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S. Kim



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    MA08 - Treatment Monitoring in Advanced NSCLC (ID 386)

    • Event: WCLC 2016
    • Type: Mini Oral Session
    • Track: Advanced NSCLC
    • Presentations: 1
    • Now Available
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      MA08.03 - Osimertinib vs Platinum-Pemetrexed for T790M-Mutation Positive Advanced NSCLC (AURA3): Plasma ctDNA Analysis (Now Available) (ID 4733)

      S. Kim

      • Abstract
      • Presentation
      • Slides

      Background:
      AURA3 (NCT02151981) is a Phase III, open-label, randomised study assessing the efficacy and safety of osimertinib, a T790M directed EGFR-TKI, vs platinum-based doublet chemotherapy in patients with EGFR T790M-positive advanced NSCLC, whose tumours progressed on previous EGFR-TKI therapy. Concordance between plasma and tissue testing, and efficacy outcomes by baseline plasma T790M status, were evaluated.

      Methods:
      Eligible patients were randomised 2:1 to osimertinib 80 mg orally once daily or platinum-pemetrexed (pemetrexed 500 mg/m2 + cisplatin 75 mg/m2 or carboplatin AUC5) every three weeks for up to six cycles. Patients were tumour tissue T790M-positive (by cobas[®] EGFR Mutation Test v2) from a biopsy after disease progression prior to study entry. Blood samples were taken at baseline for retrospective analysis of T790M mutation status by plasma ctDNA using the cobas[®] EGFR Mutation Test v2.

      Results:
      Concordance data are reported in the table. Within the intent-to-treat (ITT) population (n=419), patients plasma T790M-positive and randomised to treatment (n=172) had markedly improved progression-free survival (PFS) by investigator assessment (IA) with osimertinib vs platinum-pemetrexed: hazard ratio 0.42 (95% CI: 0.29, 0.61); median 8.2 vs 4.2 months. Objective response rate (ORR) by IA was also distinctly improved with osimertinib vs platinum-pemetrexed: 77% vs 39% (odds ratio 4.96 [95% CI: 2.49, 10.15]; p<0.001). This is consistent with the ITT population: PFS hazard ratio 0.30 (95% CI: 0.23, 0.41); p<0.001 (median 10.1 vs 4.4 months); ORR 71% vs 31% (odds ratio 5.39 [95% CI: 3.47, 8.48]; p<0.001). Figure 1



      Conclusion:
      In plasma T790M-positive patients the clinical benefit of osimertinib was superior to platinum-pemetrexed, consistent with the ITT T790M-positive population selected by tumour tissue test. PFS with osimertinib was similar regardless of selection by tissue or plasma T790M-positive status. Based on these, and AURA Phase II data, routine biopsy testing is recommended for patients with a plasma T790M-negative test where feasible.

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    OA08 - Targeted Therapies in Brain Metastases (ID 381)

    • Event: WCLC 2016
    • Type: Oral Session
    • Track: Advanced NSCLC
    • Presentations: 1
    • Now Available
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      OA08.06 - Brigatinib Activity in Patients with ALK+ NSCLC and Intracranial CNS Metastases in Two Clinical Trials (Now Available) (ID 4374)

      S. Kim

      • Abstract
      • Presentation
      • Slides

      Background:
      Patients treated with crizotinib often experience disease progression in the brain. Brigatinib, an investigational next-generation ALK inhibitor, is being evaluated in an ongoing phase 1/2 trial (Ph1/2) and an ongoing pivotal phase 2 trial (ALTA).

      Methods:
      In Ph1/2, patients with advanced malignancies, including ALK+ NSCLC, received 30–300 mg brigatinib per day. In ALTA, patients with crizotinib-resistant advanced ALK+ NSCLC received 90 mg qd (arm A) or 180 mg qd with a 7-day lead-in at 90 mg (arm B). Efficacy (in both trials) and safety (in ALTA) are reported for ALK+ NSCLC patients with brain metastases at baseline.

      Results:
      In Ph1/2 and ALTA, 50/79 (63%; IRC-assessed) and 154/222 (69%; investigator-assessed) of ALK+ NSCLC patients, respectively, had baseline brain metastases. In Ph1/2 (n=50), median age was 53 years, 76% received prior chemotherapy, and 8% were crizotinib-naive. In ALTA (n=154), median age was 52 years; 75% received prior chemotherapy. As of November 16, 2015, 25/50 (50%) patients were receiving brigatinib in Ph1/2; as of February 29, 2016, 101/154 (66%) patients were receiving brigatinib in ALTA. For patients with measurable lesions, confirmed iORR was 53% in Ph1/2 and 42%/67% in ALTA A/B (Table). Among patients with only nonmeasurable lesions (Ph1/2, n=31; ALTA A/B, n=54/n=55), 35% had confirmed complete resolution of lesions in Ph1/2; 7%/18% had confirmed complete resolution in ALTA A/B. For all evaluable patients with baseline brain metastases, median intracranial PFS was 15.6 months in Ph1/2 (n=46) and 15.6/12.8 months in ALTA A/B (n=80/n=73). Most common treatment-emergent adverse events in ALTA in patients with baseline brain metastases (n=151 treated): nausea (A/B, 32%/43%), headache (30%/30%), diarrhea (18%/36%), cough (21%/30%), vomiting (25%/26%); grade ≥3 (excluding neoplasm progression): increased blood CPK (1%/11%), hypertension (4%/7%), increased lipase (3%/3%), pneumonia (1%/4%).

      Conclusion:
      Brigatinib has demonstrated substantial clinical activity in ALK+ NSCLC patients with brain metastases in both Ph1/2 and ALTA.

      IRC-Assessed Confirmed Intracranial Response Rates for Patients With Measurable Brain Metastases at Baseline
      Any No rad/active[a]
      Ph1/2[b] n=15 n=9
      iORR 8(53) 6(67)
      iDCR 13(87) 8(89)
      ALTA[c]
      Arm A n=26 n=19
      iORR 11(42) 8(42)
      iDCR 22(85) 16(84)
      Arm B n=18 n=15
      iORR 12(67) 11(73)
      iDCR 15(83) 14(93)
      Data are n(%) iDCR=intracranial disease control rate iORR=intracranial objective response rate IRC=independent review committee [a]No prior brain radiotherapy (Ph1/2); active (untreated or treated and progressed) brain lesions (ALTA) [b]NCT01449461; last scan date: October 8, 2015 [c]NCT02094573; last scan date: April 14, 2016


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    OA23 - EGFR Targeted Therapies in Advanced NSCLC (ID 410)

    • Event: WCLC 2016
    • Type: Oral Session
    • Track: Advanced NSCLC
    • Presentations: 1
    • Now Available
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      OA23.05 - First-Line Afatinib versus Gefitinib in EGFRm+ Advanced NSCLC: Updated Overall Survival Analysis of LUX-Lung 7 (Now Available) (ID 5347)

      S. Kim

      • Abstract
      • Presentation
      • Slides

      Background:
      The irreversible ErbB family blocker afatinib and the reversible EGFR TKI gefitinib are approved for first-line treatment of advanced EGFRm+ NSCLC. This Phase IIb trial prospectively compared afatinib versus gefitinib in this setting.

      Methods:
      LUX-Lung 7 assessed afatinib (40 mg/day) versus gefitinib (250 mg/day) in treatment-naïve patients with stage IIIb/IV NSCLC harbouring a common EGFR mutation (Del19/L858R). Co-primary endpoints were PFS (independent review), time to treatment failure (TTF) and OS. Other endpoints included ORR and AEs. In case of grade ≥3/selected grade 2 drug-related AEs the afatinib dose could be reduced to 30 mg or 20 mg (minimum). The primary analysis of PFS/TTF was undertaken after ~250 PFS events. The primary OS analysis was planned after ~213 OS events and a follow-up period of ≥32 months.

      Results:
      319 patients were randomised (afatinib: 160; gefitinib: 159). At the time of primary analysis, PFS (HR [95% CI] 0.73 [0.57‒0.95], p=0.017), TTF (0.73 [0.58‒0.92], p=0.007) and ORR (70 vs 56%, p=0.008) were significantly improved with afatinib versus gefitinib. The most common grade ≥3 AEs were diarrhoea (13%) and rash/acne (9%) with afatinib and elevated ALT/AST (9%) with gefitinib. 42% of patients treated with afatinib had ≥1 dose reduction due to AEs; dose reductions were more common in females than males (77%/23%) and non-Asians than Asians (64%/36%). Dose reduction of afatinib did not negatively impact PFS (<40mg vs ≥40mg; HR [95% CI]: 1.34 [0.90‒2.00]) but reduced incidence and severity of drug-related grade ≥3 AEs. Treatment discontinuation due to drug-related AEs was the same in each arm (6%). The data cut-off for primary OS analysis occurred on 8 April 2016. At this time, median treatment duration (range) was 13.7 (0‒46.4) versus 11.5 (0.5‒48.7) months with afatinib and gefitinib. 25% (afatinib) and 13% (gefitinib) of patients received treatment for >24 months. 73% and 77% of patients in the afatinib and gefitinib arms had ≥1 subsequent systemic anti-cancer treatment, with 46% and 56% receiving a subsequent EGFR-TKI including osimertinib (14%)/olmutinib (14%). OS data, including subgroup analysis with respect to subsequent therapy will be presented at the meeting.

      Conclusion:
      Afatinib significantly improved PFS, TTF and ORR versus gefitinib in EGFRm+ NSCLC patients, with a manageable AE profile and few drug-related discontinuations. Dose adjustment of afatinib reduced drug-related AEs without compromising efficacy. Primary OS analysis will be reported.

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    P2.03a - Poster Session with Presenters Present (ID 464)

    • Event: WCLC 2016
    • Type: Poster Presenters Present
    • Track: Advanced NSCLC
    • Presentations: 2
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      P2.03a-038 - Phase III Trial of Pemetrexed/Carboplatin vs Pemetrexed Only in Chemo-Naïve Elderly Non-SQCC NSCLC Patients Aged ≥ 70 (ID 5036)

      S. Kim

      • Abstract

      Background:
      We aimed to compare pemetrexed/carboplatin doublet (PC) versus pemetrexed singlet (P) as induction therapy in chemotherapy-naïve elderly patients aged 70 or more with advanced non-squamous non–small-cell lung cancer (NSCLC) and an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1.

      Methods:
      In this open-label multicenter phase III randomized trial, elderly patients aged 70 or more with advanced non-squamous NSCLC, ECOG PS of 0-1, no prior chemotherapy, adequate organ function and measurable disease were assigned to PC doublet (P, 500 mg/m2; C, area under the curve of 5) or P singlet (500 mg/m2) after stratified randomization according to center, gender and Charson Comorbidity Index (CCI). The treatment was given every 3 weeks till disease progression, unacceptable toxicity or withdrawal of consent. However, carboplatin was given for only the first four cycles during induction therapy period. The primary end point was progression-free survival (PFS). Secondary endpoints included overall survival, response rate, and safety.

      Results:
      A total of 267 eligible patients were enrolled from six centers between March 2012 and October 2015; median age was 74 years (70~86); 95% had PS of 1; 68% were men; and 61% had CCI of 1 or more. The median PFS was 5.4 months for PC doublet and 4.2 months for P singlet, respectively (hazard ratio [HR], 0.85; 95% CI, 0.65 to 1.11; P= 0.2353). The median survival time was 12.5 months for PC and 9.0 months for P, respectively (HR, 0.86; 95% CI, 0.62 to 1.21; P =0.4108). The objective response rates for PC doublet and P singlet were 34.7% and 25.9%, respectively (p=0.1387). The most common adverse events in PC doublet arm were anemia (9.6%), fatigue (8%) and pneumonia (6.4%) while those in P singlet arm were pneumonia (4.2%), fatique (3.3%) and anemia (2.5%) in descending of frequency.

      Conclusion:
      The addition of carboplatin to pemetrexed during induction therapy period did not show the improvement of survival time in elderly patients aged 70 or more with advanced non-squamous NSCLC and ECOG PS of 0-1 even though it increased the response rate numerically. Updated data will be presented.

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      P2.03a-061 - Randomized Phase II Trial Comparing Intercalation of Afatinib to Pemetrexed with Pemetrexed Alone after Failure of Platinum Doublet Therapy (ID 5813)

      S. Kim

      • Abstract

      Background:
      The combination of pemetrexed and erlotinib was synergistic in non-small cell lung cancer in vitro, if erlotinib exposure was avoided before pemetrexed. To enhance the efficacy of 2[nd]-line pemetrexed, we designed to test the sequential administration of afatinib followed by pemetrexed (pem+afa) compared with pemetraxed (pem) monotherapy.

      Methods:
      We performed randomized phase II trial in Asan Medical Center, Seoul, Korea. Patients with histologically or cytologically confirmed as non-squamous lung cancer were enrolled. Patients were stratified by response to 1[st] line treatment and smoking history, and randomly assigned in a 2:1 ratio to receive intravenous pemetrexed (500 mg/m2) on D1 followed by afatinib 40 mg/day on D2-15 or pemetrexed (500 mg/m2) on D1 every 3 weeks. The treatment was continued until disease progression. Primary end point was objective response rate (ORR), and secondary end points were progression-free survival (PFS) and overall survival (OS).

      Results:
      From August 2012 to July 2016, a total 87 patients (male, 71.3%; never smoker 31.0%; sensitive to 1[st]-line chemotherapy (PR+SD) 65.5%; median age 59 years) were randomized to pem (n=30) or pem+afa (n=57). Median follow-up duration was 12.4 months (range, 0.4-46.6 months). Median cycles administered were both 4 cycles in each groups (range, 1-37 in pem group; 1-62 in pem+afa group). Among 57 patients in pem+afa group, 26 patients (45.6%) underwent dose reduction (30 mg/day in 18 patients; 20 mg/day in 8 patients). By July, 2016, among 81 evaluable patients, 22 responses were noticed (4 in pem group; 18 in pem+afa group). ORR were 13.3% (4/30) and 31.6% (18/57) in pem and pem+afa, respectively (2-sided p value=0.074). Median PFS were 2.9 months and 5.7 months in pem and pem+afa, respectively (HR 0.718; 95% CI, 0.427-1.148; p=0.163). Median OS were 15.6 months and 12.1 months in pem and pem+afa, respectively (HR 1.393; 95% CI, 0.794-2.445; p=0.245).

      Conclusion:
      Intercalation of afatinib to pemetrexed looks better in numerically but statistically insignificant over pemetrexed monotherapy in 2[nd]-line treatment in EGFR unselected population with non-squamous lung cancer.

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    P3.02a - Poster Session with Presenters Present (ID 470)

    • Event: WCLC 2016
    • Type: Poster Presenters Present
    • Track: Advanced NSCLC
    • Presentations: 2
    • Now Available
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      P3.02a-013 - Brigatinib in Crizotinib-Refractory ALK+ NSCLC: Central Assessment and Updates from ALTA, a Pivotal Randomized Phase 2 Trial (Now Available) (ID 4046)

      S. Kim

      • Abstract
      • Slides

      Background:
      Brigatinib, an investigational next-generation ALK inhibitor, has yielded promising activity in crizotinib-treated ALK+ NSCLC patients in a phase 1/2 trial (NCT01449461). As responses and adverse events (AEs) varied with starting dose, two brigatinib regimens are under evaluation in ALTA (NCT02094573).

      Methods:
      Patients with crizotinib-refractory advanced ALK+ NSCLC were 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) and stratified by presence of brain metastases at baseline and best response to prior crizotinib. Primary endpoint was investigator-assessed confirmed ORR per RECIST v1.1.

      Results:
      222 patients were enrolled (arm A, n=112/arm B, n=110). Median age (A/B) was 51/57 years, 55%/58% were female, 74%/74% previously received chemotherapy, and 71%/67% had brain metastases. As of February 29, 2016, 64/112 (57%) patients in arm A and 76/110 (69%) patients in arm B were receiving brigatinib; median follow-up was 7.8/8.3 months. The Table shows investigator-assessed endpoints by arm and subgroup for select baseline characteristics. Independent review committee–assessed endpoints (A/B, n=112/n=110; as of May 16, 2016): confirmed ORR 48%/53%, median PFS 9.2/15.6 months. Any-grade treatment-emergent AEs (≥25% overall frequency; A/B, n=109/n=110 treated): nausea (33%/40%), diarrhea (19%/38%), headache (28%/27%), cough (18%/34%); grade ≥3 events (excluding neoplasm progression; ≥3% frequency): hypertension (6%/6%), increased blood CPK (3%/9%), pneumonia (3%/5%), increased lipase (4%/3%). A subset of pulmonary AEs with early onset (median onset: Day 2) occurred in 14/219 (6%) treated patients (3%, grade ≥3); 7/14 patients were successfully retreated. No such events occurred after escalation to 180 mg in arm B.

      Conclusion:
      In each arm, brigatinib yielded substantial responses and prolonged PFS, with an acceptable safety profile. 180 mg with 90 mg lead-in was not associated with increased early pulmonary events and showed a consistent improvement in efficacy, compared with 90 mg, particularly with respect to PFS.

      Investigator-Assessed Endpoints by Arm and Subgroup
      Confirmed ORR, n/N(%) Median PFS, months
      Arm A B A+B A B A+B
      All patients 50/112(45) 59/110(54) 109/222(49) 9.2 12.9 11.1
      Prior chemotherapy
      Yes 35/83(42) 44/81(54) 79/164(48) 8.8 12.9 11.8
      No 15/29(52) 15/29(52) 30/58(52) 9.2 8.1 9.2
      Race
      Asian 18/39(46) 18/30(60) 36/69(52) 8.8 11.1 11.1
      Non-Asian 32/73(44) 41/80(51) 73/153(48) 9.2 12.9 11.8
      Brain metastases at baseline
      Yes 31/80(39) 43/74(58) 74/154(48) 9.2 11.8 11.1
      No 19/32(59) 16/36(44) 35/68(51) 7.4 15.6 15.6
      Best response to prior crizotinib
      Partial+complete 36/71(51) 47/73(64) 83/144(58) 11.1 15.6 15.6
      Other 14/41(34) 12/37(32) 26/78(33) 7.4 12.9 9.2
      ORR=objective response rate PFS=progression-free survival


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      P3.02a-036 - Phase 1 Study of Ceritinib 450 mg or 600 mg Taken with a Low-Fat Meal versus 750 mg in Fasted State in ALK+ Metastatic NSCLC (ID 7170)

      S. Kim

      • Abstract

      Background:
      The anaplastic lymphoma kinase (ALK) inhibitor ceritinib is approved at 750 mg fasted for the treatment of patients with ALK-rearranged (ALK+) metastatic non-small cell lung cancer (NSCLC) pretreated with crizotinib. The pharmacokinetic (PK) part of this study (Part 1) compares PK exposure of ceritinib following food consumption versus a fasted state in advanced ALK+ NSCLC patients.

      Methods:
      Part 1 of this prospective, open-label, multicenter, randomized, 3-arm, phase 1 study (ASCEND-8; NCT02299505) is investigating PK and safety of ceritinib in advanced ALK+ NSCLC patients, treatment-naïve or pretreated with multiple lines of chemotherapy and/or crizotinib. Here, we compare steady-state PK of ceritinib 450 or 600 mg taken with a low‑fat meal versus ceritinib 750 mg fasted (primary endpoint) and report preliminary safety outcomes from Part 1. Part 2 continues to randomize treatment-naïve patients and will assess safety and efficacy.

      Results:
      As of June 16, 2016 (data cut-off), 137 patients were randomized in a 1:1:1 ratio to each treatment arm; 135 patients received one dose (safety set) and 97 patients had evaluable steady-state PK data. Disease characteristics were comparable between arms. Median follow-up duration was 4.14 months (range, 0.1–13.9). Relative to 750 mg fasted, the 450 mg fed arm demonstrated comparable steady-state PK, while the 600 mg fed arm showed ~25% higher steady-state PK (Table). Preliminary safety data suggests overall frequency of AEs and types of AEs were comparable between arms. However, incidences of gastrointestinal (GI)-related AEs (diarrhea, nausea or vomiting) were lowest, with no grade 3/4 GI AEs reported, in the 450 mg fed arm.Figure 1



      Conclusion:
      Steady-state PK was comparable in advanced ALK+ NSCLC patients taking ceritinib 450 mg with a low-fat meal versus 750 mg fasted. This study continues to enroll treatment-naïve patients into Part 2 to assess efficacy across the three treatment arms and assess longer safety follow-up.