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C. Mecca

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    GR 01 - What to Do at the Time of Progression on Targeted Therapy (ID 520)

    • Event: WCLC 2017
    • Type: Grand Rounds
    • Track: Chemotherapy/Targeted Therapy
    • Presentations: 1
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      GR 01.05 - First-Line Management of ALK Mutant NSCLC (ID 8119)

      11:00 - 12:30  |  Author(s): C. Mecca

      • Abstract
      • Presentation

      The identification of anaplastic lymphoma kinase (ALK) gene rearrangements as an oncogenic driver in NSCLC has radically changed the treatment of a subset of patients harboring this molecular alteration. [1] ALK mutations occur in 3-7% of NSCLCs and are more frequently associated with never/light smoker, younger age and adenocarcinoma histology. Crizotinib, an oral small-molecule multitargeted ALK/c-MET /ROS1 tyrosine kinase inhibitors, was the first-in-class agent approved from FDA for advanced, ALK-rearranged NSCLC. The accelerated approval in 2011 was granted on the basis of pronounced activity observed in early phase I and II clinical studies, coupled with a favorable toxicity-profile and concurrent development of a diagnostic test for ALK rearrangement. [2] More recently, the results from a front-line phase III trial in ALK-positive NSCLC, PROFILE 1014, revealed the superiority, in terms of progression free survival (PFS) and overall response rate (ORR), of crizotinib versus standard pemetrexed-platinum chemotherapy.[3] Based on these data, crizotinib represents standard fist- line therapy in patients with advanced ALK mutant NSCLC. [4] Despite marked and durable initial responses to crizotinib, most patients develop progressive disease after a median of 11 months, with the brain as a common site of relapse. This can be explained by pharmacokinetic limitations rather than a biologic resistance. Several acquired resistance mechanisms have been characterized, including secondary mutations in the ALK kinase domain and/or ALK copy number alterations. ALK-independent resistance mechanisms can also occur through activation of alternative bypass signaling pathways, such as EGFR activation, KIT amplification, KRAS mutation and IGF-R1 activation.[5] This evidence has prompted the development of increasingly potent, selective and brain-penetrant ALK inhibitors, with differential spectrum of activity against the most common resistance mutations. [6] Several next-generation ALK inhibitors, such as ceritinib, alectinib, brigatinib have demonstrated clinical benefit in patients with crizotinib-refractory NSCLC patients also at the central nervous system (CNS) level. This observation has supported the assessment of these drugs as frontline therapy in patients crizotinb-naïve with advanced ALK+ NSCLC.[7] Soria and colleagues have published the results of the ASCEND-4 trial, randomizing ALK+ treatment naïve patients to ceritinib or chemotherapy. Ceritinib treatment significantly has improved median PFS compared to chemotherapy (16.6 vs 8.1 months; hazard ratio [HR] 0.55,P<0.00001). This molecule was also associated with a better control of the disease in the brain (PFS 10.7 vs 6.7 months, HR 0.70, 95% CI: 0.44–1.12). Dose-limiting gastrointestinal adverse events were common with ceritinib at the starting dose of 750 mg daily and 80% of cases required dose reduction or interruption. Although ceritinib has not been compared head-to-head with crizotinib, data confirm ALK inhibitor superior efficacy compared to standard chemotherapy in the ALK-rearranged NSCLC and suggest ceritinib as another option for the front line management. [8] First Line Head to Head trials are ongoing or recently completed. Findings from J-ALEX trial, involving untreated Japanese patients with ALK-rearranged advanced NSCLC, have shown that alectinib induces longer durations of response compared to crizotinib. Median PFS exceeded 2 years in the alectinib group, compared with just over 10 months in the crizotinib group. [9] Recently, Peters et al. have presented the results of global ALEX study. Data are consistent with previous Japanese analysis: PFS was significantly improved with alectinib as compared to crizotinib (25,7 5% vs 10,4%, HR 0.5, p<0.0001). In addition, 12% of patients in alectinib arm vs 45% in crizotinib arm has experienced brain progression (cause specific HR 0.16; 95% CI, 0.10 to 0.28; P<0.001). Alectinib appeared to be better tolerated than crizotinib with grade 3 to 5 adverse events occurring in 41% vs 50% of patients, respectively.[10] Other studies with next-generation ALK inhibitors versus crizotinib—such as lorlatinib, brigatinib, are ongoing and they will help define optimal sequencing therapy for patients with ALK-rearranged NSCLC. To improve outcomes in this patient population, some studies are also currently investigating several combination strategies, including immunotherapy, anti-angiogenetic agents or radiotherapy approach in association with ALK inhibitors as shown in Table 1. Table 1

      DRUGS (dose) Clinical trial (phase) Patient Number Comparator ORR (%) PFS (mo)
      Crizotinib (250 mg twice/day) PROFILE 1014 (III) 343 Pemetrexed+platinum 74 vs45 10.9 vs 7.0
      Ceritinib (750 mg/die) ASCEND 4 (III) 376 Pemetrexed+platinum pemetrexed±maintenance 72.7vs27.3 16.6 vs 8.1*
      Alectinib (300 mg twice/day) J-ALEX (III) 207 crizotinib (250 mg twice/day) 85vs70 NEvs10.2
      Alectinib (600 mg twice/day) ALEX (III) 303 crizotinib (250 mg twice/day) 82.9vs75.5 25.7vs10.4*
      Brigatinib (90 mg/die for 7 days, 180 mg/die) ALTA 1L (III) ongoing Crizotinib (250 mg twice/day) -
      Lorlatinib (150 mg/die) NCT03052608 (III) ongoing Crizotinib (250 mg twice/day) -
      Crizotinib+Bevacizumab (250 mg twice/day; 7.5 mg/kg every 3 wks) CAMAR01 (II) ongoing _ _ _
      Crizotinib+Pembrolizumab NCT02511184 (I) ongoing _ _ _
      ORR: overall response Rate, PFS Progression free survival, NE not evaluable, *independent review committee
      Treatment paradigms continue to evolve for patients with advanced ALK-positive NSCLC subsequently to rapid development of ALK inhibitors history. It is expected that one of the next generation of ALK inhibitors will be used as first-line. In this landscape it is necessary to define the impact of first-line choice on patterns of progression and mechanisms of resistance. [11] It is uncertain if a specific sequence of therapeutic agents influences the biology of the cancer and therefore the clinical course of the patient. The spectrum of ALK resistance mutations varies according to ALK inhibitor and it is unclear if the mechanisms of resistance to these agents as the first ALK inhibitor will be similar to the mechanisms of resistance identified when they are used after crizotinib. Future efforts should be focused on determining the best treatment sequence to maximize clinical outcomes. Key factors to guide the selection of therapies could be include: molecular characteristics of the patient's tumor, different toxicity profile of different ALK inhibitors, availability of combinations/ multimodal therapy. References 1. Identification of the transforming EML4-ALK fusion gene in non-small-cell lung cancer. Soda M et al. Nature 2007; 448:561–567 2. The continuum of care for ALK-positive NSCLC: from diagnosis to new treatment options-an overview Solomon & Soria, Ann Oncol Vol 27 Supp 3 2016 3. First-line crizotinib versus chemotherapy in ALK-positive lung cancer Solomon et al N Engl J Med 2014 Dec 4;371(23):2167-77 4. Metastatic non-small-cell lung cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Novello S et al. Annals of Oncology 27 (Supplement 5): v1–v27, 2016 5. Crizotinib resistance: implications for therapeutic strategies. Dagogo-Jack & Shaw Ann Oncol Supp 3 2016 6. Molecular Mechanisms of Resistance to First- and Second-Generation ALK Inhibitors in ALK-Rearranged LungCancer. Gainor et al Cancer Discov2016Oct;6(10): 1118-1133. 7. Ascending role of next-generation ALK inhibitors. Costa. Lancet Oncol.2017 Jul; 18(7):837-839. 8. First-line ceritinib versus platinum-based chemotherapy in advanced ALK-rearranged non-small-cell lung cancer (ASCEND-4): a randomized, open-label, phase 3 study. Soria et al Lancet 2017; 389: 917–29 9. Alectinib versus crizotinib in patients with ALK-positive non-small-cell lung cancer (J-ALEX): an open-label, randomized phase 3 trial Hida et al. Lancet 2017; 390: 29–39 10. Alectinib versus Crizotinib in Untreated ALK-Positive Non–Small-Cell Lung Cancer Peters et al for for the ALEX Trial Investigators NEJM N Engl J Med. 2017 Jun 6. 11. First-line treatment options for ALK-rearranged lung cancer. Solomon. Lancet Oncology 2017 Mar 4; 389(10072): 884-886

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