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Richard Hall
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OA12 - Novel Therapies in MET, RET and BRAF (ID 921)
- Event: WCLC 2018
- Type: Oral Abstract Session
- Track: Targeted Therapy
- Presentations: 1
- Moderators:
- Coordinates: 9/25/2018, 15:15 - 16:45, Room 106
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OA12.06 - Mutational Landscape of BRAF V600E Positive Lung Cancer Patients Following BRAF Directed Therapy Failure (ID 13540)
16:10 - 16:20 | Author(s): Richard Hall
- Abstract
- Presentation
Background
BRAF V600E mutation is identified as molecular drivers in 1-2% of lung adenocarcinomas and predicts response to combination BRAF and MEK inhibitors. Little is known about molecular mechanisms of acquired resistance to these therapies for lung cancer patients with BRAF V600E mutations, partially due to a lack of representative cancer models.
a9ded1e5ce5d75814730bb4caaf49419 Method
We identified patients with BRAF V600E mutated lung cancer who were progressing after initial response to a BRAF/MEK inhibitor combination in 5 academic institutions in the US. Potential molecular mechanisms of resistance were explored by comparing pre- and post-therapy results from comprehensive tissue and/or the Guardant360 and FoundationACT plasma-based next generation sequencing assays.
4c3880bb027f159e801041b1021e88e8 Result
We identified 6 patients. Prior to treatment with a BRAF/MEK inhibitor combination, four patients had received at least one line of chemotherapy and immune checkpoint inhibitor monotherapy, one had received chemotherapy only and one was treatment naïve. Five patients received dabrafenib/trametinib and one vemurafenib/cobimetinib combination. All 6 patients achieved a partial response. Progression free survival (PFS) ranged from 3 to 15 months (median 9.5 months). At the time of progression, all patients had the BRAF V600E mutation re-identified in their samples. Additionally, there was one patient with a new AKT1 E17K and a new KRAS G12A mutation, one patient with a new VHL R167Q mutation and one patient with a new TP53 splice site indel mutation at the time of progression. Another two patients had AKT1 E17K mutations that were present prior to BRAF/MEK inhibitor therapy. They both had oligoprogression, one in lymph nodes and one in the brain after 5.2 and 3 months, respectively; both continued on dabrafenib and trametinib combination therapy after radiation treatment to the progressing sites. Interestingly, co-occurrence of AKT1 E17K and BRAF V600E mutations is rare in the TCGA data, but was identified in three of six patients in our case series. Finally, we have established a BRAF V600E positive lung adenocarcinoma cell line from a TKI naïve patient for further functional studies of drug resistance.
8eea62084ca7e541d918e823422bd82e Conclusion
Comprehensive molecular testing can identify potential resistance mechanisms following progression of BRAF V600E positive lung cancer to TKI therapy. AKT1 mutations were common as co-alterations in BRAF V600E mutated lung adenocarcinoma before and after targeted therapy and may contribute to drug resistance. The development of patient-derived cell line models may assist in the identification and validation of drug resistance mechanisms, and may help devise strategies to overcome drug resistance.
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P2.01 - Advanced NSCLC (Not CME Accredited Session) (ID 950)
- Event: WCLC 2018
- Type: Poster Viewing in the Exhibit Hall
- Track:
- Presentations: 1
- Moderators:
- Coordinates: 9/25/2018, 16:45 - 18:00, Exhibit Hall
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P2.01-39 - Can Benefit or Futility in Treating Advanced Nsclc Be Determined Early Using the LCSS 3-Item Global Index (3-IGI) PRO? (ID 12299)
16:45 - 18:00 | Author(s): Richard Hall
- Abstract
Background
Background: Early assessment of the effect of treatment for advanced NSCLC can prevent unnecessary exposure to toxic and costly therapy while aiding in decision making to continue or change treatment. In a prior analysis in patients with mesothelioma (Symanowski JCO 2014), a 20% decline from baseline after 2 cycles of chemotherapy in the 3-Item Global Index of the LCSS identified patients unlikely to benefit. The 3-IGI (which evaluates: 1) global distress, 2) patient rated activities, and 3) quality of life, all in single VAS scales) takes less than 2 minutes to assess.
a9ded1e5ce5d75814730bb4caaf49419 Method
Methods: 164 patients with NSCLC receiving chemotherapy or checkpoint inhibitors were prospectively evaluated with the LCSS at baseline and every 3 weeks using electronic media. Patients were also randomized 1:1 so that their physicians knew the results of the LCSS immediately in half of the patients.
4c3880bb027f159e801041b1021e88e8 Result
Results: Patients: Stage IV 92%; first line 73%; female 43%; median PS 1; mean age 63. The LCSS was completed after 2 cycles of treatment and prior to planning for the next cycle (generally 6 weeks after baseline; representing 91% of the 148 patients living). Patients with a 20% decline in the 3-IGI compared with baseline had a median survival of 7.6 months, contrasted to 15.8 months for those without this degree of 3-IGI decline (p = 0.01); 1 year survivals = 26% versus 62%. Even with the marked PRO decline after 2 treatment cycles, patients in the 20% decline group received a median of 2.3 more cycles of the same chemotherapy (median cost = $10,712 per patient). In the 50% of patients for which their physicians knew the ongoing LCSS results, fewer chemotherapy and imaging studies were performed, but the differences were not significant (p = 0.8).
8eea62084ca7e541d918e823422bd82e Conclusion
Conclusions: Assessing change from baseline with the 3-IGI of the LCSS identifies after only 2 cycles of treatment those patients who have poor response and survival outcomes if continued on the same therapy. This PRO assessment is rapid, easy, and inexpensive. Physicians need to consider the impact of decline on decision options given that even when physicians were aware of the worsening PRO they often did not act on the findings. Patient responses to this validated PRO questionnaire provide valuable information that is not otherwise attainable. Responding to 3-IGI changes can result in better decisions concerning continuing or changing treatment, lessening toxicity, and savings in cost of unhelpful treatment.
Supported by: NIH/NCI R01 CA157409
6f8b794f3246b0c1e1780bb4d4d5dc53
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P3.01 - Advanced NSCLC (Not CME Accredited Session) (ID 967)
- Event: WCLC 2018
- Type: Poster Viewing in the Exhibit Hall
- Track:
- Presentations: 1
- Moderators:
- Coordinates: 9/26/2018, 12:00 - 13:30, Exhibit Hall
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P3.01-09 - Impact of Urban or Rural Residence on Overall Survival for Patients with Metastatic Non-Squamous NSCLC (ID 12735)
12:00 - 13:30 | Author(s): Richard Hall
- Abstract
Background
Although data suggests that disparities in ethnicity impact survival outcomes in lung cancer, little is known about whether disparities according to primary residence (rural vs urban) impact survival outcomes in metastatic non-squamous, non-small cell lung cancer (ns-NSCLC).
a9ded1e5ce5d75814730bb4caaf49419 Method
This is a retrospective study of 176 patients with stage IV ns-NSCLC treated at our institution from 2014-2016. Patients were classified as urban or rural residents based on zip codes using the RUCA and SAS zip code databases. Socioeconomic factors were derived from the AHRF database. Risk of death and overall survival (OS) were calculated using COX proportional hazards regression.
4c3880bb027f159e801041b1021e88e8 Result
Baseline characteristics are in Table 1. Patients from rural zip codes had worse median OS (12.2 mo, 95% CI 5.1-16.0) compared to patients from urban zip codes (15.7 mo, 95% CI 9.6-27.9), with a hazard ratio (HR) of 1.589 (95% CI 1.052-2.401, p=0.0278). When adjusted for age, gender, smoking status, median income, percent in poverty per county, and EGFR mutational status, these results remained significant (HR 1.670, 95% CI 1.016-2.743, p=0.0376). A secondary analysis based on median household income (MHI) showed that those from regions with MHI less than the median of the cohort were 1.931 times more likely to die than those from regions with greater MHI (95% CI 1.038-3.595, p=0.0378).
Table 1. Baseline patient characteristics Characteristic Rural Urban Total (%) 76 (43.2) 100 (56.8) Median age in years 65 64 Male gender (%) 36 (47.4) 50 (50) Race/ethnicity White 66 (86.8) 75 (75.0) Black 9 (11.8) 16 (16.0) Hispanic 1 (1.3) 2 (2.0) Other 0 7 (7.0) Ever-smokers (%) 65 (85.5) 80 (80.0) Median household income in dollars 52818 63343 Percent persons in poverty 14.4 14.3 EGFR mutation present (%) 14 (18.4) 19 (19.0)
8eea62084ca7e541d918e823422bd82e Conclusion
Overall survival for rural patients with metastatic ns-NSCLC was inferior to those living in urban areas. This risk was more pronounced after adjusting for potential confounders. Those from regions with MHI below the median also had increased risk of death compared to those from areas above the median, suggesting that rural financial toxicity may influence lung cancer survival in our area. Further efforts to characterize the socioeconomic determinants of poorer outcomes in rural areas are needed and could support the formation of programs aimed at improving access to care.
6f8b794f3246b0c1e1780bb4d4d5dc53
