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G.J. Riely
Moderator of
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MINI 16 - EGFR Mutant Lung Cancer 2 (ID 130)
- Event: WCLC 2015
- Type: Mini Oral
- Track: Treatment of Advanced Diseases - NSCLC
- Presentations: 15
- Moderators:G.J. Riely, M.C. Garassino
- Coordinates: 9/08/2015, 16:45 - 18:15, Four Seasons Ballroom F3+F4
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MINI16.01 - Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Treatment Response in Advanced Non-Small Cell Lung Cancer With Uncommon Mutations (ID 1170)
16:45 - 16:50 | Author(s): M. Kanazu, Y. Naoki, T. Shiroyama, M. Tamiya, A. Tamiya, N. Omachi, K. Okishio, H. Suzuki, N. Okamoto, N. Morishita, T. Hirashima, S. Atagi
- Abstract
- Presentation
Background:
Treatment of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) is the standard therapy for advanced non-small cell lung cancer (NSCLC) with common EGFR mutations such as exon 19 deletions or L858R mutations. However, the efficacy of EGFR-TKIs in patients with uncommon EGFR mutations remains unclear.
Methods:
We have retrospectively surveyed a consecutive database of NSCLC patients with EGFR mutations at Kinki-chuo Chest Medical Center, Osaka Prefectural Medical Center for Respiratory and Allergic Diseases. We analyzed the collect data of NSCLC patients with uncommon mutations including single or complex (uncommon plus uncommon mutations, or uncommon plus common mutations) mutations, treated with gefitinib or erlotinib between July 2007 and September 2014.
Results:
Forty-one patients who had any EGFR uncommon mutations were analyzed in this study. By the Response Evaluation Criteria in Solid Tumors criteria, the overall response rate (RR) was 22.0% with 9 partial response (PR) in all patients with uncommon mutations. Among uncommon single mutations, RR was 12.5% with 3 PR in patients with G719X mutation and 33.3% with 2 PR in patients with L861Q mutation. As for complex mutations, there were no patients in PR with uncommon plus uncommon mutations but RR was 50.0% with 4 PR in patients with uncommon plus common mutations. Median progression-free survival (PFS) was 3.5 months in all patients with uncommon mutations. Among uncommon single mutations, PFS in patients with G719X (median PFS: 1.8 months) was shorter than PFS in patients with L861Q mutation (median PFS: 7.6 months). Furthermore, there was a difference in the efficacy of EGFR-TKIs among patients with each G719X mutation (median PFS in G719A: 8.2 months, median PFS in G719C: 1.1 months, median PFS in G719S: 1.7 months).Figure 1
Conclusion:
First generation EGFR-TKIs are less effective in NSCLC patients with uncommon mutations than in those with common mutations. However, they had favorable response in patients with L861Q or G719A mutations, compared with G719C or G719S mutations.
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MINI16.02 - Rare and Common EGFR Mutations in Patients with Advanced NSCLC Treated with EGFR-TKIs: A Registry-Based Study (ID 2775)
16:50 - 16:55 | Author(s): M. Pesek, V. Kolek, J. Skrickova, M. Cernovska, L. Koubkova, J. Roubec, F. Salajka, M. Zemanova, J. Krejci, K. Hejduk, A. Ryska, M. Minarik, O. Fiala
- Abstract
- Presentation
Background:
Erlotinib, gefitinib and afatinib, tyrosine kinase inhibitors directed at EGFR signalling (EGFR-TKI), are currently used for the treatment of patients with advanced-stage non-small cell lung cancer (NSCLC). A considerable progress in the field of molecular oncology and cancer genomics in recent years has let to identification of several gene alterations predicting clinical outcome of patients treated with EGFR-TKIs. Activating EGFR mutations are widely recognized predictors of good response to EGFR-TKI treatment. While the predictive role of common EGFR mutations (exon 19 deletions and exon 21 L858R point mutation) is well described, very little clinical evidence data exist on the role of rare EGFR mutation types. The aim of this study was to assess the distribution of common and rare EGFR mutations in patients with NSCLC and to evaluate the efficacy of EGFR-TKIs for patients harboring rare and common EGFR mutations.
Methods:
Clinical data of 305 patients with advanced-stage NSCLC (IIIB or IV) treated with EGFR-TKIs having EGFR mutation positive primary tumors at the time of diagnosis were evaluated in a retrospective setting. The therapy included erlotinib, gefitinib or afatinib as recorded in a Czech national lung cancer registry – TULUNG. The relative frequency and survival data (PFS and OS) were evaluated for individual EGFR mutation types.
Results:
The common activating EGFR mutations (exon 19 deletion and exon 21 L858R point mutation) were found in a total of 249 (81.6%) patients. Rare EGFR mutations were found in 56 (18.4%) patients, the most frequent of which was exon 18 - G719X mutation found in 29 patients (9.5%), followed by mutations in exon 20 found in 28 patients S768I in 3 patients (0.98%) and insertion 3 mutations in 16 patients (5.2%). Patients with exon 19 deletion had median median OS 11.0 months, patients with exon 21 point mutation L858R median OS 9.4 months,respectively. Patients with rare EGFR mutations median OS 12.5 months.Comparing frequent and rare mutations, there were no differences in sex, age, PS, stage of disease and adverse effects of first line gefitinib therapy, the group of patients with rare mutations were more frequently smokers, duration of gefitinib therapy was shorter, response rate and PCR, PFS and OS were worse than in patients having frequent EGFR mutations. There were no significant differences in characteristics, PFS and OS between exon 19 deletion and exon 21 L858R point mutation tumour patients.
Conclusion:
While patients with frequent EGFR sensitive mutations have significant benefit from gefitinib therapy, patients with G719X mutation on exon 18 have marginal PFS and OS benefit, while pagtients with exon 20 insertion mutations have no demonstrable benefit from targeted therapy.Next generation tyrosinkinase inhibitors may prolong survival in some of rare EGFR mutated tumour patients.
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MINI16.03 - Dose Optimization of Rociletinib for EGFR Mutated NSCLC (ID 967)
16:55 - 17:00 | Author(s): J.W. Goldman, H.A. Wakelee, S. Gadgeel, R. Camidge, B.J. Solomon, H. Yu, G.R. Oxnard, S.I. Ou, V. Papadimitrakopoulou, M. Perol, K. Reckamp, J. Soria, A. Varga, R. Dziadziuszko, D. Despain, S. Matheny, L.V. Sequist
- Abstract
- Presentation
Background:
Rociletinib (CO-1686) is a novel, oral, irreversible mutant selective tyrosine kinase inhibitor for the treatment of patients with mutant epidermal growth factor receptor (EGFR) non-small cell lung cancer (NSCLC). Rociletinib has demonstrated efficacy against activating mutations (L858R and Del19) and the dominant acquired resistance mutation (T790M), while sparing wild-type EGFR. A maximum tolerated dose was not identified in Phase 1 with 1000 mg BID the highest dose studied. Here we assess the efficacy and safety of the three doses of rociletinib (500 mg BID, 625 mg BID and 750 mg BID) selected for Phase 2 study.
Methods:
TIGER-X (NCT01526928) is a Phase 1/2 open-label, safety, pharmacokinetics and preliminary efficacy study of rociletinib in patients with advanced EGFR mutant NSCLC progressing after ≥1 EGFR tyrosine kinase inhibitor (TKI). Efficacy is assessed using RECIST. Safety is evaluated using standard adverse event (AE) reporting.
Results:
As of April 2015, a total of 231 central T790M positive patients were evaluable for efficacy and 343 for safety (any T790M). All patients were enrolled in the USA (85%), Europe (9%) and Australia (6%). Baseline characteristics were similar in each dose group. The median number of prior therapies was 2. 85% had EGFR TKI as their most recent prior therapy and 10% had a history of diabetes/hyperglycemia. Immature ORRs are 53% (500 mg BID), 52% (625 mg BID) and 43% (750 mg BID), with disease control rates of 89% (500 mg BID), 87% (625 mg BID) and 82% (750 mg BID). The most common ≥grade 3 treatment-related AE was hyperglycemia [16% (500 mg BID), 25% (625 mg BID) and 35% (750 mg BID)] which was managed with oral hypoglycemic agents. Only one patient discontinued the study for hyperglycemia. Grade 3 QTc prolongation was uncommon, occurring in 2% (500 mg BID), 7% (625 mg BID) and 10% (750 mg BID) of patients, and demonstrated a relationship to dose. There were no clinically relevant cutaneous toxicities with 7 cases of grade 1 rash and 4 cases of grade 1 stomatitis (no dose relationship) and no paronychia.
Conclusion:
All 3 Phase 2 doses of rociletinib are active and well tolerated in a Western patient population with advanced NSCLC. The lack of cutaneous toxicities confirms the selectivity of rociletinib for mutant forms of EGFR and is an important contributor to QOL and maintaining dose intensity (Lacouture et al. 2011). Overall, the adverse event frequency appears to be related to dose, but antitumor activity does not, thus the risk/benefit profile may be optimal at the lowest dose studied.
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MINI16.04 - Activity of Rociletinib in EGFR Mutant NSCLC Patients with a History of CNS Involvement (ID 965)
17:00 - 17:05 | Author(s): R. Camidge, L.V. Sequist, J. Soria, H.A. Wakelee, S.I. Ou, J.W. Goldman, V. Papadimitrakopoulou, S. Gadgeel, T. Mekhail, G.R. Oxnard, M.A. Socisnki, B.J. Solomon, A. Varga, S. Matheny, D. Despain, H. Yu
- Abstract
- Presentation
Background:
Rociletinib (CO-1686) is a novel, oral, irreversible tyrosine kinase inhibitor for the treatment of patients with mutant epidermal growth factor receptor (EGFR) non-small cell lung cancer (NSCLC) with activity against the activating mutations (L858R and Del19) and the dominant acquired resistance mutation (T790M), while sparing wild-type EGFR. TIGER-X (NCT01526928) is a Phase I/II open-label, safety, pharmacokinetics and preliminary efficacy study of rociletinib in patients with advanced EGFR mutation-positive NSCLC with progressive disease after ≥1 EGFR tyrosine kinase inhibitor (TKI). An overall response rate of 67% has previously been reported in this trial for T790M positive patients treated with the 500 and 625 mg BID doses (Soria 2014). Here we provide preliminary data on the activity of rociletinib in the subgroup of patients with a history of CNS disease.
Methods:
Patients with a history of CNS disease were permitted if asymptomatic and stable, as defined by steroid requirements. The primary activity endpoint was RECIST overall response rate. However, patients who developed progressive disease (PD) while on study treatment were allowed to continue therapy with rociletinib if deemed clinically beneficial by the investigator.
Results:
As of 16 March 2015, a total of 401 patients received therapeutic dose levels of rociletinib (500, 625 and 750 mg BID) including 170 (42%) patients with a history of CNS metastases. Based on this interim analysis, the RECIST overall response rate among these patients with a history of CNS disease is 41%. To date, 42 patients with a history of CNS disease have continued therapy with rociletinib post-progression. Of those who continued for at least 14 days the average treatment duration beyond PD was 89 days (range: 14 - 336 days). Twenty-two of the 42 patients with a history of CNS disease with PD also received brain radiation and continued rociletinib treatment for an average of 120 days (range: 22 – 336 days) after PD. Rociletinib is held on radiation days only. Progression-free survival data for these subgroups is not yet mature. The three most common adverse events in the patient population with a history of CNS disease are similar to those found in the general TIGER-X patient population: hyperglycemia, diarrhea and nausea.
Conclusion:
In patients with a history of CNS disease, a factor associated with poor prognosis, rociletinib is active with a RECIST response rate of 41%. Local CNS radiation has been administered safely with rociletinib held on radiation days and continued afterwards. Prolonged use of rociletinib post CNS radiation suggests ongoing systemic benefit is still experienced by these patients. The role of rociletinib in NSCLC patients with CNS involvement is being further explored in the ongoing TIGER clinical development program.
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MINI16.05 - Discussant for MINI16.01, MINI16.02, MINI16.03, MINI16.04 (ID 3347)
17:05 - 17:15 | Author(s): C. Zhou
- Abstract
- Presentation
Abstract not provided
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MINI16.06 - AZD9291 in Pre-Treated T790M Positive Advanced NSCLC: AURA Study Phase II Extension Cohort (ID 943)
17:15 - 17:20 | Author(s): J.C. Yang, M. Ahn, S.S. Ramalingam, L.V. Sequist, S. Novello, W. Su, T. Hirashima, D. Kim, R. Lawrance, M. Cantarini, S. Ghiorghiu, P.A. Jänne
- Abstract
- Presentation
Background:
AZD9291 is an oral, potent, irreversible epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), selective for both EGFR-TKI-sensitizing (EGFRm) and T790M resistance mutations. The Phase I AURA study was a dose escalation/expansion study in patients with EGFRm positive advanced non-small cell lung cancer (NSCLC) who had progressed after EGFR‑TKI treatment. The 80 mg once daily (qd) dose was chosen for further evaluation in a Phase II extension cohort of the AURA study, and in an additional Phase II study (AURA2). Here we report efficacy and safety of AZD9291 from the AURA study Phase II extension cohort (NCT01802632) in patients pre-treated with EGFR-TKI and with centrally confirmed T790M positive advanced NSCLC.
Methods:
Eligible patients had measurable disease, World Health Organization performance status (WHO PS) 0 or 1, and acceptable organ function; stable brain metastases were allowed. A mandatory tumor sample was taken after disease progression on the most recent line of therapy, for prospective confirmation of T790M positive status by central laboratory testing (cobas™ EGFR Mutation Test). Patients received AZD9291 at 80 mg qd until disease progression. The primary endpoint was objective response rate (ORR) according to RECIST 1.1 (assessed by independent central review, ICR). Secondary objectives included disease control rate (DCR), duration of response (DoR), progression-free survival (PFS), investigator-assessed ORR, and safety. Planned enrollment was 175 patients to give an estimate of the ORR with 95% CI within ±8%. Data cut-off was January 9, 2015 after all patients should have undergone the second tumor assessment.
Results:
201 patients were dosed in the extension cohort of the study; two patients without measurable disease at baseline by ICR were excluded from the evaluable-for-response set. By central testing, EGFR mutation subtypes were: T790M, 98%; Ex19del, 71%; L858R, 25%; other, 3%. Median age was 62 years; female, 66%; Asian, 57%; WHO PS 0/1/2, 34%/66%/1%; second/≥third-line, 30%/70%. At the data cut-off, median treatment exposure was 4.9 months and 168 patients remain on treatment. ORR by ICR was 58% (115/199; 95% CI 51, 65) and DCR was 92% (95% CI 87, 95). ORRs were similar across lines of therapy (second-line, 59.0% [36/61] vs ≥third-line, 57.2% [79/138]). Investigator-assessed ORR was 68% (137/201; 95% CI 61, 75). Median DoR and median PFS have not been reached (maturity 2% and 21%, respectively). The most common all-causality adverse events (AEs) were diarrhea, 41% (0.5% Gr≥3) and grouped rash terms 37% (0.5% Gr≥3); 42 (21%) patients experienced Gr≥3 AEs. Interstitial lung disease grouped terms were reported in five (2.5%) patients, one of which was fatal (0.5%) and considered possibly causally related to AZD9291 by the investigator. Eight patients (4%) discontinued treatment due to an AE. Updated results from a later data cut-off will be available for presentation.
Conclusion:
In the AURA study Phase II extension cohort, AZD9291 80 mg qd demonstrates clinical activity, manageable tolerability, and a low discontinuation rate in patients with centrally confirmed EGFR T790M positive advanced NSCLC that has progressed on or after EGFR‑TKI treatment. These data provide further validation of the results from the Phase I study cohorts.
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MINI16.07 - AZD9291 in Treatment-Naïve EGFRm Advanced NSCLC: AURA First-Line Cohort (ID 1232)
17:20 - 17:25 | Author(s): S.S. Ramalingam, J.C. Yang, C. Lee, T. Kurata, D. Kim, T. John, N. Nogami, Y. Ohe, Y. Rukazenkov, P. Frewer, M. Cantarini, S. Ghiorghiu, P.A. Jänne
- Abstract
- Presentation
Background:
AZD9291 is an oral, potent, irreversible epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) selective for both EGFR-sensitizing (EGFRm) and T790M resistance mutations. It has shown anticancer activity and manageable tolerability in patients with EGFRm advanced NSCLC that had progressed after EGFR‑TKI treatment.
Methods:
In this first-line expansion cohort (AURA, NCT01802632), patients received AZD9291 at 80 or 160 mg/day, in sequential dose groups. EGFRm status was determined locally and/or by central testing using the cobas EGFR Mutation Test. Other inclusion criteria included measurable disease, World Health Organization performance status (WHO PS) 0 or 1, and acceptable organ function; stable brain metastases were allowed. Safety, tolerability, and anticancer activity were assessed in these cohorts, to evaluate AZD9291 in the first-line treatment setting. The data cut-off was December 2, 2014.
Results:
Sixty treatment-naïve patients were enrolled; 30 patients in each dose group (80 or 160 mg/day). By central testing, EGFR mutation subtypes were: L858R 40%; exon 19 deletion, 37%; other EGFR-sensitizing mutations, 3%; and T790M, 8%. Baseline median age was 63.5 years; 25% of patients were male; 57%/43% had WHO PS 0/1, respectively; 72% were Asian and 23% Caucasian. Median treatment exposure at the 80 and 160 mg dose levels was 260 and 171 days, respectively. Fifty-two out of 60 patients remained on treatment at the data cut-off. Anticancer activity of AZD9291 is shown in Table 1. One-third (33%) of patients experienced Grade ≥3 adverse events; two patients had Grade 3 diarrhea and one patient had Grade 3 skin rash. New data from a 2015 data cut of the AURA first-line expansion will be available for presentation.Table 1. Anticancer activity findings in AURA first-line expansion
Endpoint Finding Objective response rate: Overall 70% (95% CI 57, 81) AZD9291 80 mg/160 mg 60%/80% Disease control rate: Overall 97% (95% CI 89, 100) AZD9291 80 mg/160 mg 93%/100% Progression-free survival: Median Not yet reached 3-month/6-month 93%/87% Events to date 7/60 (12% mature)
Conclusion:
AZD9291 has a manageable tolerability profile and is associated with promising anticancer activity in treatment-naïve patients with EGFRm advanced NSCLC. A Phase III study (FLAURA, NCT02296125) has been initiated to assess the efficacy and safety of AZD9291 in comparison with a standard-of-care EGFR-TKI (gefitinib or erlotinib) in the first-line setting.
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MINI16.08 - AZD9291 in Pre-Treated T790M Positive Advanced NSCLC: AURA2 Phase II Study (ID 1406)
17:25 - 17:30 | Author(s): T. Mitsudomi, C. Tsai, F. Shepherd, L. Bazhenova, J.S. Lee, G. Chang, L. Crinò, M. Satouchi, Q. Chu, R. Lawrance, M. Cantarini, S. Ghiorghiu, G. Goss
- Abstract
- Presentation
Background:
The epidermal growth factor receptor (EGFR) T790M mutation is found in about half of patients who have developed resistance to EGFR-tyrosine kinase inhibitors (TKIs), gefitinib or erlotinib. AZD9291 is an oral, potent, irreversible EGFR-TKI selective for both EGFR-sensitizing (EGFRm) and T790M resistance mutations. In the Phase I AURA study, AZD9291 80 mg (dose selected for further evaluation) was found to be clinically active, with an acceptable tolerability profile. This ongoing AURA2 Phase II study (NCT02094261) investigates the efficacy and safety of AZD9291 80 mg once daily after previous EGFR-TKI treatment in patients with EGFRm and T790M positive advanced NSCLC.
Methods:
AURA2 (NCT02094261) is a global, open-label, single-arm Phase II study. To be eligible, all patients had a mandatory tumor sample taken after disease progression on the most recent line of therapy, for confirmation of T790M positive status by central laboratory testing using the cobas™ EGFR Mutation Test. Further inclusion criteria included measurable disease, World Health Organization performance status (WHO PS) 0 or 1, and acceptable organ function; stable brain metastases were allowed. Patients receive AZD9291 at 80 mg once daily until disease progression. The primary endpoint was objective response rate (ORR) according to RECIST 1.1 (assessed by independent central review, ICR). Secondary objectives included disease control rate (DCR), duration of response (DoR), progression-free survival (PFS), and safety. Planned enrollment was 175 patients to give an ORR with 95% confidence interval (CI) within ±8%. The data cut-off was January 9, 2015.
Results:
Recruitment is complete and 210 patients were enrolled; 12 patients did not have measurable disease at baseline by ICR and are excluded from the evaluable-for-response set. By central testing, in addition to T790M, patients had background EGFR mutation: Ex19del, 65%; L858R, 32%; other, 3%. Baseline characteristics: median age, 64 years; female, 70%; WHO PS 0/1, 40%/60%; Asian, 63%; second-/≥third-line, 32%/68%. Median treatment exposure was 4.0 months and 183 patients remain on treatment at the data cut-off. ORR by ICR was 64% (127/198; 95% CI 57, 71) and DCR was 90% (95% CI 85, 94). Investigator-assessed ORR was 64% (135/210; 95% CI 57, 71). Median DoR and median PFS have not been reached (maturity 6% and 20%, respectively). The estimated proportion of patients who are alive and progression free is 82% and 70% at 3 and 6 months, respectively. The most common all-causality adverse events (AEs) were diarrhea, 34% (1% Gr≥3) and grouped rash terms 40% (0.5% Gr≥3); 38 (18%) patients experienced Gr≥3 AEs. Interstitial lung disease grouped terms were reported in four (1.9%) patients, one of which was fatal (0.5%) and considered possibly causally related to AZD9291 by the investigator. Eight patients (4%) discontinued treatment due to an AE. Updated results from a later data cut-off will be available for presentation.
Conclusion:
AZD9291 80 mg once daily demonstrates clinical activity and manageable tolerability in patients with EGFRm, T790M mutation positive advanced NSCLC that has progressed on or after EGFR‑TKI treatment. AZD9291 is being investigated in the randomized AURA3 Phase III study (NCT02151981) in comparison with platinum-based doublet chemotherapy.
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MINI16.09 - Design, Execution, and Preliminary Biomarker Results from Paired Tumor Biopsy Cohorts of the AZD9291 AURA Trial (ID 941)
17:30 - 17:35 | Author(s): K. Thress, J. Leeson, J. Geradts, M. Schuler, M. Ahn, J. Wolf, K.A. Gold, J.C. Yang, F. Blackhall, W. Su, V. Jacobs, N.R. Smith, H. Angell, K. Brown, K. Vishwanathan, J.C. Barrett, M. Cantarini, P.A. Jänne
- Abstract
Background:
Epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC) exhibits sensitivity to EGFR tyrosine kinase inhibitors (TKIs) such as erlotinib and gefitinib; however, acquired resistance eventually develops in most patients. The most common mechanism of TKI resistance is a second-site mutation in the EGFR kinase domain, T790M. AZD9291 is an oral, potent, irreversible EGFR-TKI with potency against both T790M resistance and sensitizing EGFR mutations. In the ongoing Phase I AURA study (NCT01802632), AZD9291 induced durable responses in patients with acquired resistance to EGFR-TKIs. We report results of paired biopsy cohorts of the AURA trial, reviewing modulation of key molecular biomarkers of AZD9291 activity in patient tumor samples.
Methods:
Two cohorts of patients on the AURA trial were consented for collection of paired tumor biopsies. These patients had a pre-study tumor biopsy with T790M positive tumor status confirmed by central laboratory EGFR testing (Cobas™ EGFR Mutation Test). Following 8 to 15 days of once daily AZD9291 treatment (80 or 160 mg), a post-dose tumor biopsy was obtained. Baseline and post-dose tumor tissue was processed for routine histology and pathologic evaluation. More than 100 viable tumor cells per sample were required for subsequent biomarker scoring. Formalin-fixed paraffin-embedded tumor biopsies were profiled by immunohistochemistry with a suite of key pathway and tumor-relevant markers (phospho[p]-EGFR, pERK, pAKT, pS6, PD-L1, CD8). Matching plasma pharmacokinetic samples were also obtained for PK-PD correlations.
Results:
As of February 2015, 58 potential patients with an evaluable baseline biopsy were identified as candidates for post-dose biopsy collection. Sixteen of these patients did not proceed to an on-study biopsy as the identified lesions had regressed too substantially or were no longer considered suitable for re-biopsy, one patient was medically excluded from re-biopsy, and one patient’s sample was not available. In total, 40 patients supplied matched pre- and on-treatment biopsies. As of March 2015, paired tumor samples were available for QC from 26 of these 40 patients. Ten of these 26 biopsy specimens subsequently failed QC due to inadequate tumor content, leaving 16 paired tumor samples available for biomarker analyses, of which five have thus far been evaluated. AZD9291 treatment resulted in the inhibition of EGFR pathway components in the majority of post-treatment tumor biopsies. Tissue biomarker analyses are ongoing and updated data on evaluable biopsy pairs will be reported at the time of the congress.
Conclusion:
The completion of a paired biopsy cohort within the AURA trial was challenging due to the rapid onset of anti-tumor effects of AZD9291. Approximately 29% (17/58) of potentially eligible patients were unsuitable for the post-dose biopsy procedure due to tumor regression and 38% (10/26) of available post-dose biopsies were found to contain too little tumor for analysis. In the evaluable tumor pairs, pharmacodynamic modulation of the EGFR pathway was evident. Further biomarker analyses, including evidence of modulation of immune system markers, may help inform future combination strategies.
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MINI16.10 - Discussant for MINI16.06, MINI16.07, MINI16.08, MINI16.09 (ID 3348)
17:35 - 17:45 | Author(s): M. Reck
- Abstract
- Presentation
Abstract not provided
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MINI16.11 - Plasma HGF Reduction Is Associated with Better Prognosis in EGFR-Positive Advanced Lung Adenocarcinoma Patients Treated with Afatinib (ID 1729)
17:45 - 17:50 | Author(s): O. Arrieta Rodriguez, G. Cruz-Rico, L. Ramírez-Tirado, J. Negueb, E. Caballé-Pérez, I. Martínez-Alvarez, G. Socca-Chafre, H. Astudillo
- Abstract
- Presentation
Background:
Afatinib, an irreversible tyrosine kinase inhibitor (TKI), has shown clinical benefits and prolonged progression free survival in EGFR mutated patients. HGF, a ligand of c-MET, may be involved in resistance to EGFR-TKIs.
Methods:
A total of 66 patients with advanced lung adenocarcinoma (stage IIB and IV) and documented progression to first-line chemotherapy were enrolled to receive afatinib 40 mg/day. Mutational EGFR and HER-2 status were assessed by RT-PCR. HER2 amplification was evaluated by FISH. Plasma HGF levels were measured by ELISA before and 2 months after the start of treatment with afatinib. We assessed the change in plasma HGF levels and the association with objective response rate (ORR), progression free survival (PFS) and overall survival (OS). The protocol is registered in ClinicalTrials.gov (NCT01542437).
Results:
We identified 2 patients carrying a HER2 mutation and both presented stable disease (SD). HER2 amplification was not detected. HGF-positive plasma reduction status had a significant higher ORR (75.0% vs 44.1% p= 0.011), and was strongly associated with longer PFS (HR 0.40 [95% CI 0.18 - 0.87], p= 0.02) and OS (HR 0.31 [0.13 - 0.71] p=0.006). A stratified multivariate analysis in EGFR mutated patients showed that the HGF plasma levels reduction remains as a significant and independent factor associated with longer PFS (HR 0.34 [95% CI 0.13 - 0.89] p= 0.04) and OS (HR 0.34 [95% CI 0.13 - 0.88] p= 0.02).
Conclusion:
HGF plasma levels reduction is strongly related to better outcomes with afatinib therapy, irrespective of EGFR mutation status. The lack of reduction might allow the identification of a subgroup of patients who will not expected to respond and could benefit with the use of drugs targeting the HGF-c-Met axis. Further studies are warranted.
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- Abstract
- Presentation
Background:
The phenomenon of small cell lung cancer(SCLC) transformation in EGFR mutated adenocarcinoma had been previously identified as a resistant mechanism. However, this phenomenon was only reported in single case and a repeat biopsy patient cohort. Moreover, the underlying molecular mechanism remains unclear. Previous study found that the inactivation of TP53 and Rb1 could efficiently transform neuroendocrine and alveolar type 2 cells into SCLC. We inferred that TP53 and Rb1 might also play an important role in SCLC transformation. So we use the sh-RNA mediated depletion of RB1 adenocarcinoma cell line, that also have TP53 inactivation in nature, to investigate the molecular mechanism of SCLC transformation.
Methods:
Both primary and metastatic tissue were analyzed on 3 SCLC transformation patients by whole genome sequencing (WGS). We knock down RB1 in TP53 inactivation cell lines, PC-9, HCC-827 and H1975. Western blot and immunohistochemistry (IHC) were used to confirm RB1 knock down and expression of neuroendocrine (NE) markers. Trans well cell invasion assay and softer agar clone formation test were investigated the change of invasion and migration. CCK8 kit was used to evaluate relative viability of cells after RB1 knock down. Cell cycle and apoptosis were determined by folw cytometry. And we use balb/c mice for cell line tumorgenesis.
Results:
① Pathological analysis of the 3 patients’ primary lesion and the consistent EGFR mutation status confirmed the phenomenon of SCLC transformation. WGS showed the copy number variation of primary tumor and transformed metastasis was distinct. RB1 is lost in 100% of the three transformed cases but occur in one patient’s primary tissue in extremely low frequency(<5%). ② PC-9, HCC827 and H1975 cell line showed up-regulation of NE markers after sh-RNA mediated RB1 depletion, which presented more capable of invasion and migration. Cell folw cytometry showed more cells was in G2 and S phase after RB1 knock down. The expression of Bik and puma that belong to Bcl-2 family was up-regulated after RB1 inactivation compared with the control group.
Conclusion:
The NE differentiation and changes in invasion, migration, apoptosis and cell cycle indicated that the loss of TP53 and RB1 promote the process of SCLC transformation. TP53 and RB1 deficiency may be a necessary event for SCLC transformation to emerge, but is still insufficient to induce SCLC transformation.
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MINI16.13 - A Randomized Controlled Trial of Erlotinib versus Gefitinib in Advanced Non-Small-Cell Lung Cancer Harboring EGFR Mutations (CTONG0901) (ID 2762)
17:55 - 18:00 | Author(s): J. Yang, Q. Zhou, H.-. Yan, X. Zhang, H. Chen, H. Tu, Z. Wang, C.-. Xu, J. Su, Y. Huang, B. Wang, B. Jiang, X. Bai, W. Zhong, X. Yang, Y. Wu
- Abstract
- Presentation
Background:
For non-small-cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) mutations, preclinical data showed the superiority of exon 19 mutations to exon 21 mutations in both response to EGFR tyrosine kinase inhibitors (TKIs) and survival. Meanwhile, retrospective studies demonstrated that erlotinib was significantly superior to gefitinib in progression-free survival (PFS) for advanced NSCLC patients with EGFR mutations. However, no randomized controlled trials compared erlotinib to gefitinib in advanced NSCLC patients with EGFR exon 19 or 21 mutations.
Methods:
We conducted a randomized controlled trial (CTONG 0901；NCT01024413) comparing erlotinib to gefitinib in advanced NSCLC harboring EGFR exon 19 or 21 mutations from July 2009 to July 2014. Eligible patients were randomized to receive erlotinib (150 mg, qd) or gefitinib (250 mg, qd) at the ratio of 1:1 in any line settings. The primary endpoint was PFS, and the secondary endpoints included overall survival (OS), objective response rate (ORR), post-progression survival (PPS), and toxicities.
Results:
The last follow-up was on March 30, 2015. Totally, 256 patients (148 with exon 19 mutations and 108 with exon 21 mutations), of whom 165, 83 and 9 were in the first, second or further-line settings respectively, were randomized to receive erlotinib or gefitinib. Median PFS was 12.4 (95%CI: 10.6~14.1) months in erlotinib arm and 10.4 (95%CI: 8.8~11.9) months in gefitinib arm, HR=0.80 (0.61~1.05), p=0.100; ORR, median PPS and OS were 56.3% versus 52.3% (p=0.530), 6.9 (95%CI: 4.3~9.5) versus 6.9 (95%CI: 4.5~9.2) months (p=0.784), and 22.4 (95%CI: 17.9~27.0) versus 20.5 (95%CI: 17.1~23.8) months (HR=0.90 [0.67~1.22]; p=0.496) respectively. There were no significant differences in toxicities between the two arms, p＞0.05. In the four subgroups (the first-line, second or further-line setting, exon 19 and 21 mutations), except for median PFS being 11.4 versus 7.9 months (HR=0.58 [0.37~0.90], p=0.015) in the second or further-line setting, no significant differencs were observed in median PFS and OS respectively between the two arms, p＞0.05. Receiving erlotinib or gefitinib treatment, EGFR exon 19 mutant patients were superior to those with exon 21 mutations in terms of ORR (62.2% versus 43.5%, p=0.003), median PPS (9.1 [95%CI: 7.0~11.2] versus 4.6 [95%CI: 3.4~5.8] months, p=0.011 ) and OS (24.8 [95%CI: 20.9~28.8] versus 17.7 [95%CI: 15.1~20.3] months, HR=0.66 [0.48~0.89], p=0.006) respectively, even though there was no significantly difference in median PFS (11.4 [95%CI: 9.6~13.2] versus 11.1 [95%CI: 9.4~12.9] months, HR=0.80 [0.60~1.05], p=0.101). Multivariant Cox regression analysis showed that subsequent EGFR TKIs, combination of subsequent EGFR TKIs and local treatment, as well as subsequent chemotherapy were prognostic factors for OS, p＜0.05.
Conclusion:
Erlotinib was not significantly superior to gefitinib in advanced NSCLC with either exon 19 or 21 mutations in response and survival, with similar toxicities. However, EGFR exon 19 mutant patients had remarkably increased ORR, PPS and OS than those with exon 21 mutations after taking erlotinib or gefitinib. Subsequent treatments after failure to EGFR TKIs were significantly prognostic factors for OS.
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MINI16.14 - A Phase 1 Study of Erlotinib and Ruxolitinib in Patients with EGFR-Mutant Lung Cancers and Acquired Resistance to Erlotinib Therapy (ID 2818)
18:00 - 18:05 | Author(s): H. Yu, L.A. Perez, C.S. Sima, B.T. Li, S. Smith-Marrone, A. Iqbal, P. Paik, A. Drilon, M.G. Kris, J. Bromberg, G.J. Riely
- Abstract
- Presentation
Background:
Patients with EGFR-mutant lung cancers treated with EGFR tyrosine kinase inhibitors (TKI) develop clinical resistance, often associated with acquisition of EGFR T790M. Upregulation of JAK/STAT signaling is involved in resistance to EGFR TKIs and JAK inhibition is a proposed treatment strategy in the setting of acquired resistance by restoring sensitivity to erlotinib. Ruxolitinib is an FDA-approved oral JAK1/2 inhibitor given at 20mg twice daily for hematologic malignancies with a largely non-overlapping toxicity profile with erlotinib.
Methods:
We evaluated the toxicity and efficacy of once daily oral erlotinib and twice daily oral ruxolitinib in patients with EGFR-mutant lung cancers and acquired resistance to erlotinib therapy (NCT02155465). Using a 3+3 dose escalation, we assessed escalating doses of ruxolitinib (10mg BID, 15mg BID, 20mg BID) with erlotinib 150mg daily for 21 day cycles. Response was evaluated by RECIST 1.1. Tissue and peripheral blood samples were obtained; exosomes will be extracted from peripheral blood and molecular and proteomic analyses will be performed.
Results:
From May 2014 to February 2015, 12 patients (pts) were enrolled. Median age: 60; Women: 7 (58%); never-smokers: 6 (50%); EGFR L858R=4 (33%) and Exon 19 deletion=8 (67%). Two of twelve (17%) were EGFR T790M positive at rebiopsy at the time of acquired resistance. Of 12 pts treated, 3 received ruxolitinib 10mg BID, 3 received 15mg bid and 6 received 20mg BID with erlotinib 150mg daily. No dose limiting toxicities were seen. The recommended phase 2 dose is ruxolitinib 20mg BID with 150mg erlotinib daily. Treatment-related AEs were all grade 1-3. The most frequent treatment related clinical adverse events (all grade 1-3) were anemia (25%), diarrhea (25%), rash (25%), pain (17%), fatigue (8%), and pneumonitis (8%). The most frequent treatment-related laboratory adverse events (all grade 1-2) were anemia (33%), elevated ALT (17%), elevated AST (17%), and hyperbilirubinemia (8%). Of the 12 pts treated, 2 (17%) required a dose reduction of erlotinib for treatment emergent toxicities; both subjects were on lower doses of erlotinib than 150mg daily prior to study enrollment. There were no dose reductions of ruxolitinib. Of 12 evaluable patients, no partial responses were seen. The median-progression free survival is 3 months. Two patients remain on study. One patient has been on study for 10 months with ongoing stable disease. Nine patients (75%) came off study for progression, 1 (8%) for toxicity. One person discontinued treatment on study for grade 3 pneumonitis, possibly related to the combination of erlotinib and ruxolitinib. The symptoms resolved with discontinuation of erlotinib and ruxolitinib.
Conclusion:
Combination erlotinib and ruxolitinib is well-tolerated. The phase 2 dose of ruxolitinib is 20mg BID in combination with erlotinib. There were no partial responses, but durable disease control was seen in some patients. The phase 2 study of erlotinib and ruxolitinib in this population is ongoing.
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MINI16.15 - Discussant for MINI16.11, MINI16.12, MINI16.13, MINI16.14 (ID 3349)
18:05 - 18:15 | Author(s): T. Bivona
- Abstract
- Presentation
Abstract not provided
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Author of
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MINI 16 - EGFR Mutant Lung Cancer 2 (ID 130)
- Event: WCLC 2015
- Type: Mini Oral
- Track: Treatment of Advanced Diseases - NSCLC
- Presentations: 1
- Moderators:G.J. Riely, M.C. Garassino
- Coordinates: 9/08/2015, 16:45 - 18:15, Four Seasons Ballroom F3+F4
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MINI16.14 - A Phase 1 Study of Erlotinib and Ruxolitinib in Patients with EGFR-Mutant Lung Cancers and Acquired Resistance to Erlotinib Therapy (ID 2818)
18:00 - 18:05 | Author(s): G.J. Riely
- Abstract
- Presentation
Background:
Patients with EGFR-mutant lung cancers treated with EGFR tyrosine kinase inhibitors (TKI) develop clinical resistance, often associated with acquisition of EGFR T790M. Upregulation of JAK/STAT signaling is involved in resistance to EGFR TKIs and JAK inhibition is a proposed treatment strategy in the setting of acquired resistance by restoring sensitivity to erlotinib. Ruxolitinib is an FDA-approved oral JAK1/2 inhibitor given at 20mg twice daily for hematologic malignancies with a largely non-overlapping toxicity profile with erlotinib.
Methods:
We evaluated the toxicity and efficacy of once daily oral erlotinib and twice daily oral ruxolitinib in patients with EGFR-mutant lung cancers and acquired resistance to erlotinib therapy (NCT02155465). Using a 3+3 dose escalation, we assessed escalating doses of ruxolitinib (10mg BID, 15mg BID, 20mg BID) with erlotinib 150mg daily for 21 day cycles. Response was evaluated by RECIST 1.1. Tissue and peripheral blood samples were obtained; exosomes will be extracted from peripheral blood and molecular and proteomic analyses will be performed.
Results:
From May 2014 to February 2015, 12 patients (pts) were enrolled. Median age: 60; Women: 7 (58%); never-smokers: 6 (50%); EGFR L858R=4 (33%) and Exon 19 deletion=8 (67%). Two of twelve (17%) were EGFR T790M positive at rebiopsy at the time of acquired resistance. Of 12 pts treated, 3 received ruxolitinib 10mg BID, 3 received 15mg bid and 6 received 20mg BID with erlotinib 150mg daily. No dose limiting toxicities were seen. The recommended phase 2 dose is ruxolitinib 20mg BID with 150mg erlotinib daily. Treatment-related AEs were all grade 1-3. The most frequent treatment related clinical adverse events (all grade 1-3) were anemia (25%), diarrhea (25%), rash (25%), pain (17%), fatigue (8%), and pneumonitis (8%). The most frequent treatment-related laboratory adverse events (all grade 1-2) were anemia (33%), elevated ALT (17%), elevated AST (17%), and hyperbilirubinemia (8%). Of the 12 pts treated, 2 (17%) required a dose reduction of erlotinib for treatment emergent toxicities; both subjects were on lower doses of erlotinib than 150mg daily prior to study enrollment. There were no dose reductions of ruxolitinib. Of 12 evaluable patients, no partial responses were seen. The median-progression free survival is 3 months. Two patients remain on study. One patient has been on study for 10 months with ongoing stable disease. Nine patients (75%) came off study for progression, 1 (8%) for toxicity. One person discontinued treatment on study for grade 3 pneumonitis, possibly related to the combination of erlotinib and ruxolitinib. The symptoms resolved with discontinuation of erlotinib and ruxolitinib.
Conclusion:
Combination erlotinib and ruxolitinib is well-tolerated. The phase 2 dose of ruxolitinib is 20mg BID in combination with erlotinib. There were no partial responses, but durable disease control was seen in some patients. The phase 2 study of erlotinib and ruxolitinib in this population is ongoing.
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MINI 22 - New Technology (ID 134)
- Event: WCLC 2015
- Type: Mini Oral
- Track: Biology, Pathology, and Molecular Testing
- Presentations: 1
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MINI22.02 - Clinically Adoption of MSK-IMPACT, a Hybridization Capture-Based next Generation Sequencing Assay, for the Assessment of Lung Adenocarcinomas (ID 2881)
16:50 - 16:55 | Author(s): G.J. Riely
- Abstract
- Presentation
Background:
Mutation analysis plays a central role in the management of lung adenocarcinomas (LUAD). The use of multiple single gene or mutation specific assays, broadly adopted in many laboratories to detect clinically relevant genomic alterations, often leads to delays if sequentially performed, tissue exhaustion, incomplete assessment and additional biopsy procedures. Comprehensive assays using massively parallel “next-generation” sequencing (NGS) offer a distinct advantage when addressing the increased testing needs of genotype-based therapeutic approaches. Here we describe our experience with a 410 gene, clinically validated, hybrid-capture-based NGS assay applied to testing of LUAD.
Methods:
Consecutive LUAD cases submitted for routine mutation analysis within a 1 year period were reviewed. Unstained slides of formalin fixed, paraffin embedded tissue were received for each case (range 15-20 slides/case). Corresponding H&E stained slides were reviewed and cell counts were performed in a subset of cases with limited material to establish minimal tissue requirements. Testing was performed by a laboratory-developed custom hybridization-capture based assay (MSK-IMPACT) targeting all exons and selected introns of 410 key cancer genes (J Mol Diagn 17:251-264, 2015). Barcoded libraries from tumor / normal pairs were captured and sequenced on an Illumina HiSeq 2500 and analyzed with a custom analysis pipeline.
Results:
A total of 469 specimens were received for comprehensive testing (98 cytology samples, 239 needle biopsies, 132 large biopsies/resections) of which 93% (436/469) were successfully tested. Thirty four cases (7%, 34/469) failed due to very low tumor content or low DNA yield. Cell counts for failed samples averaged 239 cells / slide (range 10-270) while all successfully tested had over 1,000 cells / slide each. Failure rate was similar for cytologies and biopsies. An average of 10 genomic alterations were detected per patient (range 1-96). The most frequently mutated genes were TP53, EGFR, KRAS, KEAP1 and STK11. Copy number gains of NKX2-1 and EGFR genes and CDKN2A loss were most common. EGFR mutations and ALK fusions were detected in 28% and 4% of cases, respectively. Among the 299 EGFR / ALK WT cases, MSK-IMPACT uncovered targetable genomic alterations that would have remained undetected through focused EGFR/ALK testing alone. These included fusions in RET (10) and ROS1 (13), mutations in ERBB2 (11) and BRAF (19) and amplifications in MET (12, unrelated to EGFR), MDM2 (26) and CDK4 (20) among others. The higher than expected rates of RET and ROS1 fusions are related to enrichment of previously tested cases known to be negative for other driver alterations.
Conclusion:
Comprehensive hybrid-capture based NGS assays such as MSK-IMPACT are an efficient testing strategy for LUAD across sample types. This upfront broad approach enables more optimal patient stratification for treatment by targeted therapeutics.
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MINI 27 - Biology and Other Issues in SCLC (ID 152)
- Event: WCLC 2015
- Type: Mini Oral
- Track: Small Cell Lung Cancer
- Presentations: 1
- Moderators:P.A. Bunn, Jr, J. Sage
- Coordinates: 9/09/2015, 16:45 - 18:15, 605+607
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MINI27.11 - Comprehensive Mutation Analysis of Never-Smokers with Small Cell Lung Cancer (SCLC) (ID 3135)
17:45 - 17:50 | Author(s): G.J. Riely
- Abstract
- Presentation
Background:
Although most patients with SCLC are current or former smokers, this disease has been reported in never-smokers. In our prospective genomic profiling of SCLC patients, we have identified four never-smokers. Here, we report next generation sequencing (NGS) results for these four SCLC patients and describe how they differ from those of smokers.
Methods:
We are evaluating pathologically confirmed SCLC tumors in patients undergoing treatment. Formalin-fixed, paraffin-embedded surgical resections, core biopsies, and fine needle aspirates are being evaluated using a targeted, hybrid capture-based, NGS assay, MSK-IMPACT, which identifies single nucleotide variants, indels, and copy number alterations in 341 cancer-associated genes. We determined never-smoking status prospectively: all smoked <100 cigarettes in their lifetime. Clinical data on stage [extensive (ES), limited (LS)], treatment, and response were collected.
Results:
Four never-smokers have been identified within the 50 patient samples that have undergone NGS evaluation thus far. The median age at diagnosis of the four never-smokers is 58 (range, 47-75); 50% are male; and one presented with LS-SCLC. None of these four patients developed SCLC as acquired resistance to EGFR tyrosine kinase inhibitors after treatment for EGFR-mutant lung cancers. The tumors from the four never-smokers displayed a median of 3 non-synonymous somatic mutations, while those from moderate (<20 pack years) and heavy (20+ pack years) smokers contained 4.5 and 8 mutations, respectively (P<0.05). None of the four never-smoker samples contained smoking associated G-to-T transversions (see Table). Inactivation of RB1 and TP53 occurred in 75% and 50% of the samples, respectively. Only patient 4 had platinum-refractory disease. The median survival of these patients was 20.7 months (range, 17 to 25).Sample Gene altered Alteration Present Protein Alteration Base Pair Alteration Patient 1 PHOX2B Missense Mutation P82L G-to-A NOTCH1 Frame-Shift Insertion P2485fs RB1 Splice Site R500_splice G-to-A TP53 Frame-Shift Deletion V218fs TP53 Frame-Shift Deletion V73fs TERT Amplification Patient 2 CBL Missense Mutation C401S G-to-C GNAS Missense Mutation M102V A-to-G MYCL Amplification Patient 3 TP53 Nonsense Mutation R342 G-to-A RB1 Frame-Shift Insertion T197fs CDKN2C Amplification MYCL Amplification Patient 4 RB1 Nonsense Mutation C666 ETV1 Amplification
Conclusion:
Using a targeted NGS assay, we have shown that the molecular characteristics differ between never-smokers and smokers, while the majority of the tumors demonstrate RB loss. Whole exome sequencing of the tumors from these never-smokers is underway. Ongoing comprehensive, multiplexed genotyping is needed to fully characterize the molecular diversity of SCLC in this unique population.
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MTE 11 - Mediastinal Tumors Including Thymic Tumors, Lymphoma, Germ-Cell Tumors: Biology, Diagnosis and Treatment (Ticketed Session) (ID 63)
- Event: WCLC 2015
- Type: Meet the Expert (Ticketed Session)
- Track: Thymoma, Mesothelioma and Other Thoracic Malignancies
- Presentations: 1
- Moderators:
- Coordinates: 9/07/2015, 07:00 - 08:00, 201+203
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MTE11.02 - Mediastinal Tumors Including Thymic Tumors, Lymphoma, Germ-Cell Tumors: Biology, Diagnosis and Treatment (ID 1995)
07:20 - 07:40 | Author(s): G.J. Riely
- Abstract
- Presentation
Abstract:
While rare tumors overall, thymic tumors are one of the most common malignancies of the anterior mediastinum. The histology of these tumors is typically described using the WHO classification, which includes type A, AB, B, and type C tumors. This histologic classification system can help to determine prognosis when combined with stage. While there are multiple categories within this classification system, perhaps the most clinically relevant differentiation is between thymoma and thymic carcinoma (type C). Although there is great heterogeneity in prognosis for patients with thymic tumors in general, typically, patients with thymic carcinoma have a somewhat more rapid course of disease them those with thymoma. There are two dominant staging systems in use for description of patients with thymic tumors: the Masaoka staging system and the TNM staging system. The Masaoka staging system is probably the most widely used and centers around the primary tumor’s degree of invasion into the capsule (completely encapsulated tumors are stage I, while tumors with trans-capsular invasion or invasion into surrounding fatty tissue are stage II) or surrounding tissues (tumors with macroscopic invasion into neighboring organs are stage III). Notably, the Masaoka staging system differentiates stage IV thymic tumors into stage IV A, which is metastatic disease involving the pleura only and stage IV B, where patients have hematologic or lymphatic dissemination (including regional and local lymph nodes). One of the hallmarks of thymic tumors, is paraneoplastic syndromes. The most common paraneoplastic syndrome in patients with thymoma is myasthenia gravis. In patients newly diagnosed with myasthenia gravis, approximately 10-15% will have a thymoma. Conversely, approximately half of patients with thymoma develop myasthenia gravis. It is important to be aware of the diagnosis of myasthenia gravis prior to surgical resection. Multiple other paraneoplastic syndromes have been described in patients with thymoma including pure red cell aplasia, hypogammaglobulinemia, Good’s syndrome, and neuromyotonia. Notably, paraneoplastic syndrome such as these are distinctly uncommon in patients with thymic carcinoma. The treatment of patients with early stage thymoma is primarily surgical. For patients with a clinical diagnosis of an anterior mediastinal mass that is suggestive of thymoma or thymic carcinoma, if the tumor is small, it may be reasonable to resect the tumor rather than perform a biopsy prior to surgery. In patients with more locally advanced disease or where the diagnosis is uncertain, it is appropriate to perform a needle biopsy prior to surgery or other therapy. In general, patients with stage I and II disease are best managed with surgery alone. Given the critical nature of complete surgical resection for long-term outcomes, those patients with more locally advanced disease may benefit from induction chemotherapy prior to surgical resection. The most common chemotherapy regimens used for preoperative chemotherapy include platinum/taxane combinations, cisplatin and etoposide, and the 3 drug combination of cisplatin, doxorubicin, and cyclophosphamide. None of these regimens has been prospectively compared. For patients in whom surgical resection is not feasible, radiation therapy may be appropriate. For patients with recurrent or metastatic disease that is not amenable to surgical resection, systemic therapy is appropriate. Chemotherapy regimens similar to what is described for preoperative therapy are widely used. For those patients with thymoma, anthracycline-based combinations seem to have the highest response rates as initial therapy. For those patients with thymic carcinoma, there is supportive data for the use of platinum/taxane combinations as preferred initial therapy. At the time of progressive disease after first line therapy, multiple drugs have been explored, however as in first-line therapy, there are no randomized prospective trials to determine the optimal regimen. For those patients with octreotide-avid disease, administration of octreotide in combination with prednisone has been found to be useful. Data supporting the efficacy of a number of drugs has been reported. More recent data support the use of pemetrexed, everolimus, sunitinib (for thymic carcinoma), as well as cixutumumab, an anti-IGF 1R antibody. Given the rarity of this tumor and the multidisciplinary nature of care required for patients with thymic carcinomas or thymoma, referral to a multidisciplinary team with experience in management of patients with thymic tumors is appropriate.
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ORAL 03 - New Kinase Targets (ID 89)
- Event: WCLC 2015
- Type: Oral Session
- Track: Treatment of Advanced Diseases - NSCLC
- Presentations: 1
- Moderators:F. Blackhall, R. Juergens
- Coordinates: 9/07/2015, 10:45 - 12:15, Mile High Ballroom 4a-4f
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ORAL03.05 - Clinical Outcomes with Pemetrexed-Based Systemic Therapy in RET-Rearranged Lung Cancers (ID 2813)
11:28 - 11:39 | Author(s): G.J. Riely
- Abstract
- Presentation
Background:
Previous series have shown that clinical benefit with pemetrexed-based systemic therapy can be durable in patients with ALK- and ROS1-rearranged lung cancers. The benefit of pemetrexed-based treatment in RET-rearranged lung cancers relative to other genomic subsets has not been explored.
Methods:
A retrospective review of records of patients treated at Memorial Sloan Kettering between 2007-2014 was conducted. Eligibility criteria: pathologically-confirmed advanced (stage IIIB/IV) non-small cell lung carcinoma, treatment with pemetrexed as monotherapy or in combination with other systemic agents, documented evidence of a rearrangement involving RET, ROS1, or ALK, or a KRAS mutation. Screening for these alterations was performed via break apart fluorescence in situ hybridization, multiplex mutation hotspot testing (Sequenom), or next-generation sequencing (MSK-IMPACT, Illumina HiSeq). Progression-free survival (PFS) and time to progression (TTP) were calculated using Kaplan-Meier estimates from the date of initiation of pemetrexed-containing therapy, and overall survival (OS) from diagnosis of metastatic disease. Overall response rate (ORR, RECIST v1.1), PFS, TTP, and OS were compared between RET-rearranged lung cancers and control groups (ALK- and ROS1-rearranged and KRAS-mutant lung cancers).
Results:
Data from 104 patients (RET-rearranged n=17, ROS1-rearranged n=10, ALK-rearranged n=36, KRAS-mutant n=41) were evaluated. As expected, median pack-year cigarette smoking history significantly differed between groups (p<0.001): RET 0 (0-48 range), ROS1 0 (0-12), ALK 0 (0-74), KRAS 38 (0-93). Features such as line of pemetrexed therapy (first vs other, p=0.1186), type of therapy (platinum combination, non-platinum combination, vs single-agent, p=0.1435), and need for dose reduction (p=0.9772) did not differ between groups. ORR, TTP, PFS, and OS in RET-rearranged lung cancers were not significantly different compared to ALK- and ROS1-rearranged lung cancers, and improved compared to KRAS-mutant lung cancers (Table 1). Table 1. Clinical Outcomes of Pemetrexed-Based TherapyRET ROS1 ALK KRAS p-value ORR 45% 78% 50% 26% 0.0242 Median TTP (months) NR (20-NR) 32 (14-NR) NR 7 (5-14) <0.001 ALK vs ROS1 vs RET (p=0.90); RET vs KRAS(p=0.009) Median PFS 20 (10-NR) 23 (14-NR) 24 (15-38) 6 (5-9) <0.001 ALK vs ROS1 vs RET (p=0.94); RET vs KRAS(p=0.002) Median OS NR (24-NR) NR (24- NR) 37 (30-63) 16 (13-29) <0.001 ALK vs ROS1 vs RET (p=0.43); RET vs KRAS(p=0.002)
Conclusion:
Clinical benefit with pemetrexed-based therapy in RET-rearranged lung cancers can be durable and is comparable to ALK- and ROS1-rearranged lung cancers. Outcomes in RET-, ROS1-, and ALK-rearranged lung cancers were improved compared to KRAS-mutant lung cancers. Mechanisms responsible for pemetrexed sensitivity in these subsets should continue to be explored. Driver-independent factors such as smoking history may contribute to clinical benefit.
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ORAL 33 - ALK (ID 145)
- Event: WCLC 2015
- Type: Oral Session
- Track: Treatment of Advanced Diseases - NSCLC
- Presentations: 1
- Moderators:S. Gadgeel
- Coordinates: 9/09/2015, 16:45 - 18:15, Mile High Ballroom 1a-1f
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ORAL33.03 - Updated Efficacy/Safety Data From the Phase 2 NP28761 Study of Alectinib in ALK+ NSCLC (ID 1261)
17:07 - 17:18 | Author(s): G.J. Riely
- Abstract
- Presentation
Background:
ALK gene rearrangements occur in approximately 3–6% of patients with non-small-cell lung cancer (NSCLC). Crizotinib has demonstrated efficacy in ALK+ NSCLC, however many patients experience systemic and/or central nervous system (CNS) disease progression within one year of treatment. Alectinib, a CNS-penetrant and highly selective ALK inhibitor, has shown preclinical activity in the CNS (Ou, et al. JTO 2013) and clinical efficacy in crizotinib-naïve (Ohe, et al. ASCO 2015) and pre-treated (Ou, et al. ASCO 2015; Gandhi, et al. ASCO 2015) ALK+ NSCLC patients. We will present updated efficacy and safety outcomes from the phase II NP28761 study (NCT01871805).
Methods:
North American patients ≥18 years of age with ALK+ NSCLC (by FDA-approved FISH test), disease progression following first-line crizotinib, and ECOG PS ≤2 were enrolled. Patients received oral alectinib (600mg) twice daily until progression, death or withdrawal. The primary endpoint was overall response rate (ORR) by independent review committee (IRC) using RECIST v1.1. Secondary endpoints included investigator-assessed ORR; progression-free survival (PFS); quality of life (QoL); CNS response rate; disease control rate (DCR); and safety.
Results:
At data cut-off (24 October 2014), 87 patients were enrolled in the intent-to-treat population. Median age was 54 years; 74% had received prior chemotherapy; 60% of patients had baseline CNS metastases, of whom 65% (34/52) had prior brain radiation therapy. Median follow-up was 20.7 weeks. ORR by IRC was 48% (95% CI 36–60); median PFS was 6.3 months (Table 1). In patients with measurable CNS lesions at baseline (n=16), IRC CNS ORR was 69% (95% CI 41–89) and CNS DCR was 100% (complete response, 13%; partial response, 56%; stable disease, 31%). In patients with measurable or non-measurable CNS disease (n=52), IRC CNS ORR was 39% (95% CI 25–53) and 11 patients (21%) had complete CNS responses. The most common grade ≥3 AEs were elevated levels of blood creatine phosphokinase (8%), alanine aminotransferase (6%) and aspartate aminotransferase (5%); no GI toxicities leading to treatment withdrawal were reported. Clinically meaningful improvements were seen in EORTC QLQ-C30 items, including Global Health Status. Figure 1
Conclusion:
Alectinib (600mg twice daily) was well tolerated and demonstrated clinical efficacy in patients with ALK+ NSCLC disease who had progressed on prior crizotinib. A clinical benefit with alectinib was also observed in patients with CNS lesions at baseline. These data are preliminary; updated efficacy and safety data from a cut-off date of 27 April 2015 will be presented.
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P3.01 - Poster Session/ Treatment of Advanced Diseases – NSCLC (ID 208)
- Event: WCLC 2015
- Type: Poster
- Track: Treatment of Advanced Diseases - NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 9/09/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
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P3.01-075 - Phase 2 Trial of Bortezomib in KRAS G12D Mutant Lung Cancers (ID 2943)
09:30 - 09:30 | Author(s): G.J. Riely
- Abstract
Background:
KRAS mutations are the most common oncogenic drivers in lung cancers without any approved targeted therapy. Preclinical evidence suggests that KRAS mutations are highly dependent on the NF-kB pathway. Bortezomib, a small molecule proteasome inhibitor, has been shown to downregulate the NF-kB pathway and lead to objective responses in patients with KRAS G12D in early phase clinical trials. In this single-institution, open label, phase II study we assessed the efficacy and safety of subcutaneous bortezomib in KRAS mutant lung cancers.
Methods:
Patients with advanced KRAS G12D mutant lung cancers were eligible. Bortezomib was administered at 1.3mg/m2/dose subcutaneously on days 1, 4, 8, and 11 of a 21 day cycle until disease progression or unacceptable toxicity. The primary objective was radiographic response rate (RECIST version 1.1). The secondary endpoints were progression free survival (PFS) and overall survival (OS) determined from the time of first bortezomib treatment. Simon two-stage minimax design was used (H0=10%, H1=30%, power=90%).
Results:
Sixteen patients with KRAS G12D mutant lung adenocarcinomas were treated on study: 44% women, 38% never smokers, 31% former smokers ≤15 pack years, and 69% with invasive mucinous adenocarcinomas. Patients received treatment for a median of 2 months (range 1-12months). One patient had a partial response with a 66% reduction in disease burden (6% observed rate, 95% CI 0.2 to 30.2%). Of the 6 patients (40%) with stable disease, 2 remained on study for over 5 months. The median PFS was 1 month (95% CI 1-6). The median OS was 13 months (95% CI 6-NA). The median OS from date of diagnosis of metastatic disease was 39 months (95% CI 35-NA). The most common treatment-related toxicities of any grade were fatigue (50%), diarrhea (38%), nausea (31%), and papulopustular rash (31%). Treatment-related peripheral neuropathy occurred in 25% of patients (3 patients with grade 1, 1 patient with grade 2).
Conclusion:
In patients with G12D KRAS mutant lung cancers, bortezomib was well tolerated and associated with modest anti-tumor activity and durable disease control in a small subset of patients. Further investigation into predictive biomarkers for the efficacy of bortezomib should be pursued. Without a clear biomarker, no further study of bortezomib in KRAS- mutant lung cancers is warranted.
