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S.S. Ramalingam
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MA08 - Treatment Monitoring in Advanced NSCLC (ID 386)
- Event: WCLC 2016
- Type: Mini Oral Session
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:R. Perez-Soler, T. Reungwetwattana
- Coordinates: 12/06/2016, 11:00 - 12:30, Lehar 3-4
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MA08.03 - Osimertinib vs Platinum-Pemetrexed for T790M-Mutation Positive Advanced NSCLC (AURA3): Plasma ctDNA Analysis (ID 4733)
11:12 - 11:18 | Author(s): S.S. Ramalingam
- Abstract
- Presentation
Background:
AURA3 (NCT02151981) is a Phase III, open-label, randomised study assessing the efficacy and safety of osimertinib, a T790M directed EGFR-TKI, vs platinum-based doublet chemotherapy in patients with EGFR T790M-positive advanced NSCLC, whose tumours progressed on previous EGFR-TKI therapy. Concordance between plasma and tissue testing, and efficacy outcomes by baseline plasma T790M status, were evaluated.
Methods:
Eligible patients were randomised 2:1 to osimertinib 80 mg orally once daily or platinum-pemetrexed (pemetrexed 500 mg/m2 + cisplatin 75 mg/m2 or carboplatin AUC5) every three weeks for up to six cycles. Patients were tumour tissue T790M-positive (by cobas[®] EGFR Mutation Test v2) from a biopsy after disease progression prior to study entry. Blood samples were taken at baseline for retrospective analysis of T790M mutation status by plasma ctDNA using the cobas[®] EGFR Mutation Test v2.
Results:
Concordance data are reported in the table. Within the intent-to-treat (ITT) population (n=419), patients plasma T790M-positive and randomised to treatment (n=172) had markedly improved progression-free survival (PFS) by investigator assessment (IA) with osimertinib vs platinum-pemetrexed: hazard ratio 0.42 (95% CI: 0.29, 0.61); median 8.2 vs 4.2 months. Objective response rate (ORR) by IA was also distinctly improved with osimertinib vs platinum-pemetrexed: 77% vs 39% (odds ratio 4.96 [95% CI: 2.49, 10.15]; p<0.001). This is consistent with the ITT population: PFS hazard ratio 0.30 (95% CI: 0.23, 0.41); p<0.001 (median 10.1 vs 4.4 months); ORR 71% vs 31% (odds ratio 5.39 [95% CI: 3.47, 8.48]; p<0.001). Figure 1
Conclusion:
In plasma T790M-positive patients the clinical benefit of osimertinib was superior to platinum-pemetrexed, consistent with the ITT T790M-positive population selected by tumour tissue test. PFS with osimertinib was similar regardless of selection by tissue or plasma T790M-positive status. Based on these, and AURA Phase II data, routine biopsy testing is recommended for patients with a plasma T790M-negative test where feasible.
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OA03 - Immunotherapy Checkpoint Inhibitors in Advanced NSCLC (ID 367)
- Event: WCLC 2016
- Type: Oral Session
- Track: Chemotherapy/Targeted Therapy/Immunotherapy
- Presentations: 1
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OA03.06 - Evaluation of Toxicity Profile of PD-1 versus PD-L1 Inhibitors in Non-Small Cell Lung Cancer (NSCLC) (ID 6073)
11:55 - 12:05 | Author(s): S.S. Ramalingam
- Abstract
- Presentation
Background:
Monoclonal antibodies against Programmed Death 1 (PD-1) and Programmed Death Ligand 1 (PD-L1) have emerged as effective therapies in NSCLC. We updated our initial systematic review of trials investigating differences in the toxicities of PD-1 and PD-L1 inhibitors.
Methods:
An electronic literature search was performed of public databases (MEDLINE, EMBASE) and conference proceedings for trials utilizing PD-1 inhibitors (nivolumab, pembrolizumab) and PD-L1 inhibitors (atezolizumab, durvalumab, avelumab) in NSCLC patients. Studies that did not report toxicities were excluded. A formal meta-analysis was conducted with Comprehensive Meta-Analysis software (Version 2.2). Clinical and demographic characteristics, response, and toxicity data were compared between the two groups.
Results:
Twenty-two studies reported between 2013-2016 were eligible for this analysis. The total number of patients evaluated for toxicities were 2,863 patients in the PD-1 group and 2,006 patients in the PD-L1 group. Patient characteristics % (PD-1/PD-L1): median age 64/65, male 58/56, smokers 82/83, squamous histology 25/32, performance status 0-1 98/100. There was no difference in response rate between PD-1 (17%) and PD-L1 (18%) inhibitors, p=0.3. The incidence of overall adverse events (AEs), immune related AEs, and pneumonitis trended in favor of the PD-L1 group but did not reach statistical significance (see table). Figure 1
Conclusion:
In this updated systematic review involving 4,869 patients, the toxicity profiles of PD-1 and PD-L1 inhibitors in NSCLC patients are not significantly different.
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OA04 - Epidemiology and Prevention of Lung Cancer (ID 370)
- Event: WCLC 2016
- Type: Oral Session
- Track: Epidemiology/Tobacco Control and Cessation/Prevention
- Presentations: 1
- Moderators:L. Petruželka, S. Shastri
- Coordinates: 12/05/2016, 11:00 - 12:30, Schubert 4
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OA04.02 - Smoking Behavior in Patients with Early Stage Non-Small Cell Lung Cancer: A Report from ECOG-ACRIN 1505 Trial (ID 5385)
11:10 - 11:20 | Author(s): S.S. Ramalingam
- Abstract
- Presentation
Background:
Approximately 85% of lung cancer is related to cigarette smoking. Smoking cessation has been reported to benefit patients even after the diagnosis of lung cancer. We studied the smoking behavior of patients with lung cancer in a phase 3 study for early stage lung cancer.
Methods:
The ECOG-ACRIN 1505 study enrolled patients with stages IB, II and IIIA non-small cell lung cancer (NSCLC) after they had undergone surgical resection. It was designed to evaluate whether the addition of bevacizumab would improve survival relative to cisplatin-based chemotherapy alone. Studying the correlation between smoking status and outcome was a secondary endpoint. Patients completed a questionnaire about their smoking habits at baseline, 3, 6, 9 and 12 months after study entry.
Results:
Out of 1501 patients enrolled, 99%, 90%, 85%, 82% and 80% responded to the questionnaire at baseline, 3, 6, 9 and 12 months respectively. Nearly 90% reported having smoking during their lifetime. At study entry, 12% reported ongoing smoking. The median age patients started smoking was 17 years and the median age at which they quit smoking was 55 years. The median number of cigarettes smoked per day was 20. Approximately 4% smoked cigars (median number 2/day). Of the 40% that reported smoking after the diagnosis of lung cancer, only 15% reported smoking at 12 months. At 12 months after study entry, among those who continued to smoke, 79% reported smoking fewer cigarettes/day, whereas 11% smoked more cigarettes. When asked about the number of cigarettes smoked at 12 mos, 63% reported smoking fewer than 10 cigarettes/day. The incidence of grades 3-5 toxicity was 76% in smokers versus 69% in non-smokers (p=0.06). There were no differences in dose reductions for chemotherapy (P=0.55) or bevacizumab (P=0.90) between smokers and non-smokers. The median number of chemotherapy cycles were nearly identical for smokers and never-smokers. The disease-free survival (DFS) and OS for smokers relative to never-smokers were 0.97 (P=0.83) and 1.54 (P=0.01) respectively.
Conclusion:
This is the first comprehensive, prospective report of smoking habits of patients with lung cancer. There were a high rate of smoking cessation and reduction in number of cigarettes smoked, that was maintained at 12m after study entry. Toxicity and DFS did not differ significantly between smokers and never-smokers, though overall survival was more favorable with the never-smokers. Study was coordinated by ECOG-ACRIN (Robert L. Comis, M.D., Chair) and supported in part by Public Health Service Grants CA180820, CA180888, CA180821, & CA180863.
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P1.01 - Poster Session with Presenters Present (ID 453)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Epidemiology/Tobacco Control and Cessation/Prevention
- Presentations: 1
- Moderators:
- Coordinates: 12/05/2016, 14:30 - 15:45, Hall B (Poster Area)
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P1.01-035 - Trends, Patterns of Treatment and Outcomes in Non-Small Cell Lung Cancer (NSCLC) as a Second Primary: A National Cancer Data Base (NCDB) Analysis (ID 6185)
14:30 - 14:30 | Author(s): S.S. Ramalingam
- Abstract
Background:
The prevalence of NSCLC as a second primary tumor has been increasing over the past decades, though very little data are available in the literature. We analyzed the NCDB, an oncology outcomes database administered by the American College of Surgeons and the American Cancer Society, to study the outcomes and patterns of treatment of patients (pts) diagnosed with NSCLC as a second or subsequent primary (SP).
Methods:
The NCDB was queried from 2004 to 2012 for NSCLC pts. Pts diagnosed with NSCLC as SP were compared with pts with de novo (DN) NSCLC as defined by sequence number in the database. Univariate (UV) and multivariable analyses (MV) with overall survival (OS) were conducted by Cox proportional hazards model. Kaplan-Meier plots were produced to compare the survival curves by subgroups along with log-rank p-values.
Results:
A total of 207,518 pts in SP and 697,709 pts in DN groups were included in the analysis, which accounted for 22% and 74% of all NSCLC pts respectively. Pt characteristics (SP/DN %): median age 72/68, male 53/53, white 89/84, stage IV 28/41, treated at academic centers 33/32, government insured 72/57, mean tumor size (cm) 3.5/4.4. An increasing trend in incidence of SP was observed (19.5% in 2004 to 24% in 2012) vs. a decreasing trend in DN (75.6% in 2004 to 73% in 2012). About 12% in SP and 15% in DN received chemotherapy as part of their treatment. Surgery was performed in 39% of SP group vs. 28% in DN. Radiation was given to 43% of the pts in DN vs. 36% in SP. On UV and MV analysis, SP was associated with better survival than DN (HRs 0.84 and 0.93 respectively; p<0.001). The SP group had higher 5-year OS (23% vs. 19.6%, p<0.001) and a higher median survival (17 vs. 11.5 months) compared to DN. On stratifying by stage, DN had inferior survival in stage IV pts (HR 1.12, p<0.001) compared to SP but better survival in stage I and II pts (HRs 0.86 and 0.93, p<0.001). No difference in OS was seen in stage III pts (HR 1.01, p= 0.4).
Conclusion:
The incidence of second primary has increased over the past decade. Second primary NSCLC is diagnosed at an earlier stage, smaller tumor size, and is associated with a better survival, compared to de novo NSCLC.
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P1.07 - Poster Session with Presenters Present (ID 459)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: SCLC/Neuroendocrine Tumors
- Presentations: 1
- Moderators:
- Coordinates: 12/05/2016, 14:30 - 15:45, Hall B (Poster Area)
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P1.07-014 - Impact of Chemotherapy for Small Cell Lung Cancer in the Third Line and beyond, a SEER-MEDICARE Analysis (ID 4758)
14:30 - 14:30 | Author(s): S.S. Ramalingam
- Abstract
Background:
While there is no approved third line chemotherapy option for small cell lung cancer (SCLC), empiric use of chemotherapy is common in this setting in the absence of supporting prospective data. In order to assess the potential benefit and predictors of chemotherapy use beyond the second line setting in SCLC, we analyzed the SEER-MEDICARE database.
Methods:
We employed data of SCLC patients diagnosed between 1985 and 2005. Univariate (UVA) association of line of chemotherapies with covariates was examined with Wilcoxon rank-sum test, chi-square or Fisher’s exact test. Multivariable (MVA) logistic regression analysis for line of therapy was conducted using the following covariates: year of diagnosis, age, gender, race, Medicare status, urban/rural location, and radiation. Survival functions were estimated by the Kaplan-Meier method and the log-rank test was used to assess for difference in overall survival (OS) stratified by line of therapy. UVA and MVA survival analyses were carried out using the Cox proportional hazards model. To further balance confounders between patients receiving different lines of therapy, propensity scores were estimated using a MVA logistic regression model to predict the receipt of 3[rd] line chemotherapy based on relevant covariates. Propensity score analysis was further conducted by including the estimated propensity score as a covariate in a Cox proportional hazards model. All analyses were done using SAS 9.3 with two-sided tests and a significant level of 0.05.
Results:
There were 47,351 patients with SCLC of which 23,535 (49.7 %) received chemotherapy and 10,887 (23%) received platinum-based chemotherapy. Of the platinum-treated patients, 1424 (13.1%) received additional salvage therapy of either topotecan alone (n=801) or topotecan and additional treatments as 3[rd] line and beyond (n=623). The median OS was 11, 13, 15 and 17 months respectively for patients treated with one, two, three or > 3 lines of chemotherapy respectively. Propensity score analysis showed additional lines of therapy beyond the second line was associated with a reduced risk of death (HR: 0.786; 0.729 - 0.847, p<0.001 and 0.617; 0.564 - 0.675; p<0.001 for 3[rd] line and > 3 lines of therapy respectively). Age (p=0.043) and year of diagnosis (P<0.001) were significantly associated with treatment beyond 2[nd] line topotecan on MVA analysis.
Conclusion:
Salvage chemotherapy is not commonly used following failure of platinum containing chemotherapy in SCLC patients. However, chemotherapy beyond the second line was associated with an incremental survival benefit in US MEDICARE-eligible SCLC patients.
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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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P2.02-015 - Guideline Concordant Care is Associated with Better Survival for Patients with Stage III Non-Small Cell Lung Cancer (ID 5103)
14:30 - 14:30 | Author(s): S.S. Ramalingam
- Abstract
Background:
Current evidence-based guideline-concordant care (GCC) is administration of platinum-based chemotherapy during thoracic radiotherapy (TRT) for locally advanced non-small cell lung cancer (NSCLC) patients with good performance status. This study evaluates factors associated with lack of GCC.
Methods:
Patients (pts) with unresected stage IIIA/IIIB NSCLC diagnosed from 2005 – 2013 and Charlson-Deyo Score 0 were identified from the National Cancer Data Base (NCDB). Primary outcomes measured were receipt of GCC, defined by administration of chemotherapy with TRT commencing within 2 weeks of each other and minimum TRT dose of 60 Gy, and overall survival (OS). Multivariable logistic regression (MLR) modeling was performed to identify variables associated with non-GCC. Cox proportional hazard modeling was utilized to examine OS.
Results:
Patient characteristics (n=37,809) included: mean age 67.8 years; 55% male; 13% African American; 3.4% Hispanic, 3.6% ‘other’ race/ethnicity; 66% government-insured; mean tumor size 5.0 cm; 38% adenocarcinoma; 32% squamous cell carcinoma (SCC); 30% large cell/other histology. In total, 28% of pts received GCC. On MLR analysis, Hispanic pts were more likely to receive non-GCC (OR=1.34, p <0.001) compared to non-Hispanic pts. Uninsured pts were more likely to receive non-GCC (OR=1.57, p<0.001) compared to privately-insured pts. Patients treated in the western, southern, or northeastern U.S. were more likely to receive non-GCC (OR= 1.43, 1.45, 1.21, all p values <0.001) compared to pts treated in the Midwest. Adenocarcinoma and large-cell/other histological types were more likely to receive non-GCC (OR= 1.71, 1.39, both p<0.001) compared to SCC. For every one-year increase in age or 50-mile increase in distance to treatment facility, patients had a 4% or 3% increased odds of not receiving GCC (OR=1.04, 1.03; p<0.001, p = 0.003, respectively). On hazard modeling, those receiving non-GCC had higher death rates compared to those receiving GCC (HR=1.42, p<0.001). Survival rates were lower for Hispanics receiving non-GCC versus GCC (HR=1.24, p=0.034). Other groups with lower OS for non-GCC versus GCC included: the uninsured (HR=1.61, p<0.001), treatment in the western, southern, or northeastern US (HRs= 1.56, 1.40, 1.33, respectively, p<0.001), adenocarcinomas and large cell/other histologies (both HR=1.40, p<0.001).
Conclusion:
Socioeconomic factors, including Hispanic ethnicity, lack of insurance, geographic location, and distance from treatment facility are associated with receipt of non-GCC. Patient and disease specific factors including increasing age and adenocarcinoma histology are also associated with non-GCC. Future interventions could target these groups to improve provision of GCC.
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P2.03a - Poster Session with Presenters Present (ID 464)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 12/06/2016, 14:30 - 15:45, Hall B (Poster Area)
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P2.03a-055 - Predicting Risk of Chemotherapy-Induced Severe Neutropenia in Lung Patients: A Pooled Analysis of US Cooperative Group Trials (ID 3975)
14:30 - 14:30 | Author(s): S.S. Ramalingam
- Abstract
Background:
Neutropenia is the most serious hematologic toxicity associated with the use of chemotherapy. Severe neutropenia (SN) may result in dose delays and/or reductions, and the use of growth colony stimulating factors (CSFs) increases the cost of therapy. Lyman et al. (2011) published a risk model to predict individual risk of neutropenia in patients receiving chemotherapy for multiple types of cancer. The Lyman model (LM) has not been validated by external datasets. We investigated the LM with a large external lung cancer dataset based on clinical criteria of SN and investigated new risk prediction models for SN.
Methods:
Stage IIIA/IIIB/IV non-small cell lung cancer (NSCLC) and extensive small cell lung cancer (SCLC) chemotherapy phase II/III trials completed in 1990-2012 were assembled from U.S. cancer cooperative groups. SN was defined as any neutropenic complications grade ≥ 3 according to CTCAE. A risk score was calculated as a weighted sum of regression coefficients of the LM for all patients in the database. The performance of risk models was evaluated by the area under the ROC curve (AUC) with a good model defined as AUC ≥ 0.7. To develop new risk models, a random split was used to divide the database into training cohort (2/3) and testing cohort (1/3). Multivariable logistic regression models with stepwise selection and lasso selection (Tibshirani, 1996) were built in training cohort and validated in testing cohort. Candidate predictors included patient-level and treatment-level variables. The patients with complete data were used for validation and all patients, including those with imputed predictors, were used to develop new risk models.
Results:
Eighty seven trials with 14,829 patients were included. The LM had a good performance in SCLC patients (AUC=0.86), but it had poor performance in NSCLC patients (AUC=0.47), and an overall unsatisfactory performance in all patients (AUC=0.56). The stepwise model had superior performance than the lasso model (AUC: 0.84 vs. 0.76) in training, while the lasso model had smaller shrinkage in testing. A parsimonious model, based on histology, prior chemo, platinum-based, taxanes, gemcitabine, CSFs, age as continuous variable, relative dose intensity, and white blood cell (WBC), performed slightly worse (AUC=0.71) in testing than the stepwise model and the lasso model.
Conclusion:
The U.S. cooperative group data failed to validate the LM in predicting the risk for severe neutropenia in lung cancer patients receiving chemotherapy. The parsimonious model involving nine predictors showed good performance in predicting severe neutropenia. Prospective validation is warranted.
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P2.03b - Poster Session with Presenters Present (ID 465)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 12/06/2016, 14:30 - 15:45, Hall B (Poster Area)
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P2.03b-048 - Access to Biomarker Testing in Patients with Advanced Non-Small Cell Lung Cancer (ID 4461)
14:30 - 14:30 | Author(s): S.S. Ramalingam
- Abstract
Background:
Access to biomarker testing is critical for selecting appropriate treatment for patients with advanced non-small cell lung cancer (aNSCLC). This study assessed rates and patterns of biomarker testing among patients with aNSCLC.
Methods:
Patients aged ≥65 years diagnosed with aNSCLC between 2007-2011 were identified in the SEER-Medicare database and were followed for ≥4 months post-diagnosis (n = 9,651). Patients’ first biopsy within ±8 weeks of diagnosis was defined as the index date. Biomarker tests included procedure codes for gene analyses to test for EGFR, ALK, and other mutations. IHC tests, which are mostly used for diagnosis, were excluded. The use of biomarker tests was assessed from the index date until the end of data availability (12/31/2013) or end of Medicare Parts A, B and D eligibility. Analyses were replicated in the subgroup with cancer stages IIIB-T4 or IV and adenocarcinoma, adenosquamous or unknown type of NSCLC histology (n = 6,193).
Results:
Of 9,651 patients observed for a median of 11 months, 18% had a biomarker test during the follow-up. The use of biomarker testing increased from 5% in 2007 to 35% in 2011, and was higher among patients who saw a cancer specialist as compared to those who did not see a cancer specialist. When comparing the patients with and without a biomarker test diagnosed in 2011 (i.e., the most recent year in the data) in the full study sample, a higher proportion of patients without a biomarker test were males (51 vs 43%), non-Hispanic Blacks (13 vs 5%), resided in areas with higher poverty (27 vs 15%) and lower education levels (26 vs 17%), and had larger tumors at diagnosis (median 41 vs 38 mm; p <.05 for all). In addition, a lower proportion of them were married (44 vs. 52%), resided in big metropolitan areas (51 vs 57%), had stage IV cancer (64 vs 69%), and adenocarcinoma histology at diagnosis (43 vs. 77%; p <.05 for all). Among tested, >40% of the patients had their first biomarker test >8 weeks after biopsy. Results were similar in the subgroup, but the rate of biomarker testing was slightly higher and with slightly shorter delays.
Conclusion:
Among patients with aNSCLC diagnosed in 2007-2011 a substantial proportion did not undergo biomarker testing or had their biomarker test delayed by >8 weeks post-biopsy. Significant differences exist in demographic and cancer characteristics between patients with and without a biomarker test.
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P3.02b - Poster Session with Presenters Present (ID 494)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Advanced NSCLC
- Presentations: 2
- Moderators:
- Coordinates: 12/07/2016, 14:30 - 15:45, Hall B (Poster Area)
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P3.02b-049 - EGFR-Mutated NSCLC: Clinical Practice Assessment and Gap Analysis (ID 4707)
14:30 - 14:30 | Author(s): S.S. Ramalingam
- Abstract
Background:
For patients with advanced NSCLC, mutations in the epidermal growth factor receptor (EGFR) gene predict sensitivity to EGFR tyrosine kinase inhibitors (TKIs). Consequently, EGFR TKIs in both the first and second line (for T790M +ve) are now considered the standard of care. This study’s objective was to assess current clinical practices of oncologists and pathologists in the management of EGFR-mutated NSCLC to identify knowledge, competency, and practice gaps and barriers to improving patient care.
Methods:
An educational needs assessment consisting of 25 questions was developed. The assessment design included case vignettes and knowledge- and case -based, questions based on evidence-based consensus guidelines. The assessment was made available online to healthcare providers without monetary compensation or charge. Confidentiality of survey respondents was maintained and responses were de-identified and aggregated prior to analyses. The assessment launched on February 26, 2016, and responses were collected through June 10, 2016.
Results:
In total, 226 US physicians responded to the survey. Respondents were most likely to be oncologists. Practice setting was almost evenly divided between academic and community. . Knowledge gaps: 40% of oncologists and 52% of pathologists were unable to correctly identify the IASLC guideline recommendations on molecular profiling while 45% of oncologists and 54% of pathologists could not identify the efficacy of approved first line EGFR TKIs. Confidence gaps: Less than 10% of oncologists and pathologists are very confident in their understanding of liquid biopsies. In addition, only 23% of oncologists were very confident in their ability to individualize first line treatment. Performance gaps: Between 43%-60% of oncologists and pathologists incorrectly indicted they would prescribe first line therapy for a patient with an activating EGFR mutation. Despite an available therapy for patients with an identified T790M mutation, 41%-72% oncologists and pathologists indicated they would not undertake a biopsy in a patient with EGFR-mutated NSCLC that had progressed on a first line EGFR TKI and only 12% of oncologists noted that they always test to determine the mechanism of resistance. One-third of oncologists indicated would not select the most appropriate treatment option for a patient whose disease progressed on first line EGFR TKI therapy and whose tumor did not contain a T790M mutation.
Conclusion:
This assessment of clinical practices provided insights into gaps in the knowledge, competency and practices regarding molecular testing and management of EGFR-mutated NSCLC. Focused educational efforts are urgently needed to inform the practicing physicians on recent advances in targeted therapy for advanced NSCLC.
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P3.02b-103 - Identification of On-Target Mechanisms of Resistance to EGFR Inhibitors Using ctDNA Next-Generation Sequencing (ID 5645)
14:30 - 14:30 | Author(s): S.S. Ramalingam
- Abstract
Background:
Osimertinib (OSM) is a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) recently approved for use in EGFR T790M-positive non-small cell lung cancer (NSCLC) with a 65-70% response rate. However, patients invariably develop resistance to OSM, in ~30% of cases due to an acquired EGFR C797S mutation. Understanding additional, non-C797S resistance mechanisms will be critical to developing new therapeutic approaches. Here, we describe a case of T790M-positive NSCLC with progression on OSM, genotyped using cell-free circulating tumor DNA (ctDNA) next-generation sequencing (NGS).
Methods:
A 68-year-old male with EGFR L858R-mutant metastatic NSCLC whose disease progressed despite multiple lines of EGFR inhibitors (erlotinib, afatinib, cetuximab/afatinib) and chemotherapy was found to be T790M-positive, and initiated on OSM. Initial restaging scans demonstrated response. On disease progression 7 months later, ctDNA testing was performed with a highly sensitive and ultra-specific 70-gene NGS panel (Guardant360™) that includes all EGFR exons and reports on all EGFR single nucleotide variants, indels, and amplification.
Results:
Twelve somatic alterations were identified, including 7 mutations in EGFR. The original L858R driver mutation was present at a mutant allele fraction (MAF) of 16.9%, and T790M at MAF of 8.4%. C797S was detected at MAF of 4.6%. Four additional subclonal TK domain mutations were identified: L792H (1.4%), L718Q (0.7%), F795C (0.4%) and L792F (0.1%). Mutations within sufficient genomic proximity were phased to determine allelic origin, and a presumptive evolutionary history was constructed. T790M and C797S were in cis, and the F795C mutation arose on that allele. L792H and L792F were in cis to T790M, but arose independently from each other and from C797S. Review of the Guardant Health database, which includes 5,609 NSCLC samples, identified 1,228 samples with EGFR activating mutations L858R and exon 19 deletion. Of these, 341 (28%) had T790M, of which 17 (5%) carried C797S. Sixteen of 17 C797S mutations were in cis with T790M, and 1 in trans. There were 3 additional cases with L718 mutation and 1 with L792.
Conclusion:
Deep sequencing of ctDNA can reveal the global landscape and evolution of resistance mutations within a patient’s tumor. The T790M and C797S mutations were predominantly in cis configuration, underscoring the importance of developing new EGFR TKIs. The role of mutations L792H, L792F, and F795C is currently unknown. These mutations impinge on the ATP-binding pocket, which could be a potential structural resistance mechanism. Further studies are needed to validate and functionally characterize these candidate resistance mutations.
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PL03 - Presidential Symposium (ID 428)
- Event: WCLC 2016
- Type: Plenary
- Track:
- Presentations: 2
- 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): S.S. Ramalingam
- 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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PL03.09 - Phase 3 Study of Ganetespib, a Heat Shock Protein 90 Inhibitor, with Docetaxel versus Docetaxel in Advanced Non-Small Cell Lung Cancer (GALAXY-2) (Abstract under Embargo until December 6, 7:00 CET) (ID 5232)
10:05 - 10:15 | Author(s): S.S. Ramalingam
- Abstract
- Presentation
Background:
Heat shock protein 90 functions as a chaperone to stabilize oncoproteins. Ganetespib (G), a highly potent Hsp90 inhibitor, has demonstrated efficacy in combination with docetaxel (D) over D alone in the second-line therapy of patients with advanced adenocarcinoma of the lung in a phase 2 study.
Methods:
GALAXY-2 is a randomized (1:1), international, open-label study of D with or without G. Patients with advanced (stage IIIB/IV) non-small cell lung cancer (NSCLC) of adenocarcinoma histology, EGFR and ALK wild-type, diagnosed ≥ 6 months prior to study entry, one prior systemic therapy and ECOG PS 0-1 were eligible. D was given at 75 mg/m[2] on day 1 of three-week cycle; D was given on day 1 with G at 150 mg/m[2 ]on Days 1 and 15 of each cycle. Patients were stratified by performance status (PS), LDH, and geographic region. Primary endpoint was overall survival (OS). Secondary endpoints included progression free survival (PFS) and OS in elevated LDH (eLDH) patients. We report the results of a planned interim analysis at 336 events, which occurred on October 5, 2015, with type I error level set at 0.01 (2 sided stratified log-rank test).
Results:
677 patients were randomized with 335 patients in G+D arm and 337 patients in D arm. Baseline characteristics: females 60%, age < 65 68%; never-smoker 18%; PS 0 36%; eLDH 29%; North America/Western Europe 39%. The median number of cycles delivered was 5 in G+D and 4 in D arm. There was no difference in median OS (mOS) for the two arms: 10.9 months with G+D versus 10.5 months with D alone. The hazard ratio for OS was 1.111 (95% CI 0.899-1.372), which met the early stopping criteria for futility. Median PFS was similar in the two arms: 4.2 versus 4.3 months, G+D and D, respectively (HR 1.161, 95% CI 0.961-1.403). There was no improvement with the addition of G for any secondary endpoint, including survival in the eLDH and EGFR and ALK negative populations, response rate, or progression due to new metastatic lesions. The most common grade 3/4 treatment-emergent adverse event in both arms was neutropenia (31.1% versus 24.3%, G+D and D, respectively).
Conclusion:
The addition of ganetespib to docetaxel did not result in improved efficacy for salvage therapy of patients with advanced stage lung adenocarcinoma.
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SC15 - Clinical Trials: How to Set Priorities? (ID 339)
- Event: WCLC 2016
- Type: Science Session
- Track: Trial Design/Statistics
- Presentations: 1
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SC15.01 - The American Perspective (ID 6658)
11:00 - 11:15 | Author(s): S.S. Ramalingam
- Abstract
- Presentation
Abstract:
The treatment of lung cancer has changed dramatically in the past few years. From a time when treatment decisions were made without regard to histology or genotype, an era of personalized therapy, at least for a subset of patients with lung cancer, is a reality. The treatment of EGFR mutation-positive patients with EGFR inhibitors has resulted in significant improvements in outcomes over standard chemotherapy. Similarly, for patients with ALK- and ROS1-positive non-small cell lung cancer (NSCLC), targeted therapies have proven to be superior. However, for patients with KRAS mutations, which are seen in approximately 25-30% of lung adenocarcinomas, there is no effective targeted therapy option. For nearly 70% of patients with NSCLC, systemic chemotherapy remains the standard approach. The emergence of immune-checkpoint inhibitors has resulted in considerable change in the treatment algorithm for advanced NSCLC. These agents are now preferred salvage therapy after progression following platinum-based chemotherapy. As immunotherapy moves to the first-line therapy setting for advanced NSCLC, it is anticipated that at least 25-30% of the patients without a driver mutation will be treated with immune-checkpoint inhibitors. All of these exciting developments call for careful evaluation of ongoing and planned clinical trials, so that appropriate new priorities are established. The newly established NCI National Clinical Trials Network (NCTN) includes all the adult cancer cooperative groups (ALLIANCE, ECOG-ACRIN, SWOG, & NRG Oncology) is actively engaged in conducting the new generation of clinical trials for lung cancer. Despite, the success with targeted agents in advanced stage NSCLC, patients do not achieve a cure. Using these agents in early stage NSCLC provides the best chance for a cure. The ALCHEMIST study has been launched by the NCTN to evaluate personalized adjuvant therapy for early stage NSCLC. In this study, patients with early-stage lung cancer (stages IB, II and IIIA) are treated with systemic chemotherapy after surgical resection, as per standard of care. Subsequently, their tumor is subjected to molecular testing. Patients with ALK-positive disease are randomized to treatment with crizotinib or placebo. Patients with EGFR mutations are randomized to erlotinib or placebo. Patients who are negative for EGFR and ALK, are randomized to nivolumab or observation. These studies will evaluate the effect of the personalized adjuvant therapy on overall survival and disease-free survival. Another ongoing effort is to understand the therapeutic value of targeted strategies in patients with advanced stage squamous cell lung cancer. The lung-MAP study enrolls patients with advanced stage squamous NSCLC. Following next-gen sequencing, patients with selected targets are treated with an appropriate targeted agent. The study includes a phase 2 component, which can be rapidly adapted to phase 3 if a agent demonstrates the pre-defined level of efficacy. This trial is also designed to accelerate the development of treatments leading to full approval by the FDA by shortening timelines. These individualized treatment approaches based on genotype are likely to answer important questions in a definitive manner. As immunotherapy becomes integrated in the standard treatment paradigms, considerable changes are also warranted for patients without driver mutations. For a subset of patients, as immunotherapy becomes the first line treatment in the advanced stage disease setting, the role of platinum-based chemotherapy in the second line needs to be investigated. It is also important to evaluate the need for continued immunotherapy after disease progression when patients are switched to chemotherapy. Another key question relates to the duration of therapy for patients receiving immune checkpoint inhibitors. Appropriately designed trials to understand the optimum duration of therapy will optimize benefits, reduce toxicity, and decrease cost. Combination strategies using immune checkpoint inhibitors with chemotherapy and other targeted agents is also an important area of priority. The role of biomarkers to select therapy is another critical research priority. We should also make efforts to improve the percentage of patients enrolled to clinical trials. A major reason for this is the stringent eligibility criteria that excludes a significant proportion of patients in order to select the ‘fittest’ candidates for clinical trials. While this is certainly appropriate in early phase drug development, if patients enrolled in clinical trials do not represent the ‘real-world’ patient population, the applicability of the results are limited. The next wave of clinical trials should also take into consideration the impact of new treatments on the overall cost of care and the clinical significance of improvements in efficacy. The national Cooperative groups in the United States are committed to a collaborative approach to address key research questions and improve outcomes for lung cancer.
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