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D. Kim
Moderator of
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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: 6
- Moderators:D. Kim, Lecia V Sequist
- Coordinates: 10/16/2017, 11:00 - 12:30, Room 303 + 304
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GR 01.01 - Case Study (ID 10949)
11:00 - 11:05 | Presenting Author(s): D. Kim
- Abstract
- Presentation
Abstract not provided
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GR 01.02 - Case Study (ID 10950)
11:05 - 11:10 | Presenting Author(s): Lecia V Sequist
- Abstract
- Presentation
Abstract not provided
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GR 01.03 - First-Line Management of EGFR Mutant NSCLC (ID 7628)
11:10 - 11:30 | Presenting Author(s): Li Zhang
- Abstract
- Presentation
Abstract:
Lung cancer is still the leading cause of cancer-related deaths worldwide. Non-small cell lung cancer (NSCLC) remains the predominant form of the disease, with majority of patients being diagnosed at advanced stages. The survival benefit offered by chemotherapy regimens has reached a therapeutic plateau. Fortunately, mutation-specific targeted therapies directed against “actionable” genetic alterations have significantly improved the prognosis of advanced NSCLC. Epidermal growth factor receptor (EGFR) mutation is the most common targetable genetic alteration in NSCLC. The prevalence of EGFR mutations range from 10% in Caucasians, to 60% in never-smoking, Asian, adenocarcinoma patients. This presentation will focus on the first-line management of EGFR mutant NSCLC. Overview of EGFR-TKIs Nine large randomised controlled studies have established the superiority of EGFR tyrosine kinase inhibitors (EGFR-TKIs) against chemotherapy as first-line treatment in NSCLC harboring EGFR mutations in terms of progression-free survival (PFS), objective response rate (ORR) and quality of life (QoL) (Table 1). Several studies suggest there is no significant difference in efficacy between gefitinib and erlotinib. LUX-lung 7 (afatinib) and ACHER 1050 (dacomitinib) are two randomised head-to head trials comparing second-generation EGFR-TKIs to gefitinib, respectively. Although PFS is significantly improved with second-generation TKIs, the increased rates of grade 3 or higher adverse events such as rash and diarrhea result in more dose modification with second-generation TKIs. FLAURA study, which assesses the efficacy of third-generation EGFR-TKI osimertinib versus first-generation EGFR-TKIs as first-line treatment, has been accomplished recently. This trial may establish the role of osimertinib as first-line treatment for EGFR mutant NSCLC. Management of uncommon mutations Exon 19 deletion and L858R mutation account for about 90% of all EGFR mutations. The remaining 10% of EGFR mutations (uncommon mutations) are a heterogeneous group of molecular alterations. Results of retrospective studies and case reports of first-generation EGFR-TKIs show inconsistent responses in this population. According to the post-hoc analysis of LUX-Lung 2, LUX-Lung 3, and LUX-Lung 6, objective responses to afatinib are observed in certain types of uncommon mutations such as G719X (77.8%), L861Q (56.3%), and S768I (100%). However, Patients with de-novo Thr790Met and exon 20 insertion mutations are insensitive to afatinib. Jonathan Riess and colleagues report that osimertinib has in vivo activity across multiple exon 20 insertion mutations in preclinical study. Thus osimertinib warrants further study in patients with exon 20 insertion mutations. Combination treatment strategies Combinations of EGFR-TKIs with chemotherapy, anti-angiogenetic therapy, and immunotherapy have been explored in clinical trials. JMIT study is a randomized phase II trial comparing addition of pemetrexed to gefitinib with gefitinib alone as first-line therapy in EGFR mutant NSCLC. PFS was significantly longer with pemetrexed+gefitinib than with gefitinib (15.8 months vs 10.9 months; hazard ratio [HR], 0.68; 95% CI, 0.48 to 0.96; P = 0.029). According to JO25567 study, combination of erlotinib with bevacizumab also significantly prolongs PFS than erlotinib. Several phase III trials evaluating combination of EGFR-TKIs with anti-angiogenetic therapy are ongoing. Attention should be paid to adverse events such as interstitial lung disease when EGFR-TKIs are used with immunotherapy. Management of brain metastases Brain metastases is a major challenge when managing EGFR mutant NSCLC as up to 40% of patients would develop central nervous system (CNS) metastases during the course of their disease. Novel EGFR-TKIs provide new strategies for brain metastases treatment. AZD3759 is a CNS penetrable and reversible EGFR-TKI. The phase I study (BLOOM) of AZD3759 in TKI naïve EGFR mutant NSCLC with CNS metastases is reported in 2017 ASCO annual meeting. Intracranial response is observed in 83% of patients with measurable brain metastases lesions at baseline. The extracranial anti-tumor efficacy of AZD3759 is also promising. 13 out of 18 patients with extracranial lesions have confirmed objective response. CNS response to osimertinib in patients with T790M-positive advanced NSCLC from AURA3 study is also presented in 2017 ASCO annual meeting. In 30 patients with more than one measurable CNS metastases, the intracranial response is 70%. The median CNS PFS with osimertinib is 11.7 months. Furthermore, osimertinib shows encouraging activity in patients with leptomeningeal metastases. Table 1. First-line treatment of EGFR mutant NSCLC: EGFR-TKIs vs. ChemotherapyTrial TKI PFS (month) OS TKI Chemo HR (95%CI) HR (95%CI) IPASS Gefitinib 9.5 6.3 0.48 (0.36-0.64) 0.78 (0.50-1.20) First Signal Gefitinib 8.4 6.7 0.61 (0.31-1.22) 0.82 (0.352-1.922) NEJ002 Gefitinib 10.8 5.4 0.322 (0.236-0.438) 0.88 (0.634-1.241) WJTOG3405 Gefitinib 9.6 6.6 0.52 (0.378-0.715) 1.185 (0.767-1.829) OPTIMAL Erlotinib 13.1 4.6 0.16 (0.10-0.26) 1.19 （0.83-1.71） ENSURE Erlotinib 11.0 5.5 0.34 (0.22-0.51) 0.91 （0.63-1.31） EURTAC Erlotinib 9.7 5.2 0.37 (0.25-0.54) 0.80 (0.47-1.37) Lux-lung 3 Afatinib 11.1 6.9 0.58 (0.43-0.78) 0.88 （0.66-1.17） Lux-lung 6 Afatinib 11.0 5.6 0.29 (0.20-0.33) 0.93 （0.72-1.22）
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GR 01.04 - EGFR-Positive NSCLC Cases Who Failed Previous EGFR-TKI (ID 7629)
11:30 - 11:50 | Presenting Author(s): Gregory J Riely
- Abstract
- Presentation
Abstract not provided
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GR 01.05 - First-Line Management of ALK Mutant NSCLC (ID 8119)
11:50 - 12:10 | Presenting Author(s): Silvia Novello | Author(s): C. Mecca
- Abstract
- Presentation
Abstract:
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
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): 884-886DRUGS (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
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GR 01.06 - ALK-Positive NSCLC Cases who Failed Previous ALK Inhibitors (ID 7630)
12:10 - 12:30 | Presenting Author(s): Jürgen Wolf
- Abstract
- Presentation
Abstract not provided
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Author of
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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
- Moderators:D. Kim, Lecia V Sequist
- Coordinates: 10/16/2017, 11:00 - 12:30, Room 303 + 304
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GR 01.01 - Case Study (ID 10949)
11:00 - 11:05 | Presenting Author(s): D. Kim
- Abstract
- Presentation
Abstract not provided
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JCSE 01 - Joint IASLC/CSCO/CAALC Session: Immunotherapy for Management of Lung Cancer: Ongoing Research from East and West (ID 630)
- Event: WCLC 2017
- Type: Joint Session IASLC/CSCO/CAALC
- Track: Immunology and Immunotherapy
- Presentations: 1
- Moderators:C. Bai, Fred R. Hirsch, Tony SK Mok, Yi-Long Wu
- Coordinates: 10/15/2017, 07:30 - 11:30, F203 (Annex Hall)
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JCSE 01.27 - Patients with ALK IHC-Positive/FISH-Negative NSCLC Benefit from ALK TKI Treatment: Response Data from the Global ALEX Trial (ID 10923)
11:30 - 11:30 | Author(s): D. Kim
- Abstract
Background:
Patients with ALK-positive NSCLC have seen significant advances and increased options in ALK targeted therapies recently, and therefore rely on high quality, robust ALK status testing. Fluorescence in-situ hybridization (FISH) and immunohistochemistry (IHC) are the most common methods to determine ALK status for ALK tyrosine kinase inhibitor (TKI) treatment. However, availability of clinical outcome data from randomized trials linked directly to specific methods is limited. The ALEX trial (BO28984, NCT02075840) provides a unique dataset to assess ALK IHC- and FISH-based assays regarding clinical outcome for alectinib and crizotinib, particularly for the subset of patients with IHC-positive/FISH-negative NSCLC.
Method:
The VENTANA ALK (D5F3) CDx Assay (ALK IHC) performed in central laboratories was used as an enrollment assay for the selection of patients with ALK-positive NSCLC for inclusion in the ALEX trial. Additional samples from these patients were retrospectively tested in central laboratories with the Vysis ALK Break Apart FISH Probe Kit (ALK FISH).
Result:
Overall, 303 patients all with ALK IHC-positive NSCLC were randomized in the ALEX trial, of those 242 patients also had a valid ALK FISH result, with 203 patients having ALK FISH-positive disease and 39 patients having ALK FISH-negative disease (alectinib, n=21; crizotinib, n=18). For 61 of 303 (20.1%) patients with an ALK IHC-positive result, a valid ALK FISH result could not be obtained due to the test leading to an uninformative FISH result (10.9%), or not having adequate/no tissue available (9.2%). Ventana IHC staining success rates were higher than for Vysis FISH testing for the ALEX samples. Exploratory analysis of investigator-assessed progression-free survival (PFS) in patients with a FISH-positive result (HR 0.40, 95% CI 0.27–0.61; p<0.0001; median not reached [alectinib] versus 12.7 months [crizotinib]) was consistent with the primary endpoint analysis in the Ventana ALK IHC-positive population. Patient outcome data show that 28% of central ALK IHC-positive/ALK FISH-negative samples were from patients who responded to ALK TKI treatment (complete response or partial response) and 33% had stable disease according to investigator assessment.
Conclusion:
This analysis shows that ALK IHC is a robust testing approach, which may identify more patients with a valid ALK testing result who benefit from ALK TKI treatment than ALK FISH testing. While PFS of patients with ALK FISH-positive NSCLC was similar to that of patients with ALK IHC-positive NSCLC, the analysis also revealed that the majority of patients with ALK IHC-positive/ALK FISH-negative NSCLC may derive clinical benefit from ALK TKI treatment.
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MA 07 - ALK, ROS and HER2 (ID 673)
- Event: WCLC 2017
- Type: Mini Oral
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:Robert C. Doebele, J.C. Ho
- Coordinates: 10/17/2017, 15:45 - 17:30, Room 316
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MA 07.01 - Patients with ALK IHC-Positive/FISH-Negative NSCLC Benefit from ALK TKI Treatment: Response Data from the Global ALEX Trial (ID 9008)
15:45 - 15:50 | Author(s): D. Kim
- Abstract
- Presentation
Background:
Patients with ALK-positive NSCLC have seen significant advances and increased options in ALK targeted therapies recently, and therefore rely on high quality, robust ALK status testing. Fluorescence in-situ hybridization (FISH) and immunohistochemistry (IHC) are the most common methods to determine ALK status for ALK tyrosine kinase inhibitor (TKI) treatment. However, availability of clinical outcome data from randomized trials linked directly to specific methods is limited. The ALEX trial (BO28984, NCT02075840) provides a unique dataset to assess ALK IHC- and FISH-based assays regarding clinical outcome for alectinib and crizotinib, particularly for the subset of patients with IHC-positive/FISH-negative NSCLC.
Method:
The VENTANA ALK (D5F3) CDx Assay (ALK IHC) performed in central laboratories was used as an enrollment assay for the selection of patients with ALK-positive NSCLC for inclusion in the ALEX trial. Additional samples from these patients were retrospectively tested in central laboratories with the Vysis ALK Break Apart FISH Probe Kit (ALK FISH).
Result:
Overall, 303 patients all with ALK IHC-positive NSCLC were randomized in the ALEX trial, of those 242 patients also had a valid ALK FISH result, with 203 patients having ALK FISH-positive disease and 39 patients having ALK FISH-negative disease (alectinib, n=21; crizotinib, n=18). For 61 of 303 (20.1%) patients with an ALK IHC-positive result, a valid ALK FISH result could not be obtained due to the test leading to an uninformative FISH result (10.9%), or not having adequate/no tissue available (9.2%). Ventana IHC staining success rates were higher than for Vysis FISH testing for the ALEX samples. Exploratory analysis of investigator-assessed progression-free survival (PFS) in patients with a FISH-positive result (HR 0.40, 95% CI 0.27–0.61; p<0.0001; median not reached [alectinib] versus 12.7 months [crizotinib]) was consistent with the primary endpoint analysis in the Ventana ALK IHC-positive population. Patient outcome data show that 28% of central ALK IHC-positive/ALK FISH-negative samples were from patients who responded to ALK TKI treatment (complete response or partial response) and 33% had stable disease according to investigator assessment.
Conclusion:
This analysis shows that ALK IHC is a robust testing approach, which may identify more patients with a valid ALK testing result who benefit from ALK TKI treatment than ALK FISH testing. While PFS of patients with ALK FISH-positive NSCLC was similar to that of patients with ALK IHC-positive NSCLC, the analysis also revealed that the majority of patients with ALK IHC-positive/ALK FISH-negative NSCLC may derive clinical benefit from ALK TKI treatment.
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OA 05 - Next Generation TKI (ID 657)
- Event: WCLC 2017
- Type: Oral
- Track: Advanced NSCLC
- Presentations: 2
- Moderators:James Chih-Hsin Yang, Fiona Blackhall
- Coordinates: 10/16/2017, 15:45 - 17:30, Room 301 + 302
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OA 05.05 - Brigatinib in Crizotinib-Refractory ALK+ NSCLC: Updated Efficacy and Safety Results From ALTA, a Randomized Phase 2 Trial (ID 8027)
16:30 - 16:40 | Author(s): D. Kim
- Abstract
- Presentation
Background:
Brigatinib, a next-generation ALK inhibitor, recently received accelerated approval in the United States for the treatment of patients with metastatic ALK+ NSCLC who have progressed on or are intolerant to crizotinib. We report updated data from the randomized phase 2 trial (ALTA; NCT02094573), which was designed to investigate the efficacy and safety of 2 brigatinib regimens in patients with crizotinib-refractory, advanced ALK+ NSCLC.
Method:
Patients were stratified by presence of brain metastases at baseline and best response to prior crizotinib and randomized 1:1 to receive brigatinib at 90 mg qd (arm A) or 180 mg qd with a 7-day lead-in at 90 mg (arm B). Investigator-assessed confirmed objective response rate (ORR) per RECIST v1.1 was the primary endpoint.
Result:
Among 222 patients (n=112/n=110, arm A/B), median age was 51/57 years; 71%/67% had brain metastases. As of February 21, 2017, 17 full months since the last patient enrolled, median follow-up was 16.8/18.6 months and 32%/41% of patients continued to receive brigatinib in A/B. The table shows brigatinib efficacy. Per independent review committee, confirmed ORR was 51%/55% and median PFS was 9.2/16.7 months in A/B. Among patients with measurable baseline brain metastases (n=26/n=18, A/B), confirmed intracranial ORR was 50%/67% as of January 24, 2017; median intracranial DoR was not reached/16.6 months. The most common treatment-emergent adverse events (TEAEs) were: nausea (38%/47%, A/B), diarrhea (28%/44%), cough (28%/40%), headache (30%/35%), and vomiting (36%/30%); the most common grade ≥3 TEAEs were: increased creatine phosphokinase (5%/13%), hypertension (6%/8%), pneumonia (4%/5%), and increased lipase (5%/4%). Dose reduction (9%/30%, A/B) or discontinuation (4%/11%) due to TEAEs was reported.
Conclusion:
In ALTA, brigatinib continues to show substantial efficacy and acceptable safety at both dose levels, with numerically longer PFS and higher intracranial ORR at the recommended dosing regimen of 180 mg qd (with lead-in) vs 90 mg qd.Investigator Assessment Independent Review[a] Arm A (n=112) Arm B (n=110) Arm A (n=112) Arm B (n=110) Confirmed ORR, % 46 (35–57[b]) 55 (44–66[b]) 51 (41–61[c]) 55 (45–64[c]) Median DoR in responders,[d] months 12.0 (9.2–17.7[c]) 13.8 (10.2–17.5[c]) 13.8 (7.4–NR[c]) 14.8 (12.6–NR[c]) Median PFS,[d] months [% of events] 9.2 (7.4–11.1[c]) [65] 15.6 (11.1–19.4[c]) [50] 9.2 (7.4–12.8[c]) [54] 16.7 (11.6–NR[c]) [41] Median OS,[d] months [% of events] NR (20.2–NR[c]) [38] 27.6 (27.6–NR[c]) [29] — — 1-year OS probability,[d ]% 70 (61–78[c]) 80 (71–87[c]) — — DoR, duration of response NR, not reached OS, overall survival PFS, progression-free survival [a]Last scan date: February 28, 2017 [b]97.5% CI for primary endpoint [c]95% CI [d]Kaplan-Meier estimate
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OA 05.07 - Efficacy and Updated Safety of Ceritinib (450 Mg or 600 Mg) with Low-Fat Meal vs 750 Mg Fasted in ALK+ Metastatic NSCLC (ID 9366)
16:50 - 17:00 | Author(s): D. Kim
- Abstract
- Presentation
Background:
Ceritinib is a next-generation anaplastic lymphoma kinase (ALK) inhibitor approved for the treatment of patients with ALK+ non-small cell lung cancer (NSCLC) who are treatment-naive or have progressed on crizotinib at the recommended dose of 750 mg/day under fasted state. Gastrointestinal (GI) adverse events (AEs), eg, diarrhea, nausea, vomiting, are common with ceritinib 750 mg/day under fasting conditions. ASCEND‑8 study, (NCT02299505) evaluated alternative methods of ceritinib administration, utilizing potential benefit of dosing ceritinib with food to reduce GI toxicity, while maintaining the pharmacokinetic exposure at lower doses. Based on the primary pharmacokinetics analysis previously presented (n=137; WCLC 2016), ceritinib 450 mg with food had similar exposure and a more favorable GI safety profile vs ceritinib 750 mg fasted in patients with ALK+ NSCLC.
Method:
This is a multicenter, randomized, 3-arm (450 mg or 600 mg ceritinib taken with low-fat meal vs 750 mg ceritinib taken in fasted state), open-label, phase 1 study (ASCEND-8). Patients were eligible if they had stage IIIB or IV ALK+ advanced NSCLC, were aged 18 years or older, who were either previously treated with chemotherapy and/or crizotinib or treatment naive. We plan to report the updated safety (n=228) and preliminary efficacy for treatment-naïve patients (ALK+ by immunohistochemistry [IHC]) who were randomized at least 18 weeks before the cutoff date (March 28, 2017; n=79). Updated analysis is planned to be made available by August 2017 and the following data will be included at the time of final abstract submission: patient disposition; patient demographics; disease characteristics and prior therapies; overall response rate and duration of response by blinded independent review committee (BIRC; key secondary endpoints) in treatment-naïve patients (ALK+ by IHC) randomized at least 18 weeks prior to the cut-off date; progression-free survival per BIRC in treatment-naïve patients (ALK+ by IHC) randomized at least 18 weeks prior to the cut-off date; updated safety results with detailed information on GI (diarrhea, nausea, vomiting) and liver (alanine transaminase/aspartate transaminase) toxicities.
Result:
LBA shell - not applicable
Conclusion:
LBA shell - not applicable
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OA 14 - New Paradigms in Clinical Trials (ID 681)
- Event: WCLC 2017
- Type: Oral
- Track: Clinical Design, Statistics and Clinical Trials
- Presentations: 1
- Moderators:Alex Adjei, Eun Kyung Cho
- Coordinates: 10/18/2017, 11:00 - 12:30, Room 311 + 312
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OA 14.01 - The Impact of Measurement Variability on Response Categorization in Oncology Trials (ID 9986)
11:00 - 11:10 | Author(s): D. Kim
- Abstract
- Presentation
Background:
Radiologic assessments of the baseline and post-treatment tumor burden are subject to measurement variability, but the impact of this variability on response categorization and the resulting overall response rate (ORR) in a specific trial has been practically unpredictable.
Method:
We built up a hierarchical model of measurement variability using a clinical trial dataset of CT scans. Simulations were then performed using the model 1) to establish the behaviour of differences between the first and the hypothetical second assessments of percent change of tumor burden in various scenarios, 2) to elaborate on the probabilistic nature of decisions about categorization, and 3) to estimate the variation in the ORR due to measurement variability.
Result:
The extent of the discrepancies between assessments of the percent change depended on the baseline burden. Smaller differences were associated with larger shrinkage of tumor burdens. The simulated probability for a specific categorization (-30% or 20%) to result from reassessment had a sigmoid shape depending on the percent change in the first set of readings, inflecting at the cutoff point for the categorization. In 3 virtual trials having the same baseline burden and the same ORR of 50%, the presence of fewer percent changes around the cutoff in a trial resulted in a more reproducible ORR (95% central range, 35%-65% vs. 40%-60% vs. 45%-60%). Figure 1
Conclusion:
Since determinations of partial response or progression are probabilistic outcomes due to measurement variability, quantification of the variation in the ORR by potential measurement variability is essential and will help inform decisions made on the basis of trial data.
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P1.01 - Advanced NSCLC (ID 757)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Advanced NSCLC
- Presentations: 4
- Moderators:
- Coordinates: 10/16/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P1.01-001 - Depth of Target Lesion Response to Brigatinib and Its Association With Outcomes in Patients With ALK+ NSCLC in the ALTA Trial (ID 8035)
09:30 - 09:30 | Author(s): D. Kim
- Abstract
Background:
Depth of target lesion response to crizotinib has been associated with overall survival (OS) (J Clin Oncol 2016;34:abstract 2590). ALTA (NCT02094573) is an ongoing randomized phase 2 trial of brigatinib, an ALK inhibitor, in crizotinib-refractory advanced ALK+ NSCLC patients. As the ALTA primary endpoint of confirmed objective response rate (cORR), a binary outcome, might not fully capture clinical benefit, we examined the association of maximum decrease in target lesions with progression-free survival (PFS) and OS.
Method:
Patients were randomized to receive brigatinib at 90 mg qd (arm A; n=112) or 180 mg qd with a 7-day lead-in at 90 mg (arm B; n=110). Arms were pooled in this analysis. Patients with any target lesion shrinkage were sorted into 4 groups based on greatest decrease from baseline per RECIST v1.1; outcomes in these groups were compared with outcomes in patients with no shrinkage.
Result:
As of February 21, 2017, cORR in arm A/B (ITT population) was 46%/55% per investigators. 201/222 patients had ≥1 evaluable response assessment with 18.4-month median follow-up. Median age of these patients was 53 years; 57% were female. Patients with target lesion shrinkage (vs none) had numerically longer PFS (hazard ratios [95% CIs]: 0.61 [0.30–1.22], 1%–25% shrinkage; 0.47 [0.24–0.91], 26%–50%; 0.54 [0.28–1.05], 51%–75%; 0.30 [0.15–0.63], 76%–100%) and numerically higher estimated 1-year OS (Table). In a multivariable analysis, 76%–100% shrinkage (vs none) was independently associated with longer PFS/OS (hazard ratios [95% CIs]: 0.37 [0.18–0.76]/0.35 [0.14–0.89]); arm B (vs A) was independently associated with longer PFS.
Conclusion:
In this exploratory post hoc analysis, brigatinib-treated patients with target lesion shrinkage, including those without confirmed partial response, had improved PFS/OS vs patients without shrinkage. Patients with the deepest response (76%–100% shrinkage) appeared to have the longest PFS and higher estimated 1-year OS.Best Target Lesion Shrinkage n (%)[a] Median PFS,[b,c] Months (95% CI) Median OS,[b ]Months (95% CI) 1-year OS,[b ]% (95% CI) None 18 (9) 3.7 (1.9–11.0) 8.3 (4.7–NR) 48 (22–99) 1%–25% 40 (20) 9.3 (4.0–21.2) NR (14.5–NR) 75 (58–99) 26%–50% 60 (30) 12.8 (9.2–15.7) NR (NR–NR) 82 (70–99) 51%–75% 44 (22) 11.1 (7.4–18.2) 27.6 (20.2–NR) 77 (62–99) 76%–100% 39 (19) 19.5 (12.6–NR) NR (22.3–NR) 92 (78–99) NR, not reached [a]Evaluable patients [b]Kaplan-Meier estimate [c]Per investigator
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P1.01-004 - Hypertension With Brigatinib: Experience in ALTA, a Randomized Phase 2 Trial in Crizotinib-Refractory ALK+ NSCLC (ID 8346)
09:30 - 09:30 | Author(s): D. Kim
- Abstract
Background:
The next-generation ALK inhibitor brigatinib received accelerated approval in the United States in April 2017 for the treatment of patients with metastatic ALK+ NSCLC who have progressed on or are intolerant to crizotinib. Hypertension has been identified as an adverse event of interest with brigatinib treatment based on prior clinical data; here, we report incidence, management, and outcomes of hypertension in ALTA (NCT02094573).
Method:
In ALTA, 222 patients were randomized 1:1 to receive brigatinib at 90 mg qd (arm A; n=112 randomized, n=109 treated) or 180 mg qd with a 7-day lead-in at 90 mg (arm B; n=110 randomized and treated). A medical history of hypertension was allowed, but patients with significant, uncontrolled, or active cardiovascular disease were excluded. Blood pressure (BP) was measured at screening, on days 1, 8, and 15 of the first 28-day cycle, and then every 4 weeks (starting on day 1 of cycle 2).
Result:
Median age was 50/57 years in treated patients in A/B; 22%/25% of treated patients in A/B had a history of hypertension at baseline. As of February 21, 2017, hypertension was reported as a treatment-emergent adverse event (TEAE; any grade) in 17%/27% of patients (A/B) and as a grade 3 TEAE in 6%/8%; no grade 4 hypertension was reported. Few patients had dose interruptions (1%/2%, A/B) or reductions (1%/1%) due to hypertension; no patients discontinued brigatinib due to hypertension. Among patients with hypertension, median time to onset of first hypertension TEAE was 5.8 months/2.1 months in A/B. Among patients with baseline systolic BP <120 mmHg (n=50/n=48, A/B), 20%/42% had a maximum shift to 140–159 mmHg postbaseline (6%/10%, <120 mmHg to ≥160 mmHg); among patients with baseline diastolic BP <80 mmHg (n=68/n=72, A/B), 29%/35% had a maximum shift to 90–99 mmHg postbaseline (10%/8%, <80 mmHg to ≥100 mmHg). Among patients with hypertension TEAEs (n=19/n=30, A/B), 84%/80% started a new antihypertensive medication during the study. Among patients with hypertension TEAEs and no medical history of hypertension (n=11/n=20, A/B), 73%/70% started a new antihypertensive medication during the study. Cardiovascular events in patients with hypertension TEAEs included: angina pectoris in 1 patient without a medical history of hypertension and, in patients with a medical history of hypertension, hypertensive retinopathy (n=1), intermittent claudication (n=1), and peripheral artery stenosis (n=1).
Conclusion:
Hypertension was observed frequently with brigatinib, and appeared dose-related, but was managed with antihypertensive therapy and rarely led to dose modification or discontinuation.
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P1.01-012 - Ceritinib in Anaplastic Lymphoma Kinase (ALK)+ NSCLC Patients Pretreated With Only Crizotinib: ASCEND-1 Subgroup Analysis (ID 8972)
09:30 - 09:30 | Author(s): D. Kim
- Abstract
Background:
In phase 1 ASCEND-1 study (NCT01283516), ceritinib 750 mg/day (fasted) demonstrated durable whole-body and intracranial responses in both anaplastic lymphoma kinase inhibitor (ALKi)-naïve and ALKi-pretreated patients with ALK-rearranged non-small cell lung cancer (NSCLC). Here, we report the efficacy and safety of ceritinib in patients who were pretreated with crizotinib only from the ASCEND-1 study.
Method:
Patients with ALK+ NSCLC who were enrolled globally received ceritinib 750 mg/day (fasted). Efficacy and safety were evaluated in a subset of patients who had received prior crizotinib only (no other prior antineoplastic therapy). Data cut-off was May 03, 2016.
Result:
Overall, 246 patients with ALK+ NSCLC (83 ALKi-naïve and 163 ALKi-pretreated) received ≥1 dose of ceritinib, of whom, 26 had received prior crizotinib only. Among the 26 crizotinib-pretreated patients, 11 (42.3%) had baseline brain metastases, of which, 7 received prior radiotherapy, 6 (23.1%) had an ECOG performance status of 0, and 24 (92.3%) patients had stage IV disease. The median time from initial diagnosis to ceritinib initiation was 10.5 months (range, 2.4-33.0). At data cut-off, the median duration of exposure (range) was 41.0 weeks (2.9-180.4). In the 26 crizotinib-pretreated patients, per investigator assessment, the overall response rate was 65.4% (95% confidence interval [CI]: 44.3, 82.8), and the disease control rate was 80.8% (95% CI: 60.6, 93.4) (Table). The most frequently reported grade 3/4 adverse events (AEs), regardless of study drug relationship, were ALT increased (30.8%), AST increased (15.4%), diarrhea (11.5%), nausea (7.7%), fatigue (7.7%), and blood alkaline phosphatase increased (7.7%). All 26 patients discontinued treatment due to disease progression (n=12), consent withdrawal (n=6), AEs (n=2), administrative problems (n=4), or death (n=2).
*Median value derived from summary statistics; **Median value estimated by Kaplan-Meier method.Investigator Assessment N=26 Blinded Independent Review Committee Assessment N=26 Best overall response Complete response (CR), n (%) 1 (3.8%) 1 (3.8%) Partial response (PR), n (%) 16 (61.5%) 15 (57.7%) Stable disease (SD), n (%) 4 (15.4%) 5 (19.2%) Progressive disease (PD), n (%) 2 (7.7%) 1 (3.8%) Unknown, n (%) 3 (11.5%) 4 (15.4%) Overall response rate (ORR), % [95% CI] 65.4% [44.3-82.8] 61.5% [40.6-79.8] Disease control rate (DCR), % [95% CI] 80.8% [60.6-93.4] 80.8% [60.6-93.4] Median time to response*, weeks [95% CI] 6.1 [5.1-23.6] 6.4 [5.1-14.0] Median DOR**, months [95% CI] 8.3 [4.2-11.2] 8.5 [3.0-13.6] Median PFS**, months [95% CI] 8.5 [5.3-9.9] 8.2 [4.4-15.2]
Conclusion:
Ceritinib demonstrated durable efficacy in crizotinib-pretreated patients with ALK-rearranged NSCLC. Safety was consistent with the overall ASCEND-1 study population.
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P1.01-016 - Next-Generation Sequencing Shows Mechanisms of Intrinsic Resistance in ALK-Positive NSCLC Patients Treated with Crizotinib (ID 9514)
09:30 - 09:30 | Author(s): D. Kim
- Abstract
Background:
Crizotinib (XALKORI®) is a small molecule ALK, ROS1, and c-MET tyrosine kinase inhibitor approved for the treatment of patients with ALK-positive or ROS1-positive metastatic NSCLC. PROFILE 1005 was a single arm phase 2 study of the safety and efficacy of crizotinib in previously treated patients with advanced NSCLC that is ALK-positive as determined by the investigational use only FISH test or on a case-by-case basis using a local FISH, IHC or RT-PCR laboratory developed test. In this study 54.1% of patients exhibited a confirmed complete or partial response to crizotinib (responders) by investigator assessment, while 9.9% had a best overall tumor response of progressive disease (progressors). The objective of this analysis was to investigate mechanisms of intrinsic resistance to crizotinib by comparing progressors with responders through a targeted cancer gene panel of next-generation sequencing (NGS).
Method:
Archival tumor tissue used to screen patients for enrollment was analyzed using the FoundationOne NGS panel (Cambridge, MA). Results of the analyses from tumor tissue positive by ALK FISH were compared for a subgroup of progressors (N=22) with a randomly selected subgroup of responders (N=25).
Result:
There was a higher proportion of patients who were ALK-negative by NGS in progressors (8 of 22; 36%) as compared to responders (3 of 25; 12%) (p=0.083), including 5 patients with oncogenic driver mutations in KRAS (G12S, Q61H, amp), EGFR (L858R) and BRAF (G469A). Among responders, 4 patients (16%) had non-EML4 ALK fusions (KIDINS220, EDC4, DTWD2, AFF2) while no such case was detected in progressors. TP53 mutations were detected in 10 progressors (45%) and 5 responders (20%) (p=0.115). Excluding NGS-negative patients, TP53 mutations were detected in 7 of 14 progressors (50%) and 3 of 22 responders (13%) (p=0.026).
Conclusion:
In the small percentage of patients with ALK-positive NSCLC with a best response of progression upon treatment with crizotinib, a higher proportion are ALK-negative by NGS, representing either a technical false-positive or an accurate FISH result reflecting a non-activating gene rearrangement that is not detected by NGS. TP53 mutations were observed at a higher frequency in progressors than in responders in patients with ALK-positive NSCLC by both FISH and NGS. Both technical and biologic factors thus may contribute to apparent intrinsic resistance in patients with ALK-positive NSCLC treated with crizotinib.
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P3.01 - Advanced NSCLC (ID 621)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Advanced NSCLC
- Presentations: 2
- Moderators:
- Coordinates: 10/18/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P3.01-005 - ASTRIS: A Real World Study of Osimertinib Treatment in Patients with EGFR T790M Positive Advanced NSCLC; Interim Analysis (ID 7884)
09:30 - 09:30 | Author(s): D. Kim
- Abstract
Background:
Osimertinib is a third-generation, CNS active EGFR-TKI that potently and selectively inhibits both EGFR-sensitizing and EGFR T790M resistance mutations in non-small cell lung cancer (NSCLC). We report interim clinical and molecular diagnostic testing results from a predefined interim analysis of the ongoing ASTRIS study (NCT02474355).
Method:
Patients (pts) received osimertinib 80 mg once daily. Eligible pts had advanced NSCLC that had progressed on prior EGFR-TKI therapy and with a T790M mutation determined by local validated molecular test, WHO performance status (PS) 0−2, acceptable organ and bone marrow function and no history of interstitial lung disease or QTc prolongation. Asymptomatic, stable CNS metastases were permitted. The primary efficacy outcome was overall survival; other outcomes included local test methods, specimen type, EGFR mutations identified, investigator-assessed response rate (RR), progression-free survival and time to treatment discontinuation. Safety data are also reported.
Result:
From 18 Sept 2015 to the planned 3 Nov 2016 data cut-off (DCO), 1217 pts received osimertinib 80 mg once-daily across 14 countries with a median age 64 yrs (27–92 yrs), 67% female, 61% White, 37% Asian, 87% WHO PS 0/1, 44% prior chemotherapy, 45% prior radiotherapy. All pts tested positive for T790M; T790M was reported alone in 185 pts (15%). The most common testing methods were PNA-Clamp 317 pts (27%), Qiagen therascreen 254 pts (22%), and Roche cobas 204 pts (17%). Exon 19 deletion was the most common co-occurring mutation with T790M (57%), followed by L858R (27%). Tissue or cytology specimens were used in 720 pts (59%), plasma in 433 pts (36%), and other specimens in 64 pts (5%). At DCO, the median duration of exposure was 3.8 months (<1–13.2 months) with a median follow-up time of 4.1 months (<1−14 months). In pts evaluable for response, the investigator-assessed RR was 64% (569/886; 95% CI 61, 67). Adverse events (AEs) leading to dose modification and treatment discontinuation were reported in 122 pts (10%) and 54 pts (4%), respectively. Serious AEs were reported in 165 pts (14%) and AEs leading to death in 28 pts (2%).
Conclusion:
ASTRIS is the largest reported global study of osimertinib in pts with T790M-positive NSCLC identified by a wide array of molecular testing methods and from various specimen types. Considering this breadth of T790M testing, the clinical activity of osimertinib is like that observed in the clinical trial program and no new safety signals were identified.
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P3.01-050 - A Real World Treatment Study of Osimertinib: ASTRIS Study Korean Subgroup Analysis (ID 9678)
09:30 - 09:30 | Author(s): D. Kim
- Abstract
Background:
ASTRIS (NCT02474355) is an open-label, single-arm, multination, real world treatment study, investigating the safety and efficacy of osimertinib in patients with T790M-positive advanced non-small cell lung cancer (NSCLC), who have previously received EGFR-TKI. We report the first results of Korean subset from ASTRIS which is the largest real world treatment study of osimertinib to date.
Method:
Eligible patients had advanced NSCLC harbouring a T790M mutation determined by local validated molecular tests, received prior EGFR-TKI therapy, acceptable organ and bone marrow function and no history of interstitial lung disease (ILD) or QTc prolongation. Enrollment of patients with asymptomatic, stable CNS metastases were permitted. Patients received osimertinib 80 mg once daily. The primary efficacy outcome was overall survival; other outcomes included investigator-assessed response rate (RR), progression-free survival (PFS) and time to treatment discontinuation (TTD). Safety assessment was also conducted. Data cut-off (DCO) was 3 November 2016; results from 1,217 patients in the global study have been presented previously (ASCO 2017 Abstract 9036).
Result:
A total of 371 patients received at least one dose of osimertinib from 30 Korean sites (full analysis set); at DCO, 319 patients (81.4%) were ongoing and median follow-up time was of 3.1 (0–8) months. Baseline patients’ characteristics were median age 61.1 (27–85) years old, female 65.5%, PS 0/1 88%, prior chemotherapy 47%, prior radiotherapy 48%. Tissue was the most common specimen source to test T790M mutation as well as other EGFR mutations (287/371, 77.4%) and plasma was the next (39/371, 13.1%). Fifty two patients (13.3%) had discontinued treatment; median duration of exposure 3.3 (0–7) months, 30 pts (7.7%) had disease progression and 24 patients (6.5%) died. In patients evaluable for response, defined as at least one dose of osimertinib and one response assessment, the investigator-assessed RR was 72.1% (212/294; 95% CI 66.6 – 77.2). Due to limited follow-up period, OS, PFS, and TTD were immature to analyze. Adverse events (AEs) leading to dose modification and treatment discontinuation were reported in 26 patients (7%) and 14 patients (3.8%), respectively. Serious AEs were reported in 50 patients (13.5%) and AEs leading to death in 8 patients (2.2%). ILD/pneumonitis-like events were reported in 9 patients (2.4%), and QTc prolongation (>470ms) in 5 patients (1.3%).
Conclusion:
At DCO for the 1[st] interim analysis of ASTRIS, Korean subgroup results demonstrated similar clinical activities (RR) to that observed in the osimertinib clinical trial program with no new safety signals.
