for ALK positive NSCLC in the era of second-generation ALK-TKIs were limited.Methods:Patients who showed treatment failure to second-generation ALK-TKIs were retrospectively collected in our center.Patients who underwent progression following the treatment of first-line alectinib were included in Cohort 1(n=20)while patients who experienced progression after the sequential therapy of crizotinib followed by second-generation ALK-TKIs were enrolled in Cohort 2(n=52).Oligo-progression was defined as disease progression in ≤3 lesions,progression in pulmonary lymphangitis,pleural/serous effusion,and meningitis were not deemed as oligo-progression.Patients who developed new symptoms or experienced aggravation of previous symptoms during the radiological progression were deemed as symptomatic progression.Results:The proportion of CNS progression(15%vs 57.7%,p=0.001)and symptomatic CNS progression(5%vs 32.7%,p=0.016)was much lower in Cohort 1 than patients treated with crizotinib.Resistance mutation in ALK kinase domain(56.8%,25/44)was dominant resistance mechanism for second-generation ALK-TKIs.MET amplification(n=1),BRAF fusion(n=1),BRAF V600E mutation(n=1),KRAS amplification(n=2),KRAS mutation(G12A,n=1)and squamous carcinoma transformation(n=2)could possibly be other resistance mechanisms.Local ablative therapy(LAT)was applied to 50%(20/40)of oligo-progression cases,which could prolong 6.4 months(95%CI:5.4-7.1m)of treatment duration of previous targeted therapy.Subsequent ALK-TKIs demonstrated more favorable efficacy in patients with ALK secondary mutation(patients with ALK compound mutation were excluded)than those without(277d vs 75d p=0.0032,HR=0.34,95%CI:0.13-0.91).Platinum-based chemotherapy also showed superior response compared with the efficacy of subsequent ALK-TKIs in patients without ALK resistance mutation(172d vs 75d,p=0.025,HR=0.33,95%CI:0.13-0.87).We found that 3 patients carrying ALK compound mutation following the treatment of multiple ALK-TKIs(F1194L+G1202R*2,L1196M+G1202R*1)demonstrated primary resistance to lorlatinib.Conclusions:Patients who received first-line alectinib experienced less chance of CNS progression and symptomatic CNS progression compared with those treated with crizotinib,which reflected potent CNS protective effects of alectinib.In the era of second-generation ALK-TKIs,subsequent treatment strategy should be based on the progression pattern and resistance mechanism.LAT should be actively applied to oligo-progression,corresponding ALK-TKIs should be used in patients with single ALK resistance mutation.Patients should not lose the chance of chemotherapy which is still an important strategy especially for patients with ALK compound mutation or without ALK resistance mutation.