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M. Ahn
Moderator of
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OA09 - Locally Advanced NSCLC: Innovative Treatment Strategies (ID 384)
- Event: WCLC 2016
- Type: Oral Session
- Track: Locally Advanced NSCLC
- Presentations: 8
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OA09.01 - The Number or the Position is the Main Prognostic Factor for N2 NSCLC? A Validation of New IASLC N Staging Proposal (ID 5186)
11:00 - 11:10 | Author(s): S. Ricciardi, P. Bertoglio, M. Lucchi, V. Aprile, C.C. Zirafa, A. Mussi
- Abstract
- Presentation
Background:
The eighth edition of lung TNM does not change any N descriptors, but it suggests some potential changes that might be used in the next edition. In fact, N2 would be divided into three groups: pN2a1 (skip lymph-node involvement), pN2a2 (single mediastinal station with hilar involvement) and pN2b (multiple mediastinal involvement). The aim of this study was to verify the value of this classification proposal analyzing our recent surgical experience.
Methods:
We retrospectively selected all patients treated with lobectomy, bilobectomy or pneumonectomy for T1/T2 N2 NSCLC (VII TNM edition) in the period between 2006 and 2010. We excluded all patients who underwent any kind of extended resection and who had another active tumor at the time of operation. A systematic lymph-node dissection was always carried out according to the IASLC guidelines. All patients were then restaged according to the new IASLC proposal. Overall Survival (OS), Disease Free Interval (DFI) and most important variables were analyzed.
Results:
Among 248 surgically treated pN2 patients, 108 entered our inclusion criteria. Pathology report showed a majority of T2 tumors (67,6%) and in almost half of cases an adenocarcinoma (50,9%); a mean number of 16,4 (DS 7,8) lymph-nodes were resected (5,8 (DS 2,9) from the hilum and 10,6 (DS 5,9) from the mediastinum). After restaging all cases with the new IASLC proposal we observed: 30 (27,8%) pN2a1; 57 (52,8%) pN2a2 and 21 (19,4%) pN2b. With a median follow up of 93 months, the median overall survival of the entire cohort was 27 months. pN2a1 had a significant better overall survival compared with the other two groups (p=0,020); conversely no statistically significant difference was found in OS between pN2a2 and pN2b. 1, 3 and 5-year survival for pN2a1, pN2a2 and pN2b were 90%, 81% and 71%; 53%, 37% and 24%; 45%, 26% and 19% respectively. Concurrently DFI was significantly better for pN2a1 (p=0,025). At univariate survival analysis age>65 years, more than 4 positive lymph nodes and postoperative complications were statistically significant variables. At the multivariate analysis only age and the number of positive lymphnodes were independent prognostic factors of a worse survival.
Conclusion:
Our experience partially validate the new proposal of IASLC of N2 staging. Patients with skip lymph-node metastasis (pN2a1) have a statistically significant better prognosis. Concurrently we observed and confirmed the important prognostic value of the number of the involved lymph-node, which should be considered as well in the next editions of the lung cancer staging system.
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OA09.02 - Should Surgery Be Part of the Multimodality Treatment for Stage IIIB Non-Small Cell Lung Cancer (ID 5221)
11:10 - 11:20 | Author(s): S. Collaud, B. Provost, D. Fabre, S. Mussot, B. Besse, O. Mercier, E. Fadel
- Abstract
- Presentation
Background:
Stage IIIB non-small cell lung cancer (NSCLC) is a heterogeneous patient group, including T4N2 and T1-4N3 NSCLC. Traditionally, treatment for stage IIIB consists in definitive chemoradiation. Surgical treatment for stage IIIB NSCLC is used anecdotally in highly selected patients. Here, we studied patient outcome who underwent surgical resection as part of multimodality treatment for stage IIIB NSCLC.
Methods:
All patients from a single institution who underwent surgery for stage IIIB between 2000 and 2015 were included. Surgical candidates were selected on a case-by-case basis during multidisciplinary tumorboard conference. In general, N2-N3 diseases are not considered an absolute contraindication to surgery if lymph node involvement is limited to a non-bulky single site, the tumor is deemed completely resectable without major morbidity and the patient will tolerate multimodality treatment. Mediastinal staging comprised cervical mediastinoscopy, positron emission tomography coupled with CT from 2005 and endobronchial ultrasound guided fine-needle aspiration from 2011. Charts were retrospectively reviewed and data analyzed. Survival was calculated from the date of surgery until last follow-up. Univariate and multivariate analysis were performed to identify prognostic factors.
Results:
From 2000 to 2015, 5416 patients underwent lung resection for NSCLC in our center. Sixty patients (1%) underwent surgery for stage IIIB NSCLC. Forty-three were males (72%). Median age was 58 years (from 22 to 79). Thirty-two patients had T4N2 NSCLC involving the carina (n=16, 50%), superior vena cava (n=4, 12%), carina and superior vena cava (n=5, 16%), left atrium (n=5, 16%), pulmonary artery (n=1, 3%) and spine (n=1, 3%). Twenty-eight patients had N3-disease, involving supraclavicular (n=14, 50%) or contralateral mediastinal lymph nodes (n=14, 50%). Pneumonectomy was performed in 27 patients (45%). Twenty-nine patients (48%) had induction therapy, consisting in chemotherapy alone for all patients. Adjuvant therapy was administered to 52 patients (87%) and consisted mostly of chemoradiation (n=35, 67%). Complete resection (R0) was performed in 55 patients (92%). Post-operative mortality was 3% (n=2). Three- and 5-year overall survivals were 51% and 39%, respectively. Median survival was 40 months. Median follow-up was 17 months. Results of the multivariate analysis identified incomplete resection (p=0.008) and absence of adjuvant treatment (p=0.032) as prognostic factors for poor survival.
Conclusion:
An excellent 5-year survival of 39% was achieved in highly selected patients with stage IIIB NSCLC and treated with multimodality including surgery. Patients with stage IIIB NSCLC should therefore be discussed in a multidisciplinary setting, including thoracic surgeons.
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- Abstract
- Presentation
Background:
Adjuvant chemotherapy is the standard of care for completely resected stage II-IIIa non-small cell lung cancer (NSCLC). A few trials suggest that neoadjuvant chemotherapy is a promising strategy for resectable NSCLC. Indirect comparison meta-analysis of adjuvant versus neoadjuvant therapy showed no difference in survival. This study was conducted to determine the difference of disease-free survival(DFS) between adjuvant chemotherapy and neoadjuvant chemotherapy among patients with resectable NSCLC.
Methods:
Patients with clinical stage IB-IIIA NSCLC were eligible. Patients were randomly assigned to 3 cycles adjuvant DC (Docetaxel: 75mg/m2, Carboplatin:AUC=5 on day 1, every 3wk) after completely resection (lobectomy or pneomonectomy with mediastinal lymphnode dissection, or 3 cycles neoadjuvant DC at the same schedule followed by surgery 3-6 wk after chemotherapy. The primary end point was 3 years DFS; secondary end points were 3ys and 5ys Overall Survival(OS) and Safety. Planned sample size is 410. The trail was early closed because slowly accrued.
Results:
Between March 2006 and May 2011,198 patients from 8 Institute were randomized to neoadjuvant arm (97 cases) or adjuvant arm (101 cases). The median age was 58, male accounted for 80.3%, Adenocarcinoma 48.5%, stage Ib, II a, II b and IIIa were 32.5%, 12.2%, 28.4% and 26.9% respectively. Two arms were balanced. 100% cases received neoadjuvant chemotherapy and 87.4% finished the planned adjuvant chemotherapy. No unexpected toxicities were seen and 41.2% of patients experienced grade 3-4 neutropenia. In neoadjuvant arm, the ORR was 34% and 12.4% patients developed PD. No difference in postoperative complication was found between two arms. Survival analysis show in Table 1.Figure 1
Conclusion:
Adjuvant or neo-adjuvant chemotherapy with docetaxel plus carboplatin in resectable clinical stage IB-IIIA NSCLC are feasible and safe. The final results showed no difference in 3ys DFS and OS between two arms. Long term survival in Adjuvant arm show the tendency of superior to neoadjuvant arm.
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OA09.04 - Discussant for OA09.01, OA09.02, OA09.03 (ID 6949)
11:30 - 11:45 | Author(s): M. Tsuboi
- Abstract
- Presentation
Abstract not provided
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- Abstract
- Presentation
Background:
Tumor hypoxia is an adverse prognostic factor in many cancers. Hypoxia tracer [18]F-FAZA provides a non-invasive method of hypoxia imaging. This study aims to evaluate the feasibility and potential benefits of using FAZA-PET scans to assess NSCLC tumor hypoxia.
Methods:
The initial 17 patients of an ongoing study with stage II–III NSCLC have been analyzed prospectively by imaging with FAZA-PET before initiation of a radical course of radiotherapy. The hypoxic volume (HV) was defined as all voxels within the tumor with standard uptake value (SUV) more than 1.2 times the aorta SUVmean. The Tmax/Bmean ratio (T/B) was defined as maximum tumor SUV divided by aorta SUVmean. The hypoxic fraction (HF) was determined by dividing the HV by the entire gross tumor volume. Spearman correlation and Fisher’s test were used to explore potential correlations among several variables.
Results:
Median primary and nodal FAZA SUVmax were 1.7 (range: 1.0-3.8) and 1.7 (range: 1.0–3.3). Median primary and nodal T/B ratios were 1.4 (range: 1.0–2.5) and 1.3 (range: 1.0–2.2). Median primary and nodal HF were 3.9% (range: 0.0-38.2%) and 0.6% (range: 0.0-50.7%). The median time from diagnostic FDG PET to study FAZA PET scans was 28 days (range: 1–63). Median primary and nodal FDG SUVmax were 13.5 (range: 5.1–32.2) and 8.3 (range: 2.3–15.7). Larger primary tumor volume is correlated with higher FAZA-T/B (p=0.01) and higher HF (p=0.01). Primary tumors with higher T/B also had higher HF (p<0.0001). The same correlations also apply to nodal disease. Nodal FAZA SUVmax is correlated with primary FAZA SUVmax (p<0.0001). When comparing FAZA-PET with FDG-PET, nodal FDG SUVmax is correlated with nodal FAZA T/B (p=0.01) and nodal FAZA HF (p=0.01), which was not observed for primary disease. For each patient, the nodal station with the highest FAZA SUVmax correlates with the highest FDG SUVmax (p=0.02).
Conclusion:
Imaging intra-lesional hypoxia in NSCLC primary and nodal tumors is feasible and can be achieved with FAZA-PET. Larger tumor volume is correlated with higher T/B and HF in both primary and nodal masses. In the nodal volume only, higher FDG activity is correlated with higher FAZA T/B and higher HF. Ongoing trial accrual and follow-up of our patient cohort will provide more information with regards to the imaging and clinical value of FAZA-PET. This study may eventually lead to using FAZA-PET as a guiding tool to escalate dose to the hypoxic region of the tumor.
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OA09.06 - Metformin Use during Concurrent Chemoradiotherapy for Locally Advanced Non-Small Cell Lung Cancer (NSCLC) (Abstract under Embargo until December 6, 7:00 CET) (ID 3753)
11:55 - 12:05 | Author(s): K. Wink, J. Belderbos, E. Dieleman, M.M.G. Rossi, C. Rasch, R. Damhuis, R. Houben, E.G.C. Troost
- Abstract
- Presentation
Background:
An increasing body of (pre)clinical evidence has suggested that metformin has an anticancer effect. The aim of this study was to investigate whether the use of metformin during concurrent chemoradiotherapy (cCRT) for locally advanced non-small cell lung cancer (NSCLC) improved treatment outcome.
Methods:
A total of 682 patients were included in this retrospective cohort study (59 metformin users, 623 control patients). All received cCRT in one of three participating radiation oncology departments in the Netherlands between January 2008 and January 2013. Primary endpoint was locoregional recurrence free survival (LRFS), secondary endpoints were overall survival (OS), progression-free survival (PFS) and distant metastasis free survival (DMFS)
Results:
No significant differences in LRFS or OS were found. Metformin use was associated with an improved DMFS (74% versus 53% at 2 years; p = 0.01) and PFS (58% versus 37% at 2 years and a median PFS of 41 months versus 15 months; p = 0.01). In a multivariate cox-regression analysis, the use of metformin was a statistically significant independent variable for DMFS and PFS (p = 0.02 and 0.03).
Conclusion:
Metformin use during cCRT is associated with an improved DMFS and PFS for locally advanced NSCLC patients, suggesting that metformin may be a valuable treatment addition in these patients. Evidently, our results merit to be verified in a prospective trial.
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- Abstract
- Presentation
Background:
RTOG 0617 recommended 60Gy as the standard dose for unresectable stage Ⅲ non-small cell lung cancer (NSCLC) treated with concurrent chemoradiotherapy (CCRT) Is the conclusion true? The phase I/II trial to determine the feasibility and effects of individual isotoxic radiation dose escalation in unresectable stage Ⅲ NSCLC treated with CCRT based on bilateral lung V20 and advanced technologies was studied.
Methods:
Consecutive patients with unresectable stage III NSCLC were entered in cohorts of eight from March 2006 to May 2009. Patients were assigned to receive concurrent administration of late course accelerated hyperfrationation (LCAHF) intensity modulated radiotherapy (IMRT) and chemotherapy. Isotoxic dose escalation was based on V20 and advanced technologies including PET-CT, single-photon emission computed tomography (SPECT) and LCAHF IMRT. PET-CT was used to delineate the gross tumor volume. SPECT lung perfusion was applied to define different functional lung regions, which was used to optimize the IMRT plans. Patients with a V20 of 27% as a base level were enrolled into the first cohort. From the second cohort, the V20 further increased to 30%, 33%, 35%, 37%, and so on. The criteria for cessation of dose escalation was defined as more than 25% of patients in the cohort experienced dose limiting toxicity (DLT). To test the power of escalation dose, patients with total radiation dose over 66Gy would be assigned to the higher dose group (HD), while the other patients would be assigned to the standard dose one (SD).
Results:
Forty patients were enrolled. The maximum tolerated value of V20 was 37% in this study. Nineteen patients entered SD group, while twenty-one in HD. The overall response rate was as high as 80%. Follow-up for all patients ranged from 1 to 112 months with survival patients from 101 to 112 months. The median overall and progression free survivals were 25.0 and 13.0 months, respectively. 1-, 3-, 5- and 8-year overall survival (OS) rates were 72.5%, 22.5%, 17.5%, and 10.0%, respectively. Patients with stage Ⅲa achieved a longer median OS than those of stage Ⅲb (31 vs. 21 months, P=0.029). Especially, patients received HD radiotherapy got a significant better OS and local recurrence free survival than those in SD (27, 23 vs. 16, 19 months, P = 0.053, 0.037) without increasing severe toxicity.
Conclusion:
The protocol is feasible and effective. In the future, the radiation dose escalation for unresectable stage Ⅲ NSCLC treated with CCRT should be focused on toxicity control and advanced technology application.
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OA09.08 - Discussant for OA09.05, OA09.06, OA09.07 (ID 6955)
12:15 - 12:30 | Author(s): P. Van Houtte
- Abstract
- Presentation
Abstract not provided
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Author of
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MA06 - Locally Advanced NSCLC: Risk Groups, Biological Factors and Treatment Choices (ID 379)
- Event: WCLC 2016
- Type: Mini Oral Session
- Track: Locally Advanced NSCLC
- Presentations: 1
- Moderators:P. Van Houtte, M. Zemanová
- Coordinates: 12/05/2016, 16:00 - 17:30, Strauss 2
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MA06.03 - Recurrence Dynamics after Trimodality Therapy (Neoadjuvant Chemoradiotherapy and Surgery) in Stage IIIa(N2) Lung Cancer (ID 4963)
16:12 - 16:18 | Author(s): M. Ahn
- Abstract
- Presentation
Background:
In IIIa(N2) Non-small cell lung cancer (NSCLC), various strategies to cure have been tried but the major cause of mortality is still the recurrence. Therefore, understanding of the dynamics of recurrence is important to improve the treatment outcome. We investigated the timing and patterns of recurrence after treatment of IIIA(N2) NSCLC with trimodality treatment (neoadjuvant chemoradiotherapy and surgery).
Methods:
An institutional database of consecutive patients between 1997 and 2013 (N = 574) was reviewed retrospectively. Eligible patients had pathologically proven N2 disease of NSCLC and completion of a planned trimodality treatment. First events involving the development of loco-regional recurrence, distant metastases or both were considered. The hazard rate function was used to evaluate the dynamics of recurrence.
Results:
The 5-year overall survival rate was 47% and the 5-year recurrence free survival rate was 29%. Among the 299 patients (52.1% of total) who experienced recurrence, 26 (8.7%) had loco-regional recurrences, 248 (82.9%) had distant metastases, and 25 (8.4%) had both. The most frequent sites of distant metastases were lung (n=102, 41%), brain (n=63, 25%), and bone (n=63, 25%). The hazard rate function for the overall recurrence revealed the peak at approximately 8 months after surgery then the down-slope pattern before 38 months. A similar risk pattern was found in distant metastasis but low and steady risk pattern was detected in loco-regional recurrence. In distant metastases, similar patterns were found in individual organs, however, earlier peak at approximately 5 months presented in brain metastasis. A comparison of histology showed that adenocarcinoma exhibited higher recurrence hazard rate of distant metastasis than squamous cell carcinoma with similar pattern of recurrence (p=0.03). The status of nodal clearance after induction therapy exhibited that ypN2 patients (n= 229, 39.9%) had highest hazard rate (p=0.03). The recurrence hazard rate of ypN0 was the least, but the extent was not smaller, they showed approximately one of third of ypN2 at peak.
Conclusion:
The hazard rate of loco-regional failure after trimodality therapy was low. But the hazard rate of distant metastasis was considerably high yet and shifted to left with the peak within 12 moths after surgery. This study guides the intensive surveillance immediate after completion of trimodality therapy to identify risk groups of early recurrence and to develop therapeutic strategy.
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MA07 - ALK-ROS1 in Advanced NSCLC (ID 385)
- Event: WCLC 2016
- Type: Mini Oral Session
- Track: Advanced NSCLC
- Presentations: 1
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MA07.07 - Ceritinib in ROS1-Rearranged Non-Small-Cell Lung Cancer: An Update of Korean Nationwide Phase II Study (ID 5953)
11:42 - 11:48 | Author(s): M. Ahn
- Abstract
- Presentation
Background:
ROS1 rearrangement is a distinct molecular subset of non-small-cell lung cancer (NSCLC). We investigated the efficacy and safety of ceritinib in patients with ROS1-rearranged NSCLC.
Methods:
We enrolled 32 patients with advanced NSCLC who tested positive for ROS1 rearrangement by fluorescent in situ hybridization (FISH). ROS1 immunohistochemistry (IHC) and next-generation sequencing (NGS) was performed in available tumor samples. Ceritinib 750mg was administered once daily and the primary endpoint was objective response rate (ORR) by central independent radiologic review. The secondary endpoints included disease control rate (DCR), duration of response, progression-free survival (PFS), overall survival (OS), toxicity and concordance between FISH and IHC. ROS1 fusion partners were identified with the use of next-generation sequencing (NGS) in available tumor samples.
Results:
Between June 7, 2013, and February 1, 2016, a total of 404 patients underwent ROS1 prescreening, and 32 ROS1+ (by FISH) patients were enrolled. All patients except two (who did not respond to ceritinib) were crizotinib naïve. The median age of all patients was 62 years, and there were 24 females (75%). The majority of patients (84%) were never smokers, and all had adenocarcinoma histology. The median number of previous treatments before study enrollment was 3 (range, 2-7) and 17 (53%) patients had received three or more lines of chemotherapy. At the time of the data cut-off (April 18, 2016), the median follow-up was 7.5 months, and 15 (47%) patients had discontinued treatment. Of the 32 patients enrolled, 28 patients were evaluable for response by independent radiologic review. ORR was 63% (95% CI, 45.7-79.3), with 1 complete response and 19 partial responses. The median duration of response was 10.0 months (range, 0.4+-18.4+). Among 11 tumors that were tested by NGS, we identified 7 ROS1 fusion partners including ROS1-CD74, ROS1-SLC34A2, and ROS1-EZR. The median progression-free survival was 19.3 months (95% CI, 7.2-not reached), with 17 (53%) patients still in follow-up for progression. The median overall survival was not reached at the time of the data cut-off. Of 5 patients with retrospectively confirmed brain metastases, intracranial disease control was reported in 4 patients (80%). Gastrointestinal adverse events (vomiting, nausea, diarrhea) mostly grade 1-2, were the most frequent adverse events (80%); these events were manageable.
Conclusion:
Ceritinib demonstrated potent clinical activity in patients with advanced, ROS1-rearranged NSCLC, who received at least one prior line of platinum-based chemotherapy. ROS1 rearrangement defines a second molecular subgroup of NSCLC for which ceritinib is highly active (ClinicalTrials.gov number, NCT01964157).
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MA16 - Novel Strategies in Targeted Therapy (ID 407)
- Event: WCLC 2016
- Type: Mini Oral Session
- Track: Chemotherapy/Targeted Therapy/Immunotherapy
- Presentations: 2
- Moderators:G. Purkalne, J. Von Pawel
- Coordinates: 12/07/2016, 14:20 - 15:50, Strauss 2
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MA16.04 - Discussant for MA16.01, MA16.02, MA16.03 (ID 7102)
14:32 - 14:44 | Author(s): M. Ahn
- Abstract
- Presentation
Abstract not provided
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MA16.11 - CNS Response to Osimertinib in Patients with T790M-Positive Advanced NSCLC: Pooled Data from Two Phase II Trials (ID 4920)
15:26 - 15:32 | Author(s): M. Ahn
- Abstract
- Presentation
Background:
Brain metastases develop in 25–40% of patients with NSCLC. Osimertinib is an oral, potent, irreversible EGFR-TKI, selective for both sensitising (EGFRm) and T790M resistance mutations. Preclinical and early clinical evidence support central nervous system (CNS) penetration and activity of osimertinib. Two Phase II studies (AURA extension [NCT01802632] and AURA2 [NCT02094261]) evaluating the efficacy and safety of osimertinib are ongoing. We present a pre planned subgroup analysis assessing pooled CNS response from these two studies; data cut-off (DCO) was 1 November 2015. An earlier pooled analysis from these two studies (1 May 2015 DCO) showed the objective response rate (ORR) in patients with CNS metastases was consistent with ORR in the overall patient population.
Methods:
Patients with advanced NSCLC who progressed following prior EGFR-TKI therapy with centrally-confirmed T790M positive status (cobas® EGFR Mutation Test) received osimertinib 80 mg once daily (n=411). Patients with stable, asymptomatic CNS metastases were eligible for enrolment. CNS efficacy was assessed in an evaluable for CNS response analysis set, which included patients with at least one measurable CNS lesion on baseline brain scan (RECIST v1.1) by blinded independent central neuroradiology review (BICR). Effect of prior radiotherapy on CNS response was assessed.
Results:
As of 1 November 2015, 50/192 patients with baseline brain scans had at least one measurable CNS lesion identified by BICR. Baseline demographics were broadly consistent with the overall patient population. Confirmed CNS ORR was 54% (27/50; 95% CI: 39%, 68%), with 12% complete CNS response (6/50 patients). The median CNS duration of response (22% maturity) was not reached (95% CI: not calculable [NC], NC). The estimated percentage of patients remaining in response at 9 months was 75% (95% CI: 53, 88). CNS disease control rate (DCR) was 92% (46/50; 95% CI: 81%, 98%). Median time to first response was 5.7 weeks (range: 5.6–6.6). Median best percentage change from baseline in CNS target lesion size was 53% (range: -100% – +80%). Median follow up for CNS progression-free survival (PFS) was 11 months; the median CNS PFS was not reached (95% CI: 7, NC). At 12 months, 56% (95% CI: 40%, 70%) of patients were estimated to remain on study, alive and CNS progression-free. CNS response was observed regardless of prior radiotherapy to the brain.
Conclusion:
Osimertinib demonstrates durable efficacy in patients with T790M NSCLC and measurable CNS metastases, with a CNS response rate of 54% and a DCR of 92%.
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OA08 - Targeted Therapies in Brain Metastases (ID 381)
- Event: WCLC 2016
- Type: Oral Session
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:D. Ball, B. Perin
- Coordinates: 12/05/2016, 16:00 - 17:30, Schubert 1
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OA08.06 - Brigatinib Activity in Patients with ALK+ NSCLC and Intracranial CNS Metastases in Two Clinical Trials (ID 4374)
16:55 - 17:05 | Author(s): M. Ahn
- Abstract
- Presentation
Background:
Patients treated with crizotinib often experience disease progression in the brain. Brigatinib, an investigational next-generation ALK inhibitor, is being evaluated in an ongoing phase 1/2 trial (Ph1/2) and an ongoing pivotal phase 2 trial (ALTA).
Methods:
In Ph1/2, patients with advanced malignancies, including ALK+ NSCLC, received 30–300 mg brigatinib per day. In ALTA, patients with crizotinib-resistant advanced ALK+ NSCLC received 90 mg qd (arm A) or 180 mg qd with a 7-day lead-in at 90 mg (arm B). Efficacy (in both trials) and safety (in ALTA) are reported for ALK+ NSCLC patients with brain metastases at baseline.
Results:
In Ph1/2 and ALTA, 50/79 (63%; IRC-assessed) and 154/222 (69%; investigator-assessed) of ALK+ NSCLC patients, respectively, had baseline brain metastases. In Ph1/2 (n=50), median age was 53 years, 76% received prior chemotherapy, and 8% were crizotinib-naive. In ALTA (n=154), median age was 52 years; 75% received prior chemotherapy. As of November 16, 2015, 25/50 (50%) patients were receiving brigatinib in Ph1/2; as of February 29, 2016, 101/154 (66%) patients were receiving brigatinib in ALTA. For patients with measurable lesions, confirmed iORR was 53% in Ph1/2 and 42%/67% in ALTA A/B (Table). Among patients with only nonmeasurable lesions (Ph1/2, n=31; ALTA A/B, n=54/n=55), 35% had confirmed complete resolution of lesions in Ph1/2; 7%/18% had confirmed complete resolution in ALTA A/B. For all evaluable patients with baseline brain metastases, median intracranial PFS was 15.6 months in Ph1/2 (n=46) and 15.6/12.8 months in ALTA A/B (n=80/n=73). Most common treatment-emergent adverse events in ALTA in patients with baseline brain metastases (n=151 treated): nausea (A/B, 32%/43%), headache (30%/30%), diarrhea (18%/36%), cough (21%/30%), vomiting (25%/26%); grade ≥3 (excluding neoplasm progression): increased blood CPK (1%/11%), hypertension (4%/7%), increased lipase (3%/3%), pneumonia (1%/4%).
Conclusion:
Brigatinib has demonstrated substantial clinical activity in ALK+ NSCLC patients with brain metastases in both Ph1/2 and ALTA.IRC-Assessed Confirmed Intracranial Response Rates for Patients With Measurable Brain Metastases at Baseline
Any No rad/active[a] Ph1/2[b] n=15 n=9 iORR 8(53) 6(67) iDCR 13(87) 8(89) ALTA[c] Arm A n=26 n=19 iORR 11(42) 8(42) iDCR 22(85) 16(84) Arm B n=18 n=15 iORR 12(67) 11(73) iDCR 15(83) 14(93) Data are n(%) iDCR=intracranial disease control rate iORR=intracranial objective response rate IRC=independent review committee [a]No prior brain radiotherapy (Ph1/2); active (untreated or treated and progressed) brain lesions (ALTA) [b]NCT01449461; last scan date: October 8, 2015 [c]NCT02094573; last scan date: April 14, 2016
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P1.05 - Poster Session with Presenters Present (ID 457)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Early Stage NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 12/05/2016, 14:30 - 15:45, Hall B (Poster Area)
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P1.05-048 - Effect of Adjuvant Chemotherapy on the Patterns and Dynamics of Recurrences in Resected Stage II(N1) Lung Adenocarcinoma (ID 4990)
14:30 - 14:30 | Author(s): M. Ahn
- Abstract
Background:
Although the complete surgical resection in most cases of the non-small cell lung carcinoma with N1 involvement is feasible, a considerable number of patients develop recurrence and the disease course is highly variable. Timing and pattern of recurrence are essential to explain strong prognostic heterogeneity, however, research focusing on these subjects have rarely been reported. We investigated the patterns of recurrences and event rates over time in patients with completely resected N1-stageII lung adenocarcinoma.
Methods:
We retrospectively reviewed the medical records of 333 patients who underwent a complete surgical resection for N1-stage II lung adenocarcinoma. Survival curves were generated using the Kaplan-Meier method, and the event dynamics was estimated using the hazard function.
Results:
The median recurrence-free survival was 36.8 months. The life table survival analysis showed that the 1-year, 3-year and 5-year recurrence free survival rates were 85.1%, 50.2% and 36.6%, respectively. Approximately 151(45.2%) patients experienced recurrence, and the patterns of recurrences included loco-regional in 41 patients (27.2%), distant in 68 (45.0%), and both in 42 (27.8%). Most commonly involved organs were the lung (n=77, 47.0%), followed by lymph nodes (n=41, 27.2%), bone (n=31, 20.5%), and brain (n=30, 19.9%). There were 228 patients received adjuvant chemotherapy. Patients treated with adjuvant chemotherapy showed better recurrence free survival (chemotherapy group vs non-chemotherapy group; median survival 42.5 months vs 25.4 months), and post-recurrence survival(chemotherapy group vs non-chemotherapy group; median survival 39.8 months vs 22.6 months) compared to those of patients without adjuvant chemotherapy. The multivariate analysis revealed that adjuvant chemotherapy was significantly correlated with recurrence free survival (p=0.004) and post recurrence survival (p=0.001). Patients underwent adjuvant chemotherapy had less distant (p=0.014) and less lung (p=0.045) recurrence, while there is no difference in loco-regional (p=0.837) and brain (p=0.997) recurrence. The recurrence hazard curve demonstrated similarly shaped and sized initial and second peak at 16 and 24months, followed by a smaller peak at 40months. The temporal distribution of the recurrence risk varied depending on adjuvant chemotherapy. A visual inspection of the hazard curves suggested that the patients without adjuvant chemotherapy exhibited earlier and higher first peaks with higher hazard rate over time.
Conclusion:
In the patients who underwent completely resected N1-stageII lung adenocarcinoma, adjuvant chemotherapy not only reduced the recurrence hazard, but also delayed the recurrence, altered pattern of recurrence and improved post-recurrence survival.
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P2.02 - Poster Session with Presenters Present (ID 462)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Locally Advanced NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 12/06/2016, 14:30 - 15:45, Hall B (Poster Area)
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P2.02-044 - Impact of N2 Extent and Nodal Response on Survival after Trimodal Treatment for Stage IIIA-N2 Non-Small Cell Lung Cancer (ID 4662)
14:30 - 14:30 | Author(s): M. Ahn
- Abstract
Background:
Mediastinal nodal downstaging is an important prognostic factor of neoadjuvant concurrent chemoradiotherapy (CCRT) for stage IIIA-N2 non-small cell lung cancer (NSCLC) and the role of trimodal treatment remains controversial in patients with persistent N2 disease. We aimed to investigate survival outcomes based on the extent of pre-CCRT nodal involvement and mediastinal nodal response in patients who underwent neoadjuvant CCRT for stage IIIA-N2 NSCLC.
Methods:
A retrospective review of patients with N2 disease who underwent neoadjuvant CCRT followed by surgery at our institution was performed and survival outcomes were compared according to the extent of pre-CCRT mediastinal nodal involvement and mediastinal nodal response to CCRT. Extensive lymph node involvement was defined by short-axis diameter of lymph nodes > 2cm measured at computed tomography or involvement of 2 or more mediastinal lymph node stations.
Results:
From 2003 to 2013, 407 patients underwent curative-intent surgery after neoadjuvant CCRT for NSCLC with pathologically proven N2 disease. The mean age was 59 years (314 men, 77%) and histologic type included adenocarcinoma in 233 patients (57%), squamous cell carcinoma in 141 (35%), and large cell carcinoma in 11 (2.7%). Seventy-nine patients (19%) had extensive N2 disease on pre-CCRT imaging tests. The extent of surgery included lobectomy in 311 patients (76%), pneumonectomy in 43 (11%), and sleeve resection in 15 (3.7%). Post-CCRT pathologic nodal status was ypN0 in 155 patients (38%), ypN1 in 56 (14%), and ypN2 in 196 (48%). With a mean follow-up of 41 months, median overall survival (OS) and recurrence-free survival (RFS) were 73 months and 18 months, respectively. The 5-year OS and RFS rates were 61% and 42% in ypN0-1 and 40% and 13% in ypN2, respectively (OS, p=0.0032; RFS, p<0.0001). For patients with ypN0-1, the 5-year OS and RFS rates were 60% and 52% in extensive N2 disease and 61% and 40% in non-extensive N2 disease, respectively (OS, p=0.8106; RFS, p=0.1218). For patients with ypN2, the 5-year OS and RFS rates were 22% and 12% in extensive N2 disease and 47% and 12% in non-extensive N2 disease, respectively (OS, p=0.0403; RFS, p=0.4842).
Conclusion:
Pre-CCRT non-extensive N2 disease was associated with better OS, but was not with better RFS in patients with persistent N2 disease. Patients who achieved mediastinal downstaging showed acceptable OS and RFS regardless of N2 extensiveness. Considering heterogeneity of N2, the indication of neoadjuvant CCRT needs to be differentiated according to the extent of pre-CCRT nodal involvement and post-CCRT mediastinal nodal response.
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P3.02a - Poster Session with Presenters Present (ID 470)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 12/07/2016, 14:30 - 15:45, Hall B (Poster Area)
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P3.02a-013 - Brigatinib in Crizotinib-Refractory ALK+ NSCLC: Central Assessment and Updates from ALTA, a Pivotal Randomized Phase 2 Trial (ID 4046)
14:30 - 14:30 | Author(s): M. Ahn
- Abstract
Background:
Brigatinib, an investigational next-generation ALK inhibitor, has yielded promising activity in crizotinib-treated ALK+ NSCLC patients in a phase 1/2 trial (NCT01449461). As responses and adverse events (AEs) varied with starting dose, two brigatinib regimens are under evaluation in ALTA (NCT02094573).
Methods:
Patients with crizotinib-refractory advanced ALK+ NSCLC were randomized 1:1 to receive brigatinib at 90 mg qd (arm A) or 180 mg qd with a 7-day lead-in at 90 mg (arm B) and stratified by presence of brain metastases at baseline and best response to prior crizotinib. Primary endpoint was investigator-assessed confirmed ORR per RECIST v1.1.
Results:
222 patients were enrolled (arm A, n=112/arm B, n=110). Median age (A/B) was 51/57 years, 55%/58% were female, 74%/74% previously received chemotherapy, and 71%/67% had brain metastases. As of February 29, 2016, 64/112 (57%) patients in arm A and 76/110 (69%) patients in arm B were receiving brigatinib; median follow-up was 7.8/8.3 months. The Table shows investigator-assessed endpoints by arm and subgroup for select baseline characteristics. Independent review committee–assessed endpoints (A/B, n=112/n=110; as of May 16, 2016): confirmed ORR 48%/53%, median PFS 9.2/15.6 months. Any-grade treatment-emergent AEs (≥25% overall frequency; A/B, n=109/n=110 treated): nausea (33%/40%), diarrhea (19%/38%), headache (28%/27%), cough (18%/34%); grade ≥3 events (excluding neoplasm progression; ≥3% frequency): hypertension (6%/6%), increased blood CPK (3%/9%), pneumonia (3%/5%), increased lipase (4%/3%). A subset of pulmonary AEs with early onset (median onset: Day 2) occurred in 14/219 (6%) treated patients (3%, grade ≥3); 7/14 patients were successfully retreated. No such events occurred after escalation to 180 mg in arm B.
Conclusion:
In each arm, brigatinib yielded substantial responses and prolonged PFS, with an acceptable safety profile. 180 mg with 90 mg lead-in was not associated with increased early pulmonary events and showed a consistent improvement in efficacy, compared with 90 mg, particularly with respect to PFS.Investigator-Assessed Endpoints by Arm and Subgroup
Confirmed ORR, n/N(%) Median PFS, months Arm A B A+B A B A+B All patients 50/112(45) 59/110(54) 109/222(49) 9.2 12.9 11.1 Prior chemotherapy Yes 35/83(42) 44/81(54) 79/164(48) 8.8 12.9 11.8 No 15/29(52) 15/29(52) 30/58(52) 9.2 8.1 9.2 Race Asian 18/39(46) 18/30(60) 36/69(52) 8.8 11.1 11.1 Non-Asian 32/73(44) 41/80(51) 73/153(48) 9.2 12.9 11.8 Brain metastases at baseline Yes 31/80(39) 43/74(58) 74/154(48) 9.2 11.8 11.1 No 19/32(59) 16/36(44) 35/68(51) 7.4 15.6 15.6 Best response to prior crizotinib Partial+complete 36/71(51) 47/73(64) 83/144(58) 11.1 15.6 15.6 Other 14/41(34) 12/37(32) 26/78(33) 7.4 12.9 9.2 ORR=objective response rate PFS=progression-free survival
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P3.02b - Poster Session with Presenters Present (ID 494)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Advanced NSCLC
- Presentations: 3
- Moderators:
- Coordinates: 12/07/2016, 14:30 - 15:45, Hall B (Poster Area)
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P3.02b-053 - A Randomized, Open Label, Phase II Study Comparing Pemetrexed plus Cisplatin versus Pemetrexed Alone in EGFR Mutant NSCLC after EGFR-TKI: QOL Data (ID 5401)
14:30 - 14:30 | Author(s): M. Ahn
- Abstract
Background:
Various therapeutic strategies are available for NSCLC patients who develop disease progression on first-line EGFR-TKI. Platinum doublet is usually recommended, however, it has not been established which cytotoxic regimens are preferable for these patients. We conducted a prospective randomized phase II trial to compare the clinical outcomes between pemetrexed plus ciplatin combination therapy with pemetrexed monotherapy after failure of first-line EGFR-TKI.
Methods:
Patients with non-squamous NSCLC harboring activating EGFR mutation who have progressed on first-line EGFR-TKI were randomly assigned in a ratio of 1:1 to pemetrexed plus cisplatin or pemetrexed alone. Patients were treated with pemetrexed 500 mg/m[2] and cisplatin 70 mg/m[2] for four cycles, followed by maintenance pemetrexed as single agent every 3 weeks or treated with pemetrexed 500 mg/m[2] monotherapy every 3 weeks until progression. Primary objective wasPFS, and secondary objectives include overall response rate (ORR), OS, health-related quality of life (HRQOL), safety and toxicity profile. The HRQOL was assessed every 2 cycles by using EORTC QLQ-C30 and EORTC QLQ-LC13.
Results:
96 patients were randomized and 91 patients were treated at 14 centers in Korea. The characteristics of pemetrexed plus cisplatin (PC) arm (N=48) and pemetrexed alone (P) arm (N=48) were well balanced; the median age was 60 vs. 64 years old; 37 vs. 33 patients were females; 39 vs. 43 patients were ECOG PS 1. The ORR of PC arm (N=46) was 34.8% (16/46), while P arm (N=45) was 17.8% (8/45). With 20.4 (range 4.1-33.4) months of follow-up, the median PFS was 5.4 months (95% confidence interval [CI], 4.5-6.3) in PC arm and 6.4 months (95% CI, 3.6-9.2) in P arm (p=.313). One-year survival rate was 77% for PC arm, 68% for P arm, respectively. The most common adverse events include anorexia (N=34, 37.4%), nausea (N=24, 26.4%), neuropathy (N=10, 11.0%) and skin change (N=10, 11.0%). Adverse events ≥ Grade 3 were in 12 patients (26.1%) in PC arm and 8 patients (17.8%) in P arm. Dose reduction (5 vs. 2 patients) and dose delay (10 vs. 4 patients) were required more often in PC arm. With 385 pairs of questionnaire of EORTC QLQ-C30 and QLO-LC13 obtained from 94 patients, overall, the time trends of HRQOL were not significantly different between two arms. Further analysis of survival data will be updated.
Conclusion:
Pemetrexed plus cisplatin combination therapy showed higher response rate than pemetrexed monotherapy without significant difference in PFS. There was no significant difference in quality of life between two arms.
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P3.02b-078 - Non-Small Cell Lung Cancer with De Novo EGFR T790M Mutation: Clinical Features of 22 Cases (ID 4981)
14:30 - 14:30 | Author(s): M. Ahn
- Abstract
Background:
This study aimed to evaluate the clinical features and outcomes in patients with non-small cell lung cancer (NSCLC) with de novo epidermal growth factor receptor (EGFR) T790M mutation.
Methods:
Specimens of 6,923 NSCLC patients, from March 2009 to May 2016, tested for EGFR mutation were analyzed. EGFR mutation was performed using DNA sequencing or PNA clamp method. The clinical characteristics and the clinical outcome to chemotherapy and EGFR tyrosine kinase inhibitors (TKIs) were reviewed.
Results:
Of the 6,923 NSCLC patients, 1687 (24.4%) had activating EGFR mutations. Among them, 22 patients were found to have de novo EGFR T790M mutation, accounting for 1.3% of all the EGFR mutant cases. All but one had de novo T790M mutation without any activating EGFR mutation. Details of the 22 patients harboring the EGFR T790M mutation are listed in Table 1. The response rate to chemotherapy was 12.5% (best response; 1 PR, 4 SD and 3 PD) and the median time to progression (TTP) was 3.0 months. The response rate to EGFR TKIs treatment was 8.3% (best response; 1 PR, 3 SD and 8 PD), and the median TTP was 2.7 months. Three patients were treated with third generation EGFR TKIs (osimertinib or ASP 8237) and all achieved partial response (TTP; 33.3, 13.6 and 3.5 months, respectively).
Conclusion:
De novo EGFR T790M mutation is a rare event even in EGFR mutant NSCLC and associated with unfavorable clinical outcome to chemotherapy and EGFR TKIs.
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P3.02b-096 - Osimertinib (AZD9291) in Asia-Pacific Patients with T790M Mutation-Positive Advanced NSCLC: Open-Label Phase II Study Results (ID 4282)
14:30 - 14:30 | Author(s): M. Ahn
- Abstract
Background:
Osimertinib (AZD9291) is an oral, potent, irreversible EGFR-TKI, selective for both EGFR-sensitizing (EGFRm) and T790M resistance mutations. Following positive outcomes from recent Phase I and II trials, osimertinib is now recommended for patients with EGFR T790M mutation-positive advanced non-small cell lung cancer (aNSCLC).
Methods:
AURA17 (NCT02442349) is an open-label, single arm, Phase II study investigating the efficacy and safety of osimertinib in an Asia-Pacific patient population with EGFRm T790M mutation-positive locally advanced or metastatic NSCLC, who had progressed following EGFR-TKI therapy or EGFR-TKI and chemotherapy. T790M-positive status was confirmed via central testing of biopsy samples using the cobas[®] EGFR Mutation Test. Inclusion required measureable disease, performance status (PS) 0/1, and acceptable organ function; asymptomatic brain metastases were allowed. Patients received osimertinib 80 mg once daily until disease progression. The primary endpoint was objective response rate (ORR) according to RECIST 1.1 (by blinded independent central review, BICR). Secondary objectives included disease control rate (DCR), duration of response (DoR), progression-free survival (PFS), overall survival, and safety and tolerability.
Results:
As of 4 March 2016 data cut-off, 171 patients were enrolled, with 166 evaluable for response: median age, 60.0 years; female, 69%; Asian, 98%; never smokers, 78%; PS 0/1, 15%/85%; EGFR Exon 19 and L858R mutations, 64% and 34% patients, respectively; second-/≥third-line, 32%/68%; median treatment exposure, 5.6 months. Confirmed ORR and DCR (95% CI) by BICR were 60% (52, 68) and 88% (82, 92), respectively. DoR and PFS are not calculable as data is immature. Causally-related adverse events (AEs) grade ≥3 were reported in eight (5%) patients. AEs leading to dose interruption or dose reduction occurred in seven (4%) and two (1%) patients, respectively. Six (4%) patients discontinued treatment due to AEs, two (1%) causally-related AEs as assessed by investigator. The most commonly reported AEs (%, [grade ≥3]) were diarrhoea (29%, [0]), rashes and acnes (grouped terms) (20%, [0]), and dry skin (grouped terms) (17%, [1%]). Interstitial lung disease-like events were reported in three (2%) patients.
Conclusion:
AURA17 demonstrated clinical efficacy of osimertinib in Asia-Pacific patients with EGFR T790M mutation-positive aNSCLC, with an ORR of 60% and DCR of 88% that are comparable to global Phase II trials. Osimertinib was well tolerated, with a low frequency of AEs grade ≥3. No new safety signals were seen and the pattern of AEs was consistent with global studies
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P3.02c - Poster Session with Presenters Present (ID 472)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 12/07/2016, 14:30 - 15:45, Hall B (Poster Area)
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P3.02c-035 - Comparison of RECIST to Immune-Related Response Criteria (irRC) in Patients with NSCLC Treated with Immune-Check Point Inhibitor (ID 4962)
14:30 - 14:30 | Author(s): M. Ahn
- Abstract
Background:
Immune check point inhibitor has become essential therapeutic option for advanced non-small cell lung cancer (NSCLC). Immune-related response in NSCLC has not been well evaluated, thus we assessed the tumor response using Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST v1.1) and immune-related response criteria (irRC) to identify atypical response in patients with advanced NSCLC treated with immunotherapeutic agents.
Methods:
Patients received immune check point inhibitors (pembrolizumab, atezolizumab, nivolumab, pembrolizumab plus tremelimumab) at Samsung Medical Center between July 2014 and October 2015. The tumor response was assessed according to both RECIST v1.1 and irRC. Pseudoprogression was defined as progressive disease at any time of assessment and not at next assessment per RECIST v1.1 or irRC.
Results:
Figure 1 Total 41 patients were analyzed, most of patients (80.5%) received anti-PD-1 agents (pembrolizumab or nivolumab) and 6 patients were treated with anti-PD-L1, atezolizumab, 2 patients received combination treatment with pembrolizumab and tremelimumab. Two patients showed pseudoprogression followed by regression per RECIST v1.1 not per irRC. 4 patients with progressive disease per RECIST v1.1 were partial response per irRC, objective response was 29.2% per RECIST v1.1 and 34.1% per irRC, respectively. There was no significant difference in response rate between two methods (p=0.923). The median duration of follow-up was 19.8 months, and the median progression-free survival of all patients was 4.5 months (95% CI 2.7-6.3)
Conclusion:
These results suggest that pseuoprogression is not frequently observed in NSCLC, and conventional RECIST v1.1 might underestimate the benefit of immune check point inhibitors. Given the small number of patients studied and short-term follow-up, further study will be warranted whether treatment with immune checkpoint inhibitor beyond RECIST progression can be benefit to patient with advanced NSCLC.
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PL03 - Presidential Symposium (ID 428)
- Event: WCLC 2016
- Type: Plenary
- Track:
- Presentations: 1
- Moderators:D.P. Carbone, R. Pirker
- Coordinates: 12/06/2016, 08:35 - 10:25, Hall D (Plenary Hall)
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PL03.03 - Randomised Phase III Study of Osimertinib vs Platinum-Pemetrexed for EGFR T790M-Positive Advanced NSCLC (AURA3) (Abstract under Embargo until December 6, 7:00 CET) (ID 4452)
09:05 - 09:15 | Author(s): M. Ahn
- Abstract
- Presentation
Background:
Osimertinib is a potent, irreversible, CNS active, epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) selective for sensitising (EGFRm) and T790M resistance mutations. Osimertinib is indicated for the treatment of patients with locally advanced or metastatic EGFR T790M-positive NSCLC. AURA3 (NCT02151981) is a Phase III, open-label, randomised study assessing the efficacy and safety of osimertinib versus platinum-based chemotherapy plus pemetrexed in patients with EGFR T790M-positive advanced NSCLC, whose tumours progressed on first-line EGFR-TKI therapy.
Methods:
Eligible patients were ≥18 years with documented EGFRm, radiological disease progression following first-line EGFR-TKI and centrally confirmed T790M-positive (by cobas® EGFR Mutation Test) from a tissue biopsy after disease progression. Asymptomatic, stable CNS metastases were allowed. Patients were randomised 2:1 to osimertinib 80 mg orally, once daily or platinum-pemetrexed (pemetrexed 500 mg/m[2] plus either cisplatin 75 mg/m[2] or carboplatin AUC5) every three weeks for up to six cycles; pemetrexed could be continued as maintenance treatment. Primary endpoint was progression-free survival (PFS) by investigator assessment according to RECIST v1.1; sensitivity analysis was by blinded independent central review (BICR).
Results:
A total of 419 patients were randomised to treatment (osimertinib, n=279; platinum-pemetrexed, n=140). Baseline characteristics were generally balanced across treatment groups: female 64%, Asian 65%, never smoker 68%, CNS metastases 34%, EGFR exon 19 deletion 66%. Osimertinib significantly improved PFS compared with platinum-pemetrexed: hazard ratio [HR] 0.30; 95% CI: 0.23, 0.41; p<0.001 (median 10.1 months vs 4.4 months). The result was consistent with PFS analysis by BICR: HR 0.28; 95% CI: 0.20, 0.38; p<0.001 (11.0 months vs 4.2 months). Objective response rate was significantly improved with osimertinib (71%) vs platinum-pemetrexed (31%); odds ratio 5.39 (95% CI: 3.47, 8.48; p<0.001). Median duration of response was 9.7 months (95% CI 8.3, 11.6) with osimertinib and 4.1 months (95% CI 3.0, 5.6) with platinum-pemetrexed. Grade ≥3 causally-related adverse events (AEs) as assessed by the investigator were reported in 6% of patients (n=16) treated with osimertinib and 34% (n=46) treated with platinum-pemetrexed. Most common causally-related AEs in the osimertinib group: diarrhoea (29% [grade ≥3, 1%]), rash (28% [<1%]); in the platinum-pemetrexed group: nausea (47% [3%]), decreased appetite (32% [3%]).
Conclusion:
In patients with EGFR T790M-positive advanced NSCLC following progression on EGFR-TKI treatment, osimertinib demonstrated a superior clinically-meaningful efficacy over platinum-pemetrexed, with a 70% reduction in the risk of disease progression, and well-characterised safety profile, establishing the new standard of care for these patients.
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