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M.E.R. O'Brien
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MINI 28 - Psychological Impact of Lung Cancer and its Treatment (ID 150)
- Event: WCLC 2015
- Type: Mini Oral
- Track: Palliative and Supportive Care
- Presentations: 1
- Moderators:A. Oton
- Coordinates: 9/09/2015, 16:45 - 18:15, 102+104+106
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MINI28.11 - Randomised Study of Acupuncture, Morphine and Combination in NSCLC/Mesothelioma (ID 108)
17:45 - 17:50 | Author(s): M.E.R. O'Brien
- Abstract
- Presentation
Background:
Dyspnoea is a common symptom of lung cancer. Morphine is widely used to control dyspnoea.
Methods:
We randomised 173 patients with advanced non-small cell lung cancer or mesothelioma with a dyspnoea score ≥ 4 on visual analogue scale (VAS) to one of three arms (acupuncture [A], morphine [M] or combination [AM]). A was delivered to upper sternal, paravertebral, hand and trapezius trigger points. Patients on arm A were given rescue morphine if needed. We recorded VAS dyspnoea and relaxation, lung function tests, respiratory rate, and EORTC QLQ-30/ QLQ-LC13 questionnaires at baseline, 30mins, 90mins, 4 hours, day 2, 7 and 14. Primary endpoint was proportion of patients achieving ≥1.5 improvement in VAS dyspnoea at 4 hours.
Results:
The median age of the study population was 73. 53% were performance status 2-3. The baseline median VAS dyspnoea score was 6.5. All patients scored >7 on HAD depression score. 44.3% scored >10 on HAD anxiety. Dyspnoea improved by ≥1.5 points on the VAS in 74% of patients in arm A, 60% in arm M and 66% in arm AM (A versus M p-value 0.12, AM versus M p-value 0.50). On VAS scales there was improved anxiety, relaxation and tiredness of A over M. Analysis of EORTC questionnaire data showed a mean change from baseline global health % score for arm A of 7.08 compared to -2.08 for arm M (p-value = 0.009). There was a mean change from baseline in dyspnoea % score for arm A of -7.89 compared to -1.05 for arm M (p=0.029, not significant at 1% level). There was no improvement in lung function or respiratory rate. 21% of patients in arm A, 87% in arm M and 87% in arm AM took one of more doses of morphine (p<0.001). 123 patients had toxicity data. All toxicities were CTCAE grade 1/2 and in line with morphine’s toxicity profile, with 8% of patients in arm A, 35% in arm M and 39% of patients in arm AM reporting toxicities. Two patients stopped morphine because of side effects. There were two cases of skin irritation attributable to acupuncture site dressings. Score Changes from BaselineA M AM Mean VAS relaxation (SD) -1.06 (±2.60) 0.19 (±2.43) -1.48 (±2.05) p<0.001 Day 7 median LAR relaxation (range) -1 (-6.7–4.5) 0 (-3.5–4.4) -0.9 (-5.6–4) p=0.006 Day 7 median LAR anxiety (range) 1.5 (-2.5–8) 0 (-4–6.2) 1.2 (-5.4–6.3) p=0.003 Mean LAR tiredness (SD) -0.82 (±2.61) 0.02 (±2.20) -0.94 (±2.37) p=0.002 Mean EORTC global health % (SD) 7.08 (±25.54) -2.08 (±17.70) 2.72 (±16.96) p=0.009 Mean EORTC dyspnoea % (SD) -7.89 (±17.382) -1.05 (±17.704) -6.37 (±17.797) p=0.029 Median dose morphine (range) 32mg (1-60) 53mg (13-163) 40.63mg (3-154) p=0.007
Conclusion:
This study population was of poor performance status. A is as effective as M in the treatment of dyspnoea and has additive value for anxiety, relaxation and global health. Acupuncture is morphine sparing. Acupuncture should be a treatment available to lung cancer patients with dyspnoea and as a morphine adjunct.
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ORAL 40 - Biology 1 (ID 154)
- Event: WCLC 2015
- Type: Oral Session
- Track: Thymoma, Mesothelioma and Other Thoracic Malignancies
- Presentations: 1
- Moderators:C. Brambilla, R. Bueno
- Coordinates: 9/09/2015, 16:45 - 18:15, 702+704+706
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ORAL40.02 - Molecular Landscape of Malignant Mesothelioma from Whole Exome Sequencing (ID 2439)
16:56 - 17:07 | Author(s): M.E.R. O'Brien
- Abstract
- Presentation
Background:
Whole exome sequencing has revealed key genetic events in several cancer types that have been successfully translated into clinical benefits. These advances are still lacking in malignant mesothelioma (MM), a highly aggressive malignancy with limited effective therapy. Frequent BAP1 mutations occur in a subset of this disease but the full molecular landscape of MM is still poorly characterized.
Methods:
We have therefore conducted whole exome sequencing of tumours from the pleura for 36 cases of MM. DNA from matched blood was available for 7 of the cases and was also sequenced. The variants were identified with GATK tools and annotated with ANNOVAR. Variants were filtered with the following criteria: quality score ≤ 50, present in dbSNP138, 1000 genomes variants and NHLBI ESP 6500 variants. Mutations with deleterious functional consequences predicted by Polyphen-2, SIFT and Mutation Taster tools were confirmed by Sanger sequencing.
Results:
A total of 9,064 variants (3,256 somatic) were identified. We confirmed mutations in genes previously described to be mutated in MM in 5 cases: BAP1 (R227C, Q684X, H141P), NF2 (76_76del, R221X) and TP53 (I195N). In BAP1 wt tumours (6 of the 7 cases with matched blood), we confirmed somatic mutations in 5 genes encoding components of either MAPK or WNT signaling pathways. In addition, we validated somatic mutations in 12 genes across 4 of the 6 cases, many of which are novel in MM and are involved in chromatin modification. We also observed these genes to be mutated in BAP1 wt tumours in the 29 additional unmatched MM cases.
Conclusion:
Thus our data suggests that in addition to BAP1, mutations in genes associated with MAPK, WNT signaling and the chromatin remodeling complex may represent a consistent pattern of molecular alterations in MM.
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P2.01 - Poster Session/ Treatment of Advanced Diseases – NSCLC (ID 207)
- Event: WCLC 2015
- Type: Poster
- Track: Treatment of Advanced Diseases - NSCLC
- Presentations: 2
- Moderators:
- Coordinates: 9/08/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
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P2.01-065 - <em>nab</em>-Paclitaxel + Carboplatin in Advanced NSCLC: Analysis of Age and Renal Function (ID 1559)
09:30 - 09:30 | Author(s): M.E.R. O'Brien
- Abstract
Background:
Renal impairment increases with age and can impact treatment decisions. In a phase III trial, first-line treatment with nab-paclitaxel plus carboplatin (nab-P/C) significantly improved the overall response rate (ORR; primary endpoint) compared with solvent-based paclitaxel plus C (sb-P/C) in patients with advanced NSCLC (Socinski et al. J Clin Oncol. 2012;30:2055-2062). In a subgroup analysis of this phase III trial, nab-P/C demonstrated promising efficacy and was well tolerated in patients with or without renal impairment (Langer et al. Clin Lung Cancer. 2015;16:112-120). This analysis examined outcomes of patients in the phase III trial stratified by age and renal function.
Methods:
Patients with histologically or cytologically confirmed stage IIIB/IV NSCLC and no prior chemotherapy for metastatic disease received either nab-P 100 mg/m[2] on days 1, 8, and 15 or sb-P 200 mg/m[2] on day 1 in combination with C AUC 6 on day 1 every 21 days (randomized 1:1). Treatment continued until disease progression. Baseline renal function (creatinine clearance [CrCl]) was assessed in a central lab. ORR and progression-free survival (PFS) were assessed by blinded, centralized review. P values for ORR were based on the chi-square test, and those for overall survival (OS) and PFS were based on the log-rank test.
Results:
Treatment with nab-P/C resulted in improved outcomes compared with sb-P/C in patients with mild renal impairment, regardless of age (Table). nab-P/C also consistently demonstrated greater treatment effect compared with sb-P/C for ORR and similar or better PFS and OS in patients ≥ 60 years, regardless of renal function. In patients with either mild renal impairment or normal renal function, the toxicity profiles in each treatment arm were similar to those of the intent-to-treat population.
Conclusion:
These results suggest that, in general, clinical outcomes in patients with advanced NSCLC and mild renal impairment are better with nab-P/C vs sb-P/C, regardless of age. It should be noted that these were small subset analyses and results should be interpreted with caution. Figure 1
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P2.01-077 - A Phase 1b Trial of the Combination of Capecitabine and Erlotinib in Advanced Lung Cancer (ID 239)
09:30 - 09:30 | Author(s): M.E.R. O'Brien
- Abstract
Background:
Erlotinib is active in tumors with an EGFR mutation. Capecitabine, a thymidylate synthetase inhibitor, has shown some activity in advanced lung cancer (ALC). The combination of erlotinib and capecitabine has not been studied in ALC.
Methods:
We conducted a phase 1b trial, using a standard 3+3 dose escalation design to define the maximum tolerated dose (MTD) and safety of the combination of erlotinib and capecitabine, given on a 3-weekly cycle in 2[nd] line patients unselected for EGFR status. DLT was any grade≥2 toxicity. After MTD was defined in the 2[nd] line patients, we planned expansion of the trial to 1[st] line patients for further dose escalation. Dosing levels are listed in Table 1. Toxicity was assessed using CTCAE v3.0, response rate was assessed using RECIST 1.1, and survival assessed using Kaplan-Meier method.
Results:
We recruited 40 patients with adenocarcinoma. 55% were male, with median age of 67 years (range 38-84). 65% were ex-smokers and 28% were current smokers. Performance status was ECOG 1 in 65% and 2 in 35% of patients. 85% of patients had received platinum-doublet chemotherapy for 1[st] line ALC, with 10% having maintenance pemetrexed. One patient had an EGFR mutation. Dose escalation stopped at level 3 in 2[nd] line patients with expansion to 6 patients due to dose limiting toxicities (DLTs) of grade (G) 2 creatinine rise, G2 anemia, G3 atrial fibrillation, and G3 pneumonia in 2/6 patients. The MTD was thus at level 2 that was also expanded to 6 patients, confirming safety. First line patients were then recruited at MTD but resulted in DLTs in 3/4 patients with G3 troponin rise, G2 rash, and G2 bilirubin rise in 2 patients. Hence the 1[st] line approach was abandoned. The MTD in 2[nd] line patients was further expanded for toxicity and activity. The overall response rate was 3% with a disease control rate of 34%. A partial response was seen in 1 patient with EGFR mutation of 11.3 months duration. The median progressive free survival was 1.6 months (95%CI 1.4 – 3.5) and the median overall survival was 6.1 months (95%CI 5.1 – 12.5).
Conclusion:
The MTD for capecitabine is 750mg/m[2] bd days 1–14 and erlotinib 100mg od on a 3-weekly cycle. The addition of capecitabine does not improve the efficacy of erlotinib in unselected ALC. This combination could be explored further in ALC selected for EGFR mutation. Table 1: Patient disposition.Dose escalation No. of pts No. of pts with DLTs Level 1 - Erlotinib 100mg od, Capecitabine 500mg/m[2], bd, days 1-14 3 Level 2 - Erlotinib 100mg od, Capecitabine 750mg/m[2], bd, days 1-14 3 + 3 Level 3 - Erlotinib 100mg, od, Capecitabine 1000mg/m[2] bd, days 1-14 3 + 3 2 1[st] line ALC at level 2 4 3 Dose Expansion 2[nd] line ALC 21
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P3.01 - Poster Session/ Treatment of Advanced Diseases – NSCLC (ID 208)
- Event: WCLC 2015
- Type: Poster
- Track: Treatment of Advanced Diseases - NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 9/09/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
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P3.01-058 - <em>nab</em>-Paclitaxel + Carboplatin in Advanced Non-Small Cell Lung Cancer NSCLC: Dose Modification Analysis (ID 1570)
09:30 - 09:30 | Author(s): M.E.R. O'Brien
- Abstract
Background:
Chemotherapy dose modifications may impact clinical outcomes in patients with cancer. In a phase III trial, first-line treatment of patients with advanced NSCLC with nab-paclitaxel plus carboplatin (nab-P/C) significantly improved the overall response rate (ORR; primary endpoint) compared with solvent-based paclitaxel plus C (sb-P/C; 33% vs 25%; P = 0.005; Socinski et al. J Clin Oncol. 2012;30:2055-2062). This exploratory analysis examined the correlation between patients receiving protocol-specified dose modifications and clinical outcomes in the phase III trial.
Methods:
Patients with histologically or cytologically confirmed stage IIIB/IV NSCLC and no prior chemotherapy for metastatic disease received either nab-P 100 mg/m[2] on days 1, 8, and 15 or sb-P 200 mg/m[2] on day 1, both in combination with C AUC 6 on day 1, every 21 days (randomized 1:1). ORR and progression-free survival (PFS) were assessed by blinded, centralized review. P values for ORR were based on the chi-square test, and those for overall survival (OS) and PFS were based on the log-rank test. Patients who discontinued treatment before cycle 3 or remained on treatment after 6 months were excluded from this analysis unless otherwise specified.
Results:
Dose modification and clinical outcomes for patients treated for ≥ 3 cycles but ≤ 6 months are shown in the Table. In the nab-P/C arm, 268 of 310 patients (86%) who were treated for ≥ 3 cycles and ≤ 6 months had a dose modification compared with 200 of 319 (63%) in the sb-P/C arm. In the nab-P/C cohort, ORR and PFS were significantly higher in patients who received a dose modification vs those who did not (Table), possibly due to better tolerability and longer treatment duration. In the sb-P/C arm, there were no differences in efficacy outcomes between either group. As predicted, patients with a lower numerical incidence of toxicity were those that did not require dose modifications.
Conclusion:
This exploratory analysis suggested that, in this patient subset, protocol-specified dose modifications did not negatively impact the primary endpoint of ORR and in fact resulted in a greater ORR for those receiving nab-P/C. Figure 1
