Mutation-positive Pts Research Articles

131I-Apamistamab-Led Allogeneic Hematopoietic Cell Transplant Significantly Improves Overall Survival in Patients with TP53 Mutated R/R AML

Background : Allogeneic hematopoietic cell transplant (alloHCT) is the only potentially curative therapy for patients (pts) with relapsed or refractory (R/R) AML. Only a minority undergo alloHCT as they typically have dismal outcomes due to high relapse rates, especially those with TP53 mutations and active disease. Additionally, older pts cannot tolerate intensive treatment and hence are not eligible for alloHCT. 131I-apamistamab, an anti-CD45 radioimmunoconjugate, delivers high dose targeted radiation to hematopoietic cells, allowing for myeloablation and eradication of leukemic cells. 131I-apamistamab led induction and conditioning can thus provide these pts access to alloHCT potentially leading to better disease control and outcomes even in pts with the TP53 mutation. Methods: The SIERRA trial (NCT02665065) is a multi-center, randomized, controlled Phase 3 study comparing the rate of durable complete remission (dCR) lasting ≥6 months (mos) after complete remission with/without platelet recovery (CR/CRp) between two groups: 131I-apamistamab led induction and conditioning followed by alloHCT vs physician's choice of conventional care (CC). Pts were randomized (1:1) to CC or 131I-apamistamab with fludarabine and total body irradiation (2 Gy) followed by alloHCT. CR/CRp assessment was 28-56 days post alloHCT or 28-42 days post initiation of therapy in the CC group. Pts in the CC group not achieving leukemia-free state could crossover (CO) to 131I-apamistamab. We report the characteristics and outcomes of all pts with TP53 mutation who were enrolled in the SIERRA trial. Results: In total, 153 pts were randomized (CC, n=77; 131I-apamistamab, n=76). All pts who received the therapeutic dose of 131I-apamistamab (n=66) underwent HCT vs 14 (18.2%) in the CC group. Of evaluable pts, dCR rates at 6 months were 22% in the 131I-apamistamab group vs 0% in the CC group (95% CI;12.29, 34.73; p<0.0001). A total of 37 pts with TP53 mutation were enrolled (CC=20; 131I-apamistamab =17) with a prevalence of 24.2%. Table 1 shows the baseline characteristics of these pts. Median overall survival (OS) for pts in the 131I-apamistamab group, who were TP53 negative was 6.37 mos compared to 5.72 mos for the TP53 mutation positive pts (HR=0.66; 95% CI [0.37, 1.18]; p=0.16). In the CC group (including CO pts), the median OS for TP53 positive pts was 2.96 mos. When the CC group without CO were analyzed, the median OS was 6.51 mos and 1.66 mos for the TP53 mutation negative and positive groups respectively (HR=0.28; 95% CI [0.12, 0.67]; p=0.0022). For TP53 mutation positive pts who received 131I-apamistamab ( 131I-apamistamab plus CO pts), the median OS was 5.49 mos compared to a median 1.66 mos in pts who did not receive 131I-apamistamab (CC pts without CO) [(HR=0.23; 95% CI [0.10, 0.52]; p=0.0002) (Figure 1)]. Conclusion: Pts with TP53 mutated R/R AML have a dismal prognosis and are seldom offered alloHCT due to high post-transplant relapse rates. 131I-apamistamab led alloHCT significantly improves survival outcomes in pts with TP53 mutations, commensurate with rates observed in pts with wildtype TP53, thereby overcoming the negative impact of this mutation. These data clearly support the use of 131I-apamistamab led induction and conditioning and alloHCT in R/R AML, including in patients with a TP53 mutation.

Impact of PD-L1 and KRAS status on the efficacy of nintedanib (NIN) + docetaxel (DOC) following treatment with first-line immune checkpoint inhibitor (ICI) + chemotherapy in patients with adenocarcinoma NSCLC: Analysis of cohort C of the non-interventional VARGADO trial.

e21149 Background: The identification of targetable molecular tumor markers in patients (pts) with NSCLC has increased significantly over the past decades and has resulted in important changes to individual treatment approaches. One such marker is KRASG12C for which a specific treatment is now available following prior systemic therapy. While ICIs ± chemotherapy represent first-line (1L) standard of care, the sequence of subsequent effective therapies still needs to be investigated. Methods: Cohort C of the ongoing, prospective, non-interventional VARGADO study (NCT02392455) is investigating the combination of NIN + DOC as second-line (2L) treatment after prior 1L ICI + chemotherapy in pts with adenocarcinoma NSCLC. This updated analysis of Cohort C focuses on the safety and efficacy of NIN + DOC according to programmed death ligand-1 (PD-L1) and KRAS status. Results: At the cut-off date (December 1, 2022) 219 pts have been enrolled to Cohort C. Median age was 64 years (range: 37–84) and 58.9% (129/219) of pts were men. At baseline, 30.6% (67/219) were ECOG PS 0 and 50.2% (110/219) were ECOG PS 1. 88.1% (193/219) had stage IV disease. Brain metastases were present in 19.2% (42/219) of pts and 88.1% (193/219) had received prior 1L pembrolizumab-based combination therapy. In the overall population, median PFS was 4.5 months (mo; 95% CI: 3.6–5.3, 219 pts) and median OS was 9.6 mo (95% CI: 6.5–11.2, 217 pts) with NIN + DOC. KRAS mutation status has been documented for 119 pts. In KRAS wild-type pts (75/119), median PFS was 3.7 mo (95% CI: 2.6–5.3) and median OS was 7.7 mo (95% CI: 5.2-11.2). In KRAS mutation-positive pts (44/119) median PFS was 5.1 mo (95% CI: 3.4–6.3) and median OS was 6.7 mo (95% CI: 5.3–15.1). In 33 pts with a non-G12C KRAS mutation, median PFS was 5.0 mo (95% CI: 3.4–6.7) and median OS was 6.7 mo (95% CI: 5.3–15.1). ORR was 20.0% (15/75), 25.0% (11/44), 27.3% (9/33) and 18.2% (2/11) in pts with KRAS wild-type, KRAS mutated, non-G12C mutated and G12C mutated status, respectively. The corresponding disease control rates (DCR) were 45.3% (34/75), 47.7% (21/44), 48.5% (16/33) and 45.5% (5/11). PD-L1 status prior to 1L therapy was < 1% in 86 pts and ≥1% in 76 pts and did not impact OS (median 10.6 mo [95% CI: 6.5–15.1] and 10.5 mo [95% CI: 5.7–12.5], respectively) or DCR (51.2% and 51.3%, respectively) with NIN + DOC. The most frequent NIN-related adverse events of any grade in the overall population were diarrhea 34.7% (76/219), nausea 14.2% (31/219), vomiting 8.2% (18/219) and fatigue 7.8% (17/219). Conclusions: NIN + DOC is an effective and safe 2L treatment option after prior 1L ICI + chemotherapy for NSCLC adenocarcinoma pts independent of PD-L1 and KRAS status. Clinical trial information: NCT02392455 .

Afatinib (AFA) plus bevacizumab (BEV) combination after osimertinib (OSI) resistance in advanced EGFR-mutant NSCLC: A phase II study (ABCD-study).

9117 Background: After OSI failure, various resistant mechanisms such as C797S and uncommon EGFR mutations, or MET amplification have been reported. AFA is an irreversible EGFR-TKI with a potency as pan-HER inhibitor, including high sensitivity to uncommon EGFR mutations. Many clinical studies have also shown a synergy of EGFR-TKIs and VEGF inhibitors. Methods: ECOG PS 0-1 patients (pt) with EGFR-mutant NSCLC were enrolled after OSI resistance. AFA was prescribed at 30-40 mg QD, and BEV was administered at 15 mg/kg tri-weekly until progression. Plasma/histologic rebiopsied samples taken after OSI failure but before enrollment were analyzed to examine resistant mechanisms including gene alterations/copy-number gain using cancer personalized profiling by deep sequencing. Results: Between January 2018 and October 2020, 28 pts were enrolled. Mutation subtypes were: 9 (32%) Del-19; 5 (18%) Del-19+T790M; 5 (18%) L858R; 7 (25%) L858R+T790M; 1 (4%) Del-19+L858R+T790M; and 1 (4%) G719S. Median line of prior OSI was 2 (range, 1-9). CR/PR was obtained by prior OSI in 24 (86%) pts. Regarding AFA+BEV efficacy, one (4%) CR, 4 (14%) PR, and 17 (61%) SD were confirmed, resulting in response rate of 17.9% and disease control rate of 78.6%. Median DoR was 9.0 (range, 4.2-22.3) months. Median PFS and OS were 2.7 (95% CI, 2.0-4.6) months and not reached, respectively. Twenty-eight (100%) plasma and/or 21 (75%) histologic rebiopsies identified: 17 (61%) TP53; 15 (54%) T790M; 9 (32%) uncommon EGFR; 9 (32%) MET; 6 (21%) C797S; 3 (11%) BRAF; 2 (7%) HER2; 2 (7%) KRAS; and 2 (7%) PI3K mutations; or 14 (50%) EGFR; 6 (21%) MET; and 2 (7%) HER2 amplifications. One (4%) small cell transformation was found. Among 6 C797S pts, 1 CR, 4 SD, and 1 PD were confirmed. Three (33%) of 9 uncommon EGFR and 1 (50%) of 2 HER2 mutation positive pts achieved radiographic response. All 15 T790M-positive pts showed no response, but 5 (38%) of 13 T790M-negative pts responded to AFA+BEV. None (0%) of six pts with EGFR downstream signaling mutations such as BRAF, KRAS, or PI3K responded. Five (50%) of 10 pts without T790M/BRAF/KRAS/PIK3 mutations exhibited confirmed response. FAT1 mutation was found in two (40%) of 5 responded pts. Dose reduction/interruption of AFA was performed in 15 (54%) pts. Median number of BEV administrations was 4 (range, 1-32). There were neither TRD nor ILD. Adverse events ≥grade 3: hypertension (29%); proteinuria (7%); diarrhea (7%); and rash (4%) were observed. One (4%) grade 4 duodenal perforation was reported. Conclusions: AFA+BEV after OSI resistance demonstrated moderate efficacy and favorable safety. A small portion of C797S pts exhibited the sensitivity. Higher potency was suggested in T790M/BRAF/KRAS/PIK3 mutation-negative and uncommon EGFR/HER2 mutation-positive pts. Selected population could obtain clinical benefit from AFA+BEV, based on rebiopsy results after OSI resistance. Clinical trial information: UMIN000030545.

1450P - Frequency of epidermal growth factor receptor (EGFR) mutations in stage IB–IIIA EGFR mutation positive non-small cell lung cancer (NSCLC) after complete tumour resection

BackgroundData on the frequency of EGFR mutations in patients (pts) with NSCLC potentially eligible for adjuvant therapy are limited. Osimertinib, a 3rd-generation, irreversible, oral EGFR-tyrosine kinase inhibitor (TKI), potently and selectively inhibits both EGFR-TKI sensitising (EGFRm) and EGFR T790M mutations, and has shown efficacy in the CNS. The ADAURA study (NCT02511106) will assess osimertinib as adjuvant therapy in early-stage NSCLC after complete resection. Here we report frequency of the most common EGFR activating mutations from pts screened for ADAURA. MethodsADAURA is a Phase III, double-blind, randomised, placebo-controlled study assessing efficacy and safety of osimertinib vs placebo in adult pts with mainly non-squamous histology, stage IB–IIIA EGFRm NSCLC, following complete tumour resection, without or after adjuvant chemotherapy. At screening, EGFR mutations associated with EGFR-TKI sensitivity (ex19del, L858R), alone or in combination with exon 20 insertion, G719X, S768I, T790M or L861Q were centrally assessed from resected tumour samples using the cobas® EGFR Mutation Test (Roche Molecular Systems). Some pts may have been pre-screened for EGFR mutations using local tests. ResultsIn total, 2447 pts were screened. Median age was 63 years (range 23–88), 54% were female, and 61% were non-Asian. At screening, 1087 (44%) pts were EGFR mutation positive; 110/2447 (4%) pts had an unknown/unevaluable test result. Of pts EGFR mutation positive, the most common mutations were ex19del and L858R in 572 (53%) and 458 (42%) pts, respectively; exon 20 insertion, G719X, T790M, S768I, and L861Q mutations occurred in 28 (3%), 24 (2%), 19 (2%), 11 (1%) and 8 (1%) pts, respectively. Mutations occurred alone or in combination. A higher proportion of EGFR mutation positive pts were Asian vs non-Asian (681 [63%] vs 402 [37%]; 4 pts missing) and female vs male (755 [69%] vs 331 [30%]; 1pt missing). ConclusionsThis analysis shows a high prevalence of EGFRm mutations in Asian and female pts with stage IB–IIIA NSCLC following complete resection, which is consistent with the advanced setting. International screening for EGFR mutations in the adjuvant setting should be considered. Clinical trial identificationNCT02511106. Editorial acknowledgementNatalie Griffiths, PhD, from iMed Comms, an Ashfield Company; funded by AstraZeneca. Legal entity responsible for the studyAstraZeneca. FundingAstraZeneca. DisclosureM. Tsuboi: Research grant / Funding (institution): Boehringer Ingelheim Japan; Honoraria (self): Johnson & Johnson Japan, AstraZeneca KK, Eli Lilly Japan, Boehringer Ingelheim Japan, Daiichi-Sankyo, Chugai Pharmaceutical, Taiho Pharma, Covidien Japan, Ono Pharmaceutical, Merck Sharp & Dohme, Bristol-Myers Squibb KK, Teijin Pharma. R.S. Herbst: Advisory / Consultancy, Consulting: AbbVie Pharmaceuticals, ARMO Biosciences, AstraZeneca, Biodesix, Bristol-Myers Squibb, Eli Lilly, EMD Serrano, Genentech/Roche, Genmab, Heat Biologics, Halozyme, Loxo Oncology, Merck & Company, Nektar, NextCure, Novartis, Pfizer, Sanofi, Seattle Genetics,; Research grant / Funding (institution): AstraZeneca, Eli Lilly, Merck; Advisory / Consultancy, Scientific Advisory Boards: Neon Therapeutics, Infinity Pharmaceuticals, NextCure; Leadership role, Board Member (non-executive/independent): Junshi Pharmaceuticals. T. John: Advisory / Consultancy: Roche, Bristol-Myers Squibb, Merck, Ignyta, AstraZeneca, Takeda. M. Majem: Advisory / Consultancy, Speaker Bureau / Expert testimony: Roche; Speaker Bureau / Expert testimony, Research grant / Funding (self), Travel / Accommodation / Expenses: Bristol-Myers Squibb; Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Merck Sharp & Dohme; Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: AstraZeneca; Advisory / Consultancy, Speaker Bureau / Expert testimony: Boehringer Ingelheim; Advisory / Consultancy: Tesaro; Speaker Bureau / Expert testimony: Hellsin; Travel / Accommodation / Expenses: Lilly; Advisory / Consultancy: Takeda; Advisory / Consultancy, Speaker Bureau / Expert testimony: Pierre Fabre; Speaker Bureau / Expert testimony: Amgen. J.W. Goldman: Research grant / Funding (institution): AbbVie; Speaker Bureau / Expert testimony, Research grant / Funding (institution): Merck; Research grant / Funding (institution): Bristol-Myers Squibb; Honoraria (self), Research grant / Funding (institution): AstraZeneca. S. Novello: Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lilly, Roche, Merck Sharp & Dohme, Takeda, Pfizer, AbbVie, AstraZeneca, Celgene. D. Urban: Honoraria (self), Travel / Accommodation / Expenses: AstraZeneca. C. Akewanlop: Travel / Accommodation / Expenses: Amgen, AstraZeneca, Roche. D. Kowalski: Advisory / Consultancy, Travel / Accommodation / Expenses: Boehringer Ingelheim. D. Marmol: Shareholder / Stockholder / Stock options, Full / Part-time employment: AstraZeneca. M. Marotti: Shareholder / Stockholder / Stock options, Full / Part-time employment: AstraZeneca. G. Laus: Shareholder / Stockholder / Stock options, Full / Part-time employment: AstraZeneca. Y. Wu: Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): AstraZeneca, Roche; Honoraria (self), Advisory / Consultancy: Boehringer Ingelheim; Honoraria (self): Eli Lilly, Pfizer, Merck Sharp & Dohme, Bristol-Myers Squibb. All other authors have declared no conflicts of interest.

P1-082 - Analysis of 148 cases of EGFR mutation-positive lung cancer patients

Background: More than 10 years have passed since EGFR gene mutation was discovered in non-small cell lung cancer (NSCLC). Nowadays almost EGFR mutation-positive NSCLC patients (pts) could get longer than 2 year-survival benefit. Purpose&Pts: The clinical characteristics of 489 lung cancer pts, who underwent EGFR gene test in 2002 to 2015, were retrospectively analyzed. Results: Pts included 367 of adenocarcinomas, 9 of adenosquamous carcinomas, and 29 of NSCLCs. They also included 49 of squamous cell carcinomas, 15 of small cell carcinomas, and other lung carcinomas. The EGFR mutations were detected in 148 cases (30.3%). The mutation rate of adenocarcinomas was 37.6%. As the first treatment, 73 pts (49.3%) were treated with molecular targeted therapy, 37 pts (25%) with operation, 21 pts (14.2%) with cytotoxic chemotherapy, 5 pts (3.4%) with radiotherapy, and 1 pt (0.7%) with chemo-radiotherapy. EGFR mutation-positive 120 pts received each of 3 TKIs for any line of the treatment, but 28 pts (18.9%) did not receive TKIs at all. As the second line after TKI, 22 of 39 pts were treated with TKI, and 17 pts with cytotoxic chemotherapy. EGFR mutation-positive non-survivors were 94 (63.5%), and mutation-negative non-survivors were 218 (63.9%). Conclusion: Most of EGFR mutation-positive pts received TKI, but advanced NSCLC pts relapsed, probably due to the resistance to TKIs. New TKIs have been developed to conquer them. Moreover cancer immunotherapy has been shown to be effective in some of NSCLC pts.

Abstract 2860: Improved clinical response in patients with advanced melanoma treated with nivolumab combined with ipilimumab compared to ipilimumab alone

Abstract Background: Blockade of the immune checkpoints PD-1 and CTLA-4 each results in improved overall survival in patients (pts) with metastatic melanoma using monotherapy. In a phase 1 dose-escalation study, dual inhibition of these pathways by nivolumab (NIVO) and ipilimumab (IPI) demonstrated encouraging antitumor activity. Methods: Treatment-naïve pts with advanced melanoma were randomized (double-blind) 2:1 to IPI 3 mg/kg combined with either NIVO 1 mg/kg (NIVO+IPI combination group) or placebo (PBO; IPI alone group) every 3 weeks (Q3W) for 4 doses, followed by NIVO 3 mg/kg or PBO, respectively, Q2W until disease progression or unacceptable toxicity. Primary endpoint was investigator-assessed objective response rate (ORR) in BRAF wild-type (WT) pts. Secondary endpoints included progression-free survival (PFS), ORR in BRAF V600 mutation-positive (MT) pts, and safety. Results: In BRAF WT pts, ORR was 60% (43/72) in the NIVO+IPI group vs 11% (4/37) in the IPI group (P<0.0001); complete response reported in 12 (17%) and 0 pts, respectively. Median change in target lesions was 57% reduction for NIVO+IPI vs 4% increase for IPI alone. Median duration of response was not reached in either group. In BRAF WT pts, median PFS was 8.9 months for NIVO+IPI; 4.7 months for IPI (HR 0.40, 95% CI 0.22-0.71; P = 0.0012). Similar results for ORR and PFS favoring the combination were observed in BRAF MT pts (Table). A higher rate of drug-related grade 3-4 adverse events was observed in the NIVO+IPI group compared to IPI (Table), leading to more frequent discontinuation. Pts who discontinued NIVO+IPI due to study drug toxicity had a 67% response rate; most continue to respond. Immune-mediated AEs were manageable by standard treatment interventions, and the majority resolved with immune-modulating medication. Conclusion: NIVO+IPI significantly improved ORR and PFS compared to IPI alone in treatment-naïve pts with advanced melanoma, and had a manageable safety profile. Efficacy (evaluated in all randomized patients)BRAF WTBRAF WTBRAF MTNIVO+IPIIPINIVO+IPIIPIRandomized patients, N72372310ORR,% (95% CI)59.7 (47.5-71.1)a10.8 (3.0-25.4)a43.5 (23.2-65.5)0 (0-30.8)Best overall response, n (%)Complete response12 (16.7)04 (17.4)0Partial response31 (43.1)4 (10.8)6 (26.1)0Stable disease10 (13.9)12 (32.4)5 (21.7)2 (20.0)Progressive disease10 (13.9)16 (43.2)5 (21.7)7 (70.0)Median PFS, mo (95% CI)8.9 (7.0, NE)4.7 (2.8, 5.3)7.4 (2.8, NE)2.7 (0.99, 5.4)HR, (95% CI)0.40 (0.22-0.71) P = 0.00120.33 (0.1, 0.9)bSafety (evaluated in all treated patients)Patients reporting AE, n (%)NIVO+IPI (N = 94)IPI (N = 46)Any GradeGrade 3-4Any GradeGrade 3-4Treatment-related AEs86 (91.5)48 (51.1)42 (91.3)9 (19.6)aP<0.0001; estimated odds ratio for objective response 12.23 (95% CI, 3.69-51.40)bDue to the small sample size in the BRAF MT subgroup, no P-value is provided NE = not estimable Citation Format: F. Stephen Hodi, Michael A. Postow, Jason Chesney, Anna C. Pavlick, Caroline Robert, Kenneth Grossmann, David McDermott, Gerald Linette, Nicolas Meyer, Jeffrey Giguere, Sanjiv S. Agarwala, Montaser Shaheen, Marc S. Ernstoff, David R. Minor, April Salama, Matthew H. Taylor, Linda Rollin, Christine Horak, Paul Gagnier, Jedd D. Wolchok. Improved clinical response in patients with advanced melanoma treated with nivolumab combined with ipilimumab compared to ipilimumab alone. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2860. doi:10.1158/1538-7445.AM2015-2860

O1-9-2 - Tumor Genomic Profiling of Nsclc From the Phase III Trial of First-Line S-1/Cbdca Versus Paclitaxel/Cbdca (Wjog6611Ltr)

Background: Over the last decade, substantial advances have been made in developing genotype-based target therapies for advanced NSCLC. There is an increasing need to develop high-throughput genotyping tests to evaluate larger number genetic abnormalities.Method: Archived FFPE specimens obtained at the diagnosis were available for 304 (53.9%) of the 564 patients (Pts) who were enrolled in LETS study. With the use of Sequenom's MassARRAY system, we conducted high-throughput genotyping including somatic mutations and gene fusions (ALK, ROS1 and RET). We also evaluated MET amplification by FISH.Results: A somatic mutation in at least one was identified in 105 (48%) of the 217 pts with non-squamous cell carcinoma (SCC) and 26 (45%) of the 58 pts with SCC. Overall, we identified EGFR mutations in 46 patients (17%), TP53 mutations in 30 (11%), STK11 mutations in 27 (9.8%), MET mutations in 21 (7.6%), KRAS mutations in 17 (6.2%), PIK3CA mutations in 6 (2.2%), BRAF and NRAS mutations in each 3 (1.1%), and DDR2, ERBB2, NRF2 and PTEN mutations in each one patient (0.4%). The median overall survival (OS) of EGFR mutation-positive pts was significantly longer than that of pts without EGFR mutations (23.7 v 12.6 months; P = 0.004). Conversely, pts whose tumors had KRAS mutations had a significantly shorter survival than KRAS-wild type pts (9.9 v 15.3 months; P = 0.04). LungFusion panel identified ALK fusions in six cases (2.5%), ROS1 fusions in five cases (2.1%), and RET fusion in one case (0.4%), and these three rearrangements were mutually exclusive. Among five ROS1-fusion positive patients, two patients concomitantly had KRAS mutations, and one patient had EGFRL858R and PIK3CAE542K. Nine out of 229 advanced NSCLC pts (3.9%) were identified as having de novo MET amplification.Conclusions: MassARRAY-based multiplex genetic testing for somatic mutations and fusion genes performs well with nucleic acid derived from FFPE NSCLC tissues obtained from advanced NSCLC.

BREAK-MB: A phase II study assessing overall intracranial response rate (OIRR) to dabrafenib (GSK2118436) in patients (pts) with BRAF V600E/k mutation-positive melanoma with brain metastases (mets).

8501 Background: Melanoma brain mets carry a poor prognosis (median survival ≤4 months), for which more effective therapies are needed. Dabrafenib is a potent, selective oral inhibitor of mutated BRAF that has demonstrated clinical efficacy in pts with BRAF V600E/K mutant melanoma and previously untreated brain mets in a phase I study. Therefore, a phase II study (BREAK-MB) was initiated. Methods: Stage IV pts with ≥ 1 intracranial met (0.5 cm–4 cm assessed by MRI) without prior brain therapy (Cohort A) or with progression following prior brain therapy (Cohort B) were eligible with V600E/K mutation. Pts received dabrafenib 150 mg BID. The primary endpoint was investigator-assessed OIRR among V600E mutation-positive pts. Results: Overall, 172 pts were recruited. At interim analysis, of 127 pts enrolled (safety population), 41 (Cohort A n=24; Cohort B n=17) had reached 8-week disease assessment. Unconfirmed OIRR in Cohort A was 10/19, (53%; 95% CI: 28.9–75.6%) for V600E and 1/5 (20%; 95% CI: 0.5–71.6%) for V600K pts. In Cohort B unconfirmed OIRR was 8/15 (53%; 95% CI: 26.6%–78.7%) for V600E and 1/2 (50%; 95% CI: 1.3–98.7%) for V600K pts. Unconfirmed overall response rate (ORR) in Cohort A was 10/19 (53%; 95% CI: 28.9–75.6%) for V600E and 1/5 (20%; 95% CI: 0.5–71.6%) for V600K pts. In Cohort B unconfirmed ORR was 6/15 (40%; 95% CI: 16.3–67.7%) for V600E and 1/2 (50%; 95% CI: 1.3–98.7%) for V600K pts. In the safety population, 12/63 pts (19%) in Cohort A reported an SAE; 1 (2%) was fatal (cerebral hemorrhage). In Cohort B 15/64 pts (25%) reported an SAE; 1 (2%) was fatal (seizure). In Cohort A, 47 pts (75%) experienced AEs: 9 grade 3 (14%) and 3 grade 4 (5%). The most common AEs were headache (21%), hyperkeratosis and rash (17% each). In Cohort B, 47 pts (73%) experienced AEs: 12 grade 3 (19%) and 3 grade 4 (5%). The most common AEs were fatigue or nausea (22% each) and pyrexia (17%). Conclusions: Dabrafenib shows high clinical activity both in pts with intra- and extracranial mets with acceptable toxicity. Final data will be presented.

Clinical activity of the oral MEK1/MEK2 inhibitor GSK1120212 in pancreatic and colorectal cancer.

246 Background: GSK1120212 is a reversible, highly selective allosteric inhibitor of MEK1/MEK2. The objectives of this phase I study are to define the maximum tolerated dose (MTD), and to evaluate the pharmacokinetics (PK), pharmacodynamics (PD), and response rate of GSK1120212 in advanced solid tumors. Cohorts of advanced chemoresistant pancreas (PC) and colorectal cancer (CRC) patients have been enrolled. Methods: GSK1120212 is given orally, once daily (QD). In this three-part study GSK1120212 was escalated to an MTD, was administered in selected tumor types to evaluate recommended phase II doses (RP2D), and was evaluated for minimum biological activity using PD assessments. Results: 202 patients (pts) have received ≥ 1 dose of GSK1120212, including 26 PC and 27 CRC pts. The MTD is 3 mg QD and the RP2D is 2 mg QD. Dose limiting toxicities are rash (N=2), diarrhea (N=1), central serous retinopathy (N=2) and are reversible. At 2 mg QD (N=68), the most common adverse events are rash (47% G1, 37% G2, 4% G3) and diarrhea (41% G1, 12% G2, 1% G3). There has been one event of retinal vein occlusion. GSK1120212 has a small peak:trough ratio of ∼ 2 and an effective half life of ∼ 4.5 days. Steady state is reached by ∼ day 15. In the 26 evaluable PC pts, 2 partial responses (PR) and 11 stable diseases (SD) have been observed. 1 PR is KRAS mutation positive and is ongoing at 28 weeks. Among the SD pts, 2 achieved ≥ 20% tumor reduction and at least 3 were on study for 16 weeks or longer. CA19-9 reduction ≥ 55% was observed in both PR and 3 SD pts, 1 of which remained on study for 40 weeks. Among the KRAS mutation positive CRC pts (n=12), 4 SD were observed. These pts were on study for 31, 28, 16, and 16 weeks. Among the KRAS mutation negative or status unknown pts (n=12), 2 SD were observed; no pt was on study for > 19 weeks. Among the B-RAF mutation positive pts (n=3), 2 SD were observed; both are still ongoing at >16 weeks. Conclusions: The RP2D is well tolerated. The long effective half life and small peak:trough ratio of GSK1120212 allow constant target inhibition within a narrow range of exposure. GSK1120212 demonstrates durable clinical activity in a subset of pts with PC or CRC. [Table: see text]

First-line gefitinib versus first-line chemotherapy by carboplatin (CBDCA) plus paclitaxel (TXL) in non-small cell lung cancer (NSCLC) patients (pts) with EGFR mutations: A phase III study (002) by North East Japan Gefitinib Study Group

8016 Background: Based on our promising results of phase II studies estimating gefitinib in NSCLC pts with sensitive EGFR mutations (JCO 2006, BJC 2006), this multicenter phase III trial compared progression free survival (PFS) of first line gefitinib versus first line chemotherapy in EGFR mutation positive pts with stage IIIB/IV NSCLC. Per protocol, an analysis for safety except response, PFS and overall survival were estimated. Methods: PNA-LNA PCR clamp test, which had been developed and validated by us (Cancer Res 2005, Cancer Sci 2007), was employed to detect EGFR mutations using cytological samples or histological samples. Pts having sensitive EGFR mutations, measurable site(s), ECOG PS 0–1, age of 20–75 years, and no prior chemotherapy were randomized (1:1 ratio; balanced for institution, sex, and stage) to receive Arm A: gefitinb (250 mg/ day) orally, or Arms B: CBDCA AUC 6 and TXL 200mg/m2 in 21-day cycles until disease progression. The primary endpoint was PFS, and the sample size was calculated to be 320 in total (alpha=5%, power=80%) to confirm the superiority of Arm A (hazard ratio = 0.69). Results: From April 2006 to July 2008, 155 pts were enrolled (Arm A=80; Arm B=75). Their characteristics were well balanced between arms: median age=65 years; 64% female; 77% Stage IV; 93% adenocarcinoma, 61% non-smoker. There were several differences in toxicities between Arm A and Arm B (grade 4 neutropenia: 1% vs. 29%, grade 3–4 liver dysfunction: 24% vs. 1%, grade 3 neuropathy: 0% vs. 5%, respectively, p<0.01). But these were tolerable in both arms. Furthermore, there were no interstitial lung disease and no toxic deaths in both arms. Analyzing both arms together, preliminary response rate and PFS of the 155 pts were 53.7% and 6.5 mos, respectively. Conclusions: This is the first prospective study to compare first line gefitinib with first line chemotherapy for advanced NSCLC pts harboring EGFR mutations. Due to acceptable toxicities, the independent safety committee decided to continue this study further. At the end of 2008, 200 pts have been entered to this study, and, per protocol, an interim analysis to investigate PFS will be performed in May 2009. No significant financial relationships to disclose.

EGFR mutations and gefitinib sensitivity in patients with metastatic non-squamous non-small cell lung cancer

19075 Background: Probability of clinical benefit from EGFR tyrosine kinase inhibitors in previously treated NSCLC pts is strongly associated with the presence of EGFR mutation. However, the experience of gefitinib application as the first-line therapy in mutation-positive pts remains limited. Methods: EGFR analysis included the detection of the exon 19 deletions and 858TG mutation in paraffin embedded tumor specimens. Chemo-naïve mutation-positive pts received gefitinib (250 mg/d p.o.) until disease progression or unacceptable toxicity. The primary outcome was the response rate (RR) according to RECIST criteria. Results: tumor specimens from 52 pts with advanced non-squamous NSCLC were enrolled (median age - 58,6 years; adenocarcinomas - 82%, BAC - 8%, other - 10%). EGFR mutations were found in 11 of 52 pts (21%) with adenocarcinomas only. 9 mutations were exon 19 deletions and 2 - codon 858 substitutions. 6 chemo-naïve pts with stage IV adenocarcinomas were selected for treatment with gefitinib (median age: 62,6 years; M/F - 4/2; ECOG PS 1/2/3 - 2/3/1; exon 19 deletions - 6/6). Adverse events were mainly grade 1–2 rash (4/6) and grade 3 rash in 2 pts. The overall RR was 67% (PR 67% and CR 0%) (4/6) with disease stabilization in 33% (2/6). Median time to disease progression was 8.0 months (2.5–12.5 months). Conclusions: 1st-line gefitinib therapy in EGFR mutation-positive NSCLC pts is feasible, well tolerated, and yields a substantial RR and PFS. No significant financial relationships to disclose.

ITARGET: A phase II trial to assess the response to gefitinib in epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC) tumors

7504 Background: Somatic EGFR mutations correlate with increased response and survival in NSCLC patients (pts) treated with gefitinib. We conducted the 1st prospective US trial of 1st-line gefitinib in pts with advanced NSCLC harboring EGFR mutations. Methods: Chemotherapy-naïve pts with stage IIIB with effusion or IV NSCLC, measurable disease, and = 1 characteristic associated with mutations (female (F), adenocarcinoma (AC), never-smoking (NS), East Asian (EA)) underwent direct DNA sequencing of tumor tissue EGFR exons 18–24. Mutation-positive pts received gefitinib (250 mg/d) until progression or unacceptable toxicity. The primary outcome was response rate (RR) by RECIST criteria. Results: We sequenced 98 pts and detected EGFR mutations in 34 (35%); 3 were not assessable. Observed mutations were 18 (53%) exon 19 deletions (del), 9 (26%) L858R, 3 (9%) exon 20 insertions (ins), 2 T790M/L858R, 1 G719A, and 1 L861Q. Characteristics of the 98 screened pts were 69 F, 89 AC, 37 NS, and 5 EA; those of the 34 mutation pts were 20 (59%) F, 31 (91%) AC, 19 (56%) NS and 2 (6%) EA. The best predictor of EGFR mutation was NS. Of the 34 mutation pts, 31 (91%) received gefinitib. Reasons for non-treatment were pt preference (1 exon 19 del) and mutation associated with gefitinib-resistance (1 T790M/L858R, 1 exon 20 ins). Adverse events were mainly grade 1–2 rash and diarrhea; 1 case of grade 4 interstitial lung disease occurred after 2 weeks of therapy. The RR was 58% (95% confidence interval 39–75) and was 78% in L858R pts and 65% in del 19 pts. There were no responses among the G719A, L861Q, T790M/L858R and exon 20 ins pts treated. 12 pts have progressed, 18 remain on therapy. The median progression-free survival (PFS) is currently 11.8 mo and does not differ by mutation type, though follow-up is short (median 6.8 mo, range 1–24). 27 pts are still alive. Of the 31 pts treated, 22 (71%) had high EGFR gene copy number (amplification (3) or high polysomy (19)); RR and PFS did not vary by copy number. Conclusions: 1st-line gefitinib therapy in EGFR mutation-positive NSCLC pts is feasible in a multi-institutional study, well tolerated, and yields a substantial RR and PFS. This strategy should be compared to standard chemotherapy in a genotype-directed randomized trial. No significant financial relationships to disclose.