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L. Crinò
Moderator of
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MINI 15 - Chemotherapy Developments for Lung Cancer (ID 128)
- Event: WCLC 2015
- Type: Mini Oral
- Track: Treatment of Advanced Diseases - NSCLC
- Presentations: 15
- Moderators:L. Crinò, C.P. Belani
- Coordinates: 9/08/2015, 16:45 - 18:15, Mile High Ballroom 1a-1f
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MINI15.01 - A Phase I/II Study Evaluating the Combination of Resminostat and Docetaxel for Platinum-Pretreated NSCLC (ID 700)
16:45 - 16:50 | Author(s): A. Horiike, T. Takahashi, H. Nokihara, N. Yanagitani, H. Kenmotsu, Y. Fujiwara, Y. Tambo, S. Kanda, M. Nishio, T. Tamura
- Abstract
- Presentation
Background:
Resminostat, an oral hydroxamate-type inhibitor of class I and II histone deacetylases, has shown a broad spectrum of anti-tumor activity against human cancer cell lines, and synergetic or additive effects in combination with docetaxel in non-small cell lung cancer (NSCLC) cell lines. We initiated a phase I/II study to evaluate the safety and efficacy of combining resminostat and docetaxel in patients (pts) with NSCLC pretreated with platinum-based therapy. The purpose of the phase I portion was to evaluate dose-limiting toxicities (DLTs) in the first cycle, estimate the maximum tolerated dose (MTD) of resminostat when administered in combination with docetaxel, and determine the recommended dose (RD) for the phase II portion. Here, we report the results of the phase I portion.
Methods:
NSCLC pts with failure of a platinum-based therapy were eligible for the study. Patients were treated with docetaxel on day 1 and resminostat on days 1 to 5 every 21 days. Phase I was an open-label, 3+3 cohort, dose-escalation study. While the docetaxel dose was fixed at 75 mg/m[2], the resminostat dose was escalated from 400mg (Dose Level 1: DL1) to 600 mg (DL2). DLT was defined as follows: grade 4 thrombocytopenia, grade 4 neutropenia lasting >7 days, febrile neutropenia lasting >3 days, and any other clinically significant grade 3/4 non-hematological toxicity.
Results:
A total of 9 pts (DL1: 3 pts, DL2: 6 pts) were enrolled in the phase I portion: male/female, 6/3; median age, 60 yr (50-71 yr); histologically proven adenocarcinoma/squamous cell carcinoma, 7/2; performance status, 0/1 in 7/2 pts. No DLTs were observed at DL1 or DL2. The most frequent grade 3/4 adverse events in any cycle were neutropenia (8 pts, 88.9%), leukocytopenia (8 pts, 88.9%), and febrile neutropenia (4 pts, 44.4%). These events were transient and resolved prior to the next cycle. No pharmacokinetic (PK) interaction between resminostat and docetaxel was observed. A partial response was observed in 1 pts (DL1) and stable disease in 3 pts (DL2).DL1 N=3 DL2 N=6 PK parameters (Geometric Mean) Resminostat Docetaxel Resminostat Docetaxel C~max ~(ng/mL) 3,010 2,840 5,610 3,140 T~max ~(h) 1.78 1.00 1.47 1.03 AUC~inf~(h∙ng/mL) 11,800 3,030 25,500 3,280 t~1/2~ (h) 2.98 8.21 3.02 8.73
Conclusion:
The combination of resminostat and docetaxel was tolerable up to DL2 (docetaxel 75 mg/m[2], resminostat 600 mg); the MTD was not reached. Dose Level 2 was determined as the RD for the phase II portion of this study, which is currently ongoing.
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MINI15.02 - NEJ016: Phase II Study of CBDCA and Weekly PTX plus BEV Followed by BEV for Highly Selected Elderly Non-Squamous NSCLC Patients (ID 977)
16:50 - 16:55 | Author(s): O. Yamaguchi, S. Miura, M. Maemondo, A. Iwashima, T. Harada, S. Sugawara, K. Kobayashi, A. Inoue, T. Nakagawa, Y. Takiguchi, H. Watanabe, M. Seike, T. Ishida, M. Terada, A. Gemma, H. Yoshizawa
- Abstract
- Presentation
Background:
It is considered that there is a population of “fit-elderly” patients, but how to select this population is undetermined. Two-drug regimen consisted of carboplatin (CBDCA) + weekly paclitaxel (PTX) in elderly patients with non-small cell lung cancer (NSCLC) was reported to be active but to have 4.4% of toxic deaths. When considering to add bevacizumab (BEV) to the two-drug regimen, meta-analysis of BEV-related adverse events taught that congestive heart failure (CHF) and arterial thromboembolic events increased in elderly patients. In this phase II study, we employed exclusion criteria of having both congestive heart failure (CHF) and diabetes mellitus (DM), which relates to arterial thromboembolism.
Methods:
Elderly (≥70 years old) patients with chemotherapy-naive, stage IIIB/IV or recurrent non-squamous NSCLC, ECOG-PS 0-1, measurable target lesion, and adequate organ functions were eligible for this study. Pts with CHF (i.e. those with brain natriuretic peptide (BNP) ≥ 100 pg/ml and ejection fraction (EF) ≤ 50%) and with DM (i.e. those with HbA1c ≥ 7.0%) were excluded. Treatment included CBDCA at AUC 5 on day 1, PTX at 90 mg/m[2] on days 1 and 8, and BEV at 15 mg/kg on day 1 of each 21-day cycle for up to 4 cycles, followed by maintenance BEV.
Results:
Thirty-six eligible patients (14 male, 22 female; median age, 75 years) were enrolled between February 2012 and September 2014. Fifteen and 21 patients had ECOG-PS of 0 and 1, respectively. The median number of CBDCA + weekly-PTX + BEV treatment cycles received was 4, and that of BEV maintenance dosing was 5. Grade 3/4 non-hematological and hematological toxicities were observed in 13 (36.1%) and 20 pts (55.6%), respectively. The most common grade 3/4 AEs included neutropenia (52.8%), hypertension (11%), anemia (8.3%), and infection (8.3%). No fatal AE was observed. The response rate, the primary endpoint of this study, was 69.4% (95% CI = 51.9–83.7), and median progression free survival was 9 months.
Conclusion:
CBDCA + weekly PTX + BEV followed by BEV was a feasible and effective first-line regimen for selected elderly non-squamous NSCLC patients. BNP, EF, and HbA1c may aid in selecting “bevacizumab-fit” elderly patients. Clinical information: UMIN000006622.
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MINI15.03 - Phase I & II Studies of the Decitabine-Genistein Drug Combination in Advanced Solid Tumours (ID 1091)
16:55 - 17:00 | Author(s): E. Kassouf, M. Tehfe, M. Florescu, D. Soulieres, B. Lemieux, J.M. Ayoub, D. Charpentier, L. Yelle, L. Daigneault, P. Colin, R.L. Momparler, I. Plante, G. Lassonde, M.R. Charbonneau, N.J. Raynal, N. Blais
- Abstract
- Presentation
Background:
The combination of epigenetic drug decitabine with genistein, a natural isoflavone, produces synergistic responses in preclinical studies with particular activity shown in lung cancer cell lines. Our phase I dose-escalation study of decitabine with a fixed dose of genistein to treat advanced solid tumor was followed by a phase II study in advanced lung cancer patients.
Methods:
In phase I, decitabine was administered over 10-hours at increasing doses (60, 120, 240 mg/m[2]) with continuous administration of genistein 300 mg/day orally. The MTD was 120 mg/m[2] with neutropenia as DLT. Decitabine at 120 mg/m[2 ]and genistein produced plasma levels of 0.62±0.06 µM and 8.5±5.6 µM, respectively.
Results:
The drug combination was well tolerated and produced stable disease for more than 6 months (7-14 months) in 5/10 patients. One gastric cancer patient had a 50% reduction in tumor burden after 6 months of therapy. Stable disease was also achieved in patients with desmoplastic small round cell tumor, oncocytic carcinoma, follicular thyroid carcinoma and bladder cancer. The phase II study was focused on nine patients with non-small cell lung cancer refractory to 3-4 lines of therapy. Eight progressed within the first radiologic evaluation at week 6. One NSCLC patient remains on therapy with SD after 3 months of treatment. A total of 60 adverse events were reported during the study with all patients experiencing at least one AE. Grade 3 & 4 treatment related toxicities were observed in 6/9 patients (66%) : neutropenia (4) anemia (2) febrile neutropenia (1) and hypertension (1).
Conclusion:
This combination of genistein with decitabine was well tolerated in advanced patients with solid tumors. The activity of the combination seen in some patients with tumors of more indolent biology was modest in the phase II cohort of heavily pretreated NSCLC patients. The efficacy profile observed in this trial suggests that tumors with slower tumor kinetics might benefit more from this type of epigenetic therapy.
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- Abstract
- Presentation
Background:
Endostar [TM ](rh-endostatin, 7.5mg/m[2], 3-hour intravenous infusion (IV) daily for 14 days) was approved by Chinese FDA for treatment of advanced NSCLC in 2005. Considering continuous intravenous infusion (CIV) may be a more favorable way to deliver Endostar, we designed the phase I study to evaluate pharmacokinetics, tolerability and efficacy of Endostar CIV at different doses combined with pemetrexed and carboplatin in untreated advanced non-squamous NSCLC patients.
Methods:
In phase Ia, 19 patients were assigned to 4-6 cycles (21 days/cycle) of pemetrexed (500mg/m[2], day 1), carboplatin (AUC 5, day 1), and CIV Endostar from day 2 to day 21 at doses of 7.5mg (8 patients), 15mg (6 patients), 30mg (5 patients) /m[2]/d, respectively. Serum samples were obtained 0h、1h、2h、4h、8h、24h、48h、72h、96h、120h、122h、124h、128h、132h and 144h after the Endostar infusion. In phase Ib, another 21 patients received CIV Endostar at doses of 7.5mg (10 patients) or 15mg (11 patients) /m[2]/d with pemetrexed + carboplatin.
Results:
The AUC~0-120h~ of Endostar 7.5mg/m[2] CIV and 7.5mg/m[2] 3-hour IV daily were comparable (12.6±7.6 vs 13.3±8.8 ug/mL × hour). C~max~ (ng/ml) (7.5mg: 152.4±83.7; 15mg: 287.2±122.6; 30mg: 398.2±52.6) and AUC~0-120h~ (ug/mL × hour) (7.5mg: 12.6±7.6; 15mg: 21.2±10.8; 30mg: 33.4±8.5) were linear with dose. In phase Ia, the most common adverse events were anemia (78.9%, G3/4 10.5%), neutropenia (68.4%, G3/4 31.6%), thrombocytopenia (63.2%, G3/4 10.5%), LDH increase (47.4%), aminotransferase increase (42.1%), and supraventricular arrhythmia (26.3%). No grade 3 or 4 non- hematologic adverse event was observed. The incidence of supraventricular arrhythmia in 30mg cohort (40%) was higher than the other two cohorts. Thus 30mg cohort was excluded in Ib phase. Totally, 15 patients in 7.5mg cohort and 17 patients in 15mg cohort were evaluable for treatment response. The DCR and ORR were 80.0% and 60.0% in 7.5mg cohort, 94.1% and 76.5% in 15mg cohort, respectively.
Conclusion:
The pharmacokinetics of Endostar CIV and daily IV were comparable. At doses of 7.5mg and 15mg/m[2]/d, Endostar CIV was well tolerated with encouraging anti-tumor efficacy. Increasing dose of Endostar might lead to better response.
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MINI15.05 - Discussant for MINI15.01, MINI15.02, MINI15.03, MINI15.04 (ID 3344)
17:05 - 17:15 | Author(s): G.D.L. Lopes Júnior
- Abstract
- Presentation
Abstract not provided
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MINI15.06 - Impact of Three and Further Lines in Advanced Non-Small Cell Lung Cancer Patients According to Molecular Profile: A Retrospective Analysis (ID 2919)
17:15 - 17:20 | Author(s): E. Carcereny, T. Moran, M.D.L.L. Gil, I. Teruel, L. Vila, M. Hardy-Weber, A. Estival
- Abstract
- Presentation
Background:
There is little evidence supporting the efficacy of third-line systemic therapy in non-small cell lung cancer (NSCLC) patients (p) with advanced (a) disease, except for erlotinib, and its role is unclear in unselected population. Nonetheless, further-line chemotherapy(CT) is frequently offered in daily clinical practice. We retrospectively analyzed the clinical, pathological characteristics and outcomes of p with aNSCLC who received >3 CT regimens to identify subsets of patients more likely to benefit. The presence of underlying molecular alterations has also been evaluated.
Methods:
The study included data from all consecutive p diagnosed with aNSCLC in our Institution from January 2008 to December 2013. Median overall survival (mOS) and progression free survival (PFS) were evaluated with Kaplan-Meier curves and groups were compared using the Log-rank test. Variables analyzed included p tumor and treatment characteristics. Overall response rate(ORR) was calculated according to the RECIST criteria.
Results:
A total of 486 p were included .175 p (36%) received >3 lines (group3+). Table 1 summarized p characteristics. Group 3+included more females (35.4%vs22.8%; p= 0.0041),younger p (58.9vs61.9;p =0.0016), more never-smoker p (26.9%vs18%;p=0.015), less lung (10.9%vs22.2%;p= 0.0020) and heart (4%vs11.6%;p=0.0020) comorbidities, a higher proportion of molecular alterations (EGFR/ALK) (25.7%vs12.9%; p= 0.0005), more adenocarcinoma (68.6%vs55%;p=0.0045) and less brain metastasis (14.3%vs23.5%;p=0.018). ORR to first line was higher in group 3+ (45.8%vs 29%;p=0.0009). 82.3% non-squamous histology were tested for at least one molecular alteration. There were no differences in PFS between both groups. The mOS of p in group 3+ was longer [24.3 m vs. 7.7 m, p<0.0001)], including p with EGFR/ALK/ROS1 wild-type or unknown [21.6 m vs. 7.4 m, p<0.0001) ]. OS was also longer in the group 3+ harboring a molecular alteration [32.2 m vs 12.7m;p=0.0002]. In the univariate analysis the presence of a molecular alteration were related to longer PFS. In univariate analysis having received >3, female gender, age<65 and the presence of molecular alterations were associated with longer OS. In the multivariate analysis >3 therapeutic lines and the presence of molecular alterations were related to longer OS.
Conclusion:
P treated with >3 systemic treatments were more likely to respond better, progress later and live longer. This better prognosis could be related to the presence of molecular alteration. However p without or unknown molecular alteration could benefit from receiving subsequent lines.
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MINI15.07 - Prognostic Importance of Pretreatment Sodium Levels in Patients of NSCLC Treated with Pemetrexed-Platinum Doublet Chemotherapy (ID 2926)
17:20 - 17:25 | Author(s): M. Nookala Krishnamurthy, V. Gota, K. Doshi, B. Shriyan, A. Joshi, K. Prabhash, V. Noronha
- Abstract
- Presentation
Background:
A recent study has shown pretreatment sodium levels to be a predictive and prognostic marker in NSCLC patients treated with erlotinib. The objective of this study was to evaluate the prognostic impact of pretreatment sodium levels on progression free survival (PFS) and overall survival (OS) in patients of NSCLC treated with pemetrexed-platinum doublet chemotherapy.
Methods:
Stage IIIB/ IV NSCLC patients aged ≥ 18 years treated between January 2011 to November 2014 at our centre were included in this retrospective study. Patients received pemetrexed 500 mg/m[2] with either cisplatin 75 mg/m[2 ]or carboplatin (AUC 5) on day 1 of a 21 day cycle for 6 cycles followed by maintenance pemetrexed till progression. Electronic medical record (EMR) database of our hospital was used to retrieve demographic data, pretreatment sodium levels, PFS and OS data. LSS was defined as serum sodium < 136mEq/L. Survival analysis was performed using Kaplan-Meier curves and compared between LSS and normal serum sodium (NSS) groups using Log-Rank test and proportional hazard model.
Results:
Figure 1Data was available for 256 patients (M/F = 172/84) with median age of 53 (25-79) years. Majority had ECOG PS of 1 (0 = 34, 1 = 172, 2 = 44, 3 = 6). Stage IIIB = 24 (9%), stage IV = 232 (91%). Pretreatment LSS was observed in 75 (29%) patients while 181 (71%) had NSS. Median duration of follow-up was 17 months. Patients with NSS had significantly longer PFS (10.7 vs. 7.4 months; P < 0.05) and OS (17.6 vs. 13.4 months; P < 0.05) compared to LSS group. Cox-proportional hazard model has shown LSS was an independent prognostic biomarker for poor survival (P < 0.05).
Conclusion:
Pretreatment serum sodium level is an important prognostic marker in stage IIIB/ IV NSCLC patients. The simple possibility of testing coupled with low cost makes it an attractive marker to implement in clinical practice.
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MINI15.08 - A Phase II Study of Pemetrexed plus Carboplatin Followed by Maintenance Pemetrexed in Elderly Patients with Advanced Non-Squamous NSCLC (ID 2453)
17:25 - 17:30 | Author(s): M. Tamiya, A. Tamiya, H. Kaneda, K. Nakagawa, K. Goto, K. Yoh, H. Okamoto, T. Shimokawa, H. Tanaka, T. Abe, H. Daga, K. Takeda, T. Hirashima, S. Atagi
- Abstract
- Presentation
Background:
Non-small-cell lung cancer (NSCLC) accounts for >80% of all lung cancers, and the risk of lung cancer clearly increases with advancing age. Because of the progressive aging of population, the number of elderly patients with NSCLC is increasing and the desease is becoming an increasing public health problem worldwide. We previously reported a phase I study that recommended a dose of carboplatin (Cb, area under the curve = 5) plus pemetrexed (PEM, 500 mg/m[2]) for elderly (≥75-years-old) patients with non-squamous NSCLC. Furthermore, PEM maintenance therapy, following the combination therapy, was also found to be well tolerated. Therefore, we conducted a multicenter phase II trial to evaluated the efficacy and safety of Cb (area under the curve = 5) plus PEM (500 mg/m[2]) followed by maintenance PEM for elderly (≥75-years-old) patients with non-squamous NSCLC.
Methods:
Treated patients received 4 courses of Cb plus PEM, followed by maintenance PEM, without showing disease progression or severe toxicities. The primary endpoint was the 1-year overall survival (OS) rate, and the secondary endpoints were OS, progression free survival (PFS), response rate (RR), and safety.
Results:
Thirty four patients were enrolled between June 2012 and May 2013. All patients had an ECOG performance status 0 or 1, and adenocarcinoma. The median patient age was 77 years (75-84 years). Twenty four patients were male and ten patients were female. Three patients harbored activating epidermal growth factor recepter mutation (exon19 or 21). The median observation time was 22.7 months. In clinical outcome, the overall RR was 41.2%, and the disease control rate was 85.3%. No patient showed a complete response, 14 showed partial responses, 15 showed stable disease, 4 showed disease progression, and 1 was not evaluated. The maintenance therapy rate was 58.8%. The median PFS for all patients was 5.7 months (95% confidence interval, 3.3–8.5 months), whereas the median OS was 20.5 months (95% confidence interval, 7.8–25.4 months). The 1-year OS rate was 58.0%. In adverse events (total phase of this study), hematological adverse events ≥grade 3 were leucopenia (in 23.5% of patients), neutropenia (55.9%), anemia (35.3%), and thrombocytopenia (20.6%), and major non-hematological adverse events ≥grade 3 were febrile neutropenia (in 8.8% of patients), increased levels of aminotransferase (5.9%), infection (23.5%), and anorexia/fatigue (5.9%). There was 1 treatment-related death due to interstitial lung disease.
Conclusion:
The combination of Cb plus PEM followed by maintenance PEM was effective and reasonably well tolerated in chemotherapy-naïve elderly (≥75-years-old) patients with non-squamous NSCLC. This data was promising and valuable to conduct the phase III study compared with docetaxel (DOC) monotherapy in the first-line setting. Now, the phase III trial compared Cb plus PEM followed by maintenance PEM with DOC for chemotherapy-naïve elderly (≥75-years-old) patients with non-squamous NSCLC (JCOG1210/WJOG7813L: UMIN000011460) is ongoing and the result is warranted. Clinical trial information: UMIN000004810
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MINI15.09 - Bayesian Network Meta-Comparison of Maintenance Treatments for Advanced Non-Small-Cell Lung Cancer (NSCLC) Patients (ID 636)
17:30 - 17:35 | Author(s): G. De Lima Lopes, P.S. Tan, S. Acharyya, M. Bilger, B. Haaland
- Abstract
- Presentation
Background:
Recent trials suggested that maintenance treatments improve outcomes for patients not progressing after first-line therapy for advanced NSCLC. However, physicians have little guidance on selecting which patients benefit the most and what drug or regimen is optimal. Here, we report a systematic review and network meta-analysis (NMA) of current evidence assessing relative efficacies of maintenance options in unselected populations, as well as in subgroups determined by EGFR mutation, histology, and response to induction.
Methods:
PubMed and conference proceedings were reviewed and individual study relative efficacy measures were meta-analyzed in a Bayesian hierarchical model. The primary and secondary outcomes, Overall Survival (OS) and Progression Free Survival (PFS), respectviely, were evaluated in terms of (i) posterior surface under cumulative ranking curve (SUCRA), (ii) probability of being best treatment, (iii) probability of outperforming no maintenance, and (iv) posterior median hazard ratios with 95% credible intervals, in an unselected population, as well as by EGFR mutation status, histology, and response to induction. Secondary outcomes were overall survival (OS) and adverse events.
Results:
Twelve trials evaluating eight maintenance treatments in 3,850 patients were included in NMA. Selected maintenance treatments showed substantial PFS and OS benefits with probabilities ≥99% and ≥92% respectively of outperforming no maintenance. Results suggest the following strategy for optimal OS and PFS: (i) switch to or continue pemetrexed or switch to anti-EGFR TKI for nonsquamous patients, (ii) continue gemcitabine for squamous patients, (iii) switch to docetaxel or continue gemcitabine for responders to previous induction, and (iv) switch to or continue pemetrexed or switch to anti-EGFR TKI for patients with stable disease post-induction.
Conclusion:
Maintenance treatments improve PFS and OS in good performance status patients with stage IIIb/IV NSCLC not progressing after first-line chemotherapy. Benefits are optimized by targeting specific maintenance treatments to selected patient groups guided by histology and response to previous induction.
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MINI15.10 - Discussant for MINI15.06, MINI15.07, MINI15.08, MINI15.09 (ID 3345)
17:35 - 17:45 | Author(s): L. Crinò
- Abstract
- Presentation
Abstract not provided
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- Abstract
- Presentation
Background:
Pemetrexed and cisplatin (P-C) has become the standard 1st line chemotherapy in NSCLC patients with wild-type EGFR. The recommended drugs in the 2nd line are docetaxel, docetaxel plus ramucirumab, gemcitabine or EGFR TKIs. Gemcitabine and vinorelbine have good clinical efficacies and low toxicity profiles, so this two drug combination therapy is challenged for their clinical efficacy as 2nd line treatment. The optimal 2nd line chemotherapy following failure of 1st line P-C treatment in advanced NSCLC patients with wild-type EGFR is not yet defined. Therefore, we evaluated the optimal 2nd line chemotherapy in P-C non-responders with advanced NSCLC.
Methods:
We conducted a retrospective analysis of patients with stage IIIB or IV NSCLC who had been treated with P-C as a first line treatment from February 2010 to May 2014. Patients who had EGFR mutation or were on pemetrexed maintenance therapy were excluded. We compared the progression free survival, overall response rate and adverse effects of each regimen.
Results:
Among 110 patients, 52 were eligible for the study. 28 received EGFR TKI (gefitinib or erlotinib); 13 received docetaxel monotherapy; 11 received gemcitabine-vinorelbine (G-V) combination therapy. Median age was 64.5, 61 and 63 years, respectively. All patients showed adenocarcinoma type histology except two in docetaxel and G-V group with large cell type histology. Best response rates were 15.4% in docetaxel group, 18.1% in G-V group and 11% in EGFR TKIs group. Median progression free survival time was 62 days(95% CI 54-70) in EGFR TKIs group, 63 days (95% CI 30-96) in docetaxel group, and 83 days (95% CI 55-111) in G-V group (P=0.17). In pairwise comparisons, p-value was 0.54 for EGFR TKI versus docetaxel group, 0.08 for TKI versus G-V group, and 0.23 for docetaxel versus G-V group. There were no difference in progression-free survival and response rate among the groups. There was a higher rate of grade 3/4 neutropenia in the Docetaxel group.
Conclusion:
Despite the absence of statistical significance, there was a trend that G-V combination therapy had longer progression-free survival outcome compared to EGFR TKI or Docetaxel groups. G-V as well showed better toxicity profiles compared to Docetaxel group. A larger study is required to confirm the efficacy of cytotoxic chemotherapy, especially G-V, as a second line treatment in EGFR mutation negative NSCLC patients.
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MINI15.12 - Satisfaction with Therapy and the Relation with Quality of Life in Patients with Advanced NSCLC Receiving Chemotherapy (ID 2253)
17:50 - 17:55 | Author(s): S. Visser, M. De Mol, C. Cheung, N. Van Walree, J. Van Toor, B.L. Den Oudsten, B. Stricker, J.G. Aerts
- Abstract
- Presentation
Background:
In advanced non-small cell lung cancer (NSCLC) decisions regarding palliative treatment are based on tumor response, increasingly combined with patient reported outcomes, especially quality of life (QoL). However, considering treatment decisions in this manner ignores patients’ own opinion about (change in) QoL. A more patient-oriented view regarding therapy could offer valuable information in the process of shared decision-making about treatment initiation or continuation with chemotherapy. We assessed patients’ satisfaction with the received chemotherapy using the Cancer Therapy Satisfaction Questionnaire (CTSQ) in relation with QoL during treatment.
Methods:
In a prospective observational multi-center study, patients with stage IIIB or IV NSCLC receiving pemetrexed (PEM)-based chemotherapy as first or second line treatment were enrolled. Prior to and after four cycles of chemotherapy, patients completed the WHO Quality of Life-BREF (WHOQoL-BREF) and EORTC-Quality of Life Questionnaire-Core 30 (EORTC-QLQ-C30), which both contain one item measuring overall QoL on a 1-5 and 1-7 scale, respectively. After four cycles patients also completed the CTSQ, which consists of 16 items scored on a 1-5 scale and is divided in three domains, including the domain satisfaction with therapy (SWT). Linear transformation of the domain score results in a score range 0-100, with a higher score representing a better treatment satisfaction. Items of special interest were Question 7 (Q7) “Chemotherapy was worth taking even with side effects”, Question 16 (Q16) “If given the choice again, would you decide to take this chemotherapy treatment” and Question 2 (Q2) “Chemotherapy would cure the cancer”. From all patients tumor response measurements were obtained according to RECIST 1.1.
Results:
Of the 88 patients receiving four cycles of PEM-based chemotherapy, 65 patients completed the WHOQoL-BREF, EORTC-QLQ-30 and the CTSQ. The majority of these patients had stage IV NSCLC (87.7%) and received PEM-based therapy as first line treatment (92.3%). Treatment resulted in stable disease (53.8%), partial response (40.0%) and progressive disease (6.2%). Eighteen patients often (13.8%) or always (13.8%) expected chemotherapy would cure the cancer. During therapy, overall QoL measured by WHOQoL-BREF increased (1.3±0.6), remained stable (0±0) and decreased (-1.4±0.7) in respectively 15 (23.1%), 30 (46.2%) and 20 (30.8%) patients. The SWT domain score (77.5±12.3 vs. 83.8±13.1) and single item scores Q7 (4.1±0.9 vs. 4.4±0.8) and Q16 (4.4±0.7 vs. 4.5±0.6) in patients with decrease vs. increase of overall QoL did not differ significantly between the groups (p> 0.05). Change in overall QoL measured by the EORTC-QLQ-C30 related to SWT, Q7 and Q16 showed similar results.
Conclusion:
Despite a decrease of QoL during chemotherapy, patients still consider the treatment as worth taking and would decide to receive the chemotherapy again. Since the majority of patients understand that the treatment has no curative intentions, it is unlikely that the satisfaction with treatment only reflects false expectations of cancer cure. Our results represent a group of patients who mainly established disease stabilization, which could have influenced our findings. In shared decision-making on palliative treatment, patients’ QoL cannot be used as a single decision criterion because it does not reflect patients’ satisfaction with treatment. This study is funded by ZonMw, the Netherlands
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MINI15.13 - An Evaluation of Chemotherapy Regimens in an Unselected Population of NSCLC Patients (ID 2314)
17:55 - 18:00 | Author(s): A.A. Badawy, S. Bae, S.C. Grant
- Abstract
- Presentation
Background:
Randomized clinical trials have demonstrated the benefits of chemotherapy in carefully selected NSCLC patients. How generalizable these results are to the general population of NSCLC patients, who often have multiple comorbidities that would have rendered them ineligible for licensing trials, is unresolved.
Methods:
The outcomes of unselected patients with stage IV NSCLC who did not participate in a clinical trial and who were treated with standard chemotherapy regimens (paclitaxel/carboplatin; gemcitabine/carboplatin; pemetrexed/carboplatin; paclitaxel/carboplatin/bevacizumab) as first line therapy between 2002 and 2012 at a tertiary teaching hospital were compared to the reported outcomes observed in the licensing trials supporting the use of these drug regimens.
Results:
Results are summarized in Table 1 Patients treated with three-weekly paclitaxel plus carboplatin at recommended dosages had a median progression free survival of 4.9 months for patients responding to this regimen and an overall survival of 13.1 months for responders vs 9.2 months for non-responders. In patients’ treated with gemcitabine plus carboplatin on a three or four week cycle the median progression free survival was 4.8 months for patients responding to the regimen and overall survival of 13 months for responders vs 8.9 months for non-responder group of patients. For patients receiving pemetrexed plus carboplatin the median progression free survival was 7.1 months for patients responding to the regimen with an overall survival of 15.5 months for responders vs 5.9 months for non-responders. Those patients’ treated with paclitaxel plus carboplatin plus bevacizumab the median progression free survival was 7.3 months for patients responding to treatment and overall survival was 16.7 months vs 14.6 months for those patients who did not respond to this regimen as initial treatment. Table I: Patient demographics and results for each regimenpaclitaxel and carboplatin N=105 Gemcitabine and carboplatin N=35 pemetrexed and carboplatin N=26 paclitaxel and carboplatin and bevacizumab N=28 Age 70> 15.2% 31.4% 26.9% 25.0% < 70 84.8% 68.6% 73.1% 75.0% Gender Male Female 64.8% 35.2% 51.4% 48.6% 57.7% 42.3% 60.7% 39.3% Smoker 89.2% 91.2% 84.6% 71.4% ECOG 0 12.6% 12.1% 8.7% 23.1% 1 68.9% 63.6% 47.8% 76.9% 2 17.5% 24.2% 43.5% 0.0% 3 1.0% 0.0% 0.0% 0.0% PFS (months) 4.9 4.8 7.1 7.3 OS (months) PR PD 13.1 9.2 13 8.9 15.5 5.9 16.7 14.6
Conclusion:
Progression free survival in an unselected population of NSCLC patients was similar to that reported in clinical trials supporting the approval of these drugs and regimens. The present analysis provides further support for the use of combination chemotherapy in patients with stage IV NSCLC, including those who would have been ineligible for many clinical trials due to comorbidities. Further analysis is ongoing.
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MINI15.14 - The Role of Breath Sampling in Monitoring Response to Treatment in Lung Cancer (ID 2551)
18:00 - 18:05 | Author(s): I. Nardi Agmon, M. Abud-Hawa, O. Liran, N. Gai-Mor, M. Ilouze, A. Onn, J. Bar, R. Navon, D. Shlomi, H. Haick, N. Peled
- Abstract
- Presentation
Background:
The current available method to monitor response to treatment in lung cancer patient is by Computerized Tomography (CT) scans. However, time intervals between consecutive CT scans might be too long to allow early identification of treatment failure. The aim of this study is to examine the use of breath sampling as a tool for monitoring response to anti-cancerous treatment in patients with advanced lung cancer.
Methods:
In a prospective study, repeated exhaled breath samples were collected from patients with advanced lung cancer before and under systemic therapy. VOCs[1] profiles were determined by GC-MS[2] and nanomaterial-based array of sensors and correlated with response to therapy, assessed by CT scans as Complete Response (CR), Partial Response (PR), Stable Disease (SD), or Progressive Disease (PD). [1] Volatile Organic Compounds [2] gas-chromatography/mass-spectrometry
Results:
One hundred forty three breath samples were collected from 39 patients with stage III/IV lung cancer. GC-MS anaylsis identified 3 VOCs as significantly indicating PR/SD samples. One of them was also significantly discriminated between PR/SD and PD. Further, the NA-NOSE signals were able to alarm per a change in tumor response across therapy, i.e. indicating lack of further response to therapy, or developement of resistance to therapy. PR/SD was detected in a sensitivity of 93%, specificity of 85% and accuracy of 89% and ppositive/negative predictive values (PPV; NPV) of 86% and 92% respectively. PD was detected with 100% specificity and 92% accuracy, but the sensitivity was only 28%. The PPV and NPV were 100% and 91%, respectively. The achieved results indicate high reliability in predicting a progression of the disease and detecting patient's lack of response to treatment (i.e., PD).
Conclusion:
Breath analysis may serve as a serogate marker for response to systemic therapy in lung cancer. Such a monitoring tool can provide the oncologist with a quick and simple method to identify patient's response to anti-cancerous treatment in shorter intervals than currently available by CT scans.
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MINI15.15 - Discussant for MINI15.11, MINI15.12, MINI15.13, MINI15.14 (ID 3547)
18:05 - 18:15 | Author(s): P.J. Hesketh
- Abstract
- Presentation
Abstract not provided
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Author of
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MINI 10 - ALK and EGFR (ID 105)
- Event: WCLC 2015
- Type: Mini Oral
- Track: Biology, Pathology, and Molecular Testing
- Presentations: 1
- Moderators:T. Yap, T. Li
- Coordinates: 9/07/2015, 16:45 - 18:15, Mile High Ballroom 1a-1f
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MINI10.01 - Frequency of Concomitant EGFR, EML4-ALK or KRAS Alterations in NSCLC Patients and Correlation with Response to Treatment (ID 942)
16:45 - 16:50 | Author(s): L. Crinò
- Abstract
- Presentation
Background:
Epidermal growth factor receptor (EGFR) and KRAS mutations, and echinoderm microtubule-associated protein-like 4 (EML4) anaplastic lymphoma kinase (ALK) translocation are generally considered to be mutually exclusive. However, some reports show that a number of patients may have concomitant mutations, and it is not yet clear what impact these double mutations could have on response to targeted therapy.
Methods:
We took into consideration 380 NSCLC patients who underwent non-sequential testing for EGFR and KRAS mutations and EML4-ALK translocation between January 2010 and December 2013. EGFR mutation and EML4-ALK translocation analysis were performed on the entire case series and KRAS mutation analysis was performed on 282 cases.
Results:
EGFR mutation and EML4-ALK translocation were present in 44 (11.6%) and 32 (8.4%) of patients, respectively. Ninety-two patients (32.6%) showed a KRAS mutation. Two concomitant mutations among EGFR, KRAS or EML4-ALK genes were observed in 16 patients. In particular, 6 of the 380 (1.6%) patients analyzed had concomitant EGFR mutation and EML4-ALK translocation. Of the 282 patients who also underwent KRAS mutation, 3 (1.1%) showed a concomitant EGFR and KRAS mutation and 7 (2.5%) a concomitant EML4-ALK and KRAS alteration. Of the 44 EGFR-mutated patients, 28 received a TKI-based treatment (24 with gefitinib and 4 with erlotinib) as first-line therapy, and 6 of these also had an EML4-ALK translocation. Among the 22 patients with EGFR mutation only, we observed 2 complete response (CR) (9%), 16 partial response (PR) (72.7%) and 4 progressive disease (PD) (18%). Of the 6 patients who also had an EML4-ALK translocation, one had CR (17%), 3 PR (50%) and 2 PD (33%). No differences were seen in terms of overall survival (OS). Of the 32 patients harboring the EML4-ALK translocation, 6 (those also carrying the EGFR mutation) were treated with a TKI as first-line therapy, while the others received chemotherapy. Twelve patients received crizotinib as second-line treatment and 7 progressed within 3 months of starting therapy. Of these, 2 showed a concomitant KRAS mutation (G12C) and one a concomitant EGFR mutation (exon 19 del). Two patients had stable disease, one of whom also showed a KRAS mutation (G12V). Two patients had PR and one had CR, all of whom showed a EML4-ALK translocation only. The median OS of the patients carrying an EML4-ALK translocation alone or a concomitant KRAS mutation was 57.1 (range 10.7-nr) and 10.7 (range 4.6-nr) months, respectively.
Conclusion:
The concomitant presence of EGFR, EML4-ALK or KRAS mutations is a possible event in NSCLC. KRAS mutation in patients with EML4-ALK translocation represents the most common double mutation and seems to confer a poor prognosis.
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MINI 15 - Chemotherapy Developments for Lung Cancer (ID 128)
- Event: WCLC 2015
- Type: Mini Oral
- Track: Treatment of Advanced Diseases - NSCLC
- Presentations: 1
- Moderators:L. Crinò, C.P. Belani
- Coordinates: 9/08/2015, 16:45 - 18:15, Mile High Ballroom 1a-1f
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MINI15.10 - Discussant for MINI15.06, MINI15.07, MINI15.08, MINI15.09 (ID 3345)
17:35 - 17:45 | Author(s): L. Crinò
- Abstract
- Presentation
Abstract not provided
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MINI 16 - EGFR Mutant Lung Cancer 2 (ID 130)
- Event: WCLC 2015
- Type: Mini Oral
- Track: Treatment of Advanced Diseases - NSCLC
- Presentations: 1
- Moderators:G.J. Riely, M.C. Garassino
- Coordinates: 9/08/2015, 16:45 - 18:15, Four Seasons Ballroom F3+F4
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MINI16.08 - AZD9291 in Pre-Treated T790M Positive Advanced NSCLC: AURA2 Phase II Study (ID 1406)
17:25 - 17:30 | Author(s): L. Crinò
- Abstract
- Presentation
Background:
The epidermal growth factor receptor (EGFR) T790M mutation is found in about half of patients who have developed resistance to EGFR-tyrosine kinase inhibitors (TKIs), gefitinib or erlotinib. AZD9291 is an oral, potent, irreversible EGFR-TKI selective for both EGFR-sensitizing (EGFRm) and T790M resistance mutations. In the Phase I AURA study, AZD9291 80 mg (dose selected for further evaluation) was found to be clinically active, with an acceptable tolerability profile. This ongoing AURA2 Phase II study (NCT02094261) investigates the efficacy and safety of AZD9291 80 mg once daily after previous EGFR-TKI treatment in patients with EGFRm and T790M positive advanced NSCLC.
Methods:
AURA2 (NCT02094261) is a global, open-label, single-arm Phase II study. To be eligible, all patients had a mandatory tumor sample taken after disease progression on the most recent line of therapy, for confirmation of T790M positive status by central laboratory testing using the cobas™ EGFR Mutation Test. Further inclusion criteria included measurable disease, World Health Organization performance status (WHO PS) 0 or 1, and acceptable organ function; stable brain metastases were allowed. Patients receive AZD9291 at 80 mg once daily until disease progression. The primary endpoint was objective response rate (ORR) according to RECIST 1.1 (assessed by independent central review, ICR). Secondary objectives included disease control rate (DCR), duration of response (DoR), progression-free survival (PFS), and safety. Planned enrollment was 175 patients to give an ORR with 95% confidence interval (CI) within ±8%. The data cut-off was January 9, 2015.
Results:
Recruitment is complete and 210 patients were enrolled; 12 patients did not have measurable disease at baseline by ICR and are excluded from the evaluable-for-response set. By central testing, in addition to T790M, patients had background EGFR mutation: Ex19del, 65%; L858R, 32%; other, 3%. Baseline characteristics: median age, 64 years; female, 70%; WHO PS 0/1, 40%/60%; Asian, 63%; second-/≥third-line, 32%/68%. Median treatment exposure was 4.0 months and 183 patients remain on treatment at the data cut-off. ORR by ICR was 64% (127/198; 95% CI 57, 71) and DCR was 90% (95% CI 85, 94). Investigator-assessed ORR was 64% (135/210; 95% CI 57, 71). Median DoR and median PFS have not been reached (maturity 6% and 20%, respectively). The estimated proportion of patients who are alive and progression free is 82% and 70% at 3 and 6 months, respectively. The most common all-causality adverse events (AEs) were diarrhea, 34% (1% Gr≥3) and grouped rash terms 40% (0.5% Gr≥3); 38 (18%) patients experienced Gr≥3 AEs. Interstitial lung disease grouped terms were reported in four (1.9%) patients, one of which was fatal (0.5%) and considered possibly causally related to AZD9291 by the investigator. Eight patients (4%) discontinued treatment due to an AE. Updated results from a later data cut-off will be available for presentation.
Conclusion:
AZD9291 80 mg once daily demonstrates clinical activity and manageable tolerability in patients with EGFRm, T790M mutation positive advanced NSCLC that has progressed on or after EGFR‑TKI treatment. AZD9291 is being investigated in the randomized AURA3 Phase III study (NCT02151981) in comparison with platinum-based doublet chemotherapy.
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MINI 31 - ALK (ID 158)
- Event: WCLC 2015
- Type: Mini Oral
- Track: Treatment of Advanced Diseases - NSCLC
- Presentations: 1
- Moderators:S. Malik, I. Ou
- Coordinates: 9/09/2015, 18:30 - 20:00, Mile High Ballroom 1a-1f
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MINI31.13 - Symptoms and QOL with Ceritinib in ALK+ NSCLC Patients with/without Brain Metastases (ID 1655)
19:40 - 19:45 | Author(s): L. Crinò
- Abstract
Background:
In the pivotal ASCEND-1 study, ceritinib, an anaplastic lymphoma kinase inhibitor (ALKi), showed clinical activity in patients with ALK-rearranged (ALK+) non-small cell lung cancer (NSCLC), including in patients with brain metastases (BrM). Here, patient-reported outcomes (PROs) from the recently reported ASCEND-2 study (NCT01685060) are described for chemotherapy- and ALKi-pretreated patients with ALK+ NSCLC with and without baseline BrM
Methods:
In ASCEND-2, adult patients with ALK+ NSCLC previously treated with chemotherapy and an ALKi (crizotinib) received oral ceritinib 750 mg daily. PROs were assessed at baseline and Day 1 of treatment cycles 2, 3, and every two cycles thereafter (1 cycle=28 days), using the Lung Cancer Symptom Scale (LCSS) and EORTC quality of life and lung cancer surveys (QLQ-C30 and QLQ-LC13, respectively). Data were analyzed by presence/absence of baseline BrM. Data beyond cycle 9 are not reported due to small sample sizes.
Results:
All 140 patients enrolled (median age [range] 51 [29–80] years; 50.0% male), had received ≥2 antineoplastic regimens and 100 (71.4%) had BrM at baseline. At data cutoff (13 August 2014), median follow-up was 11.3 months. PRO questionnaire compliance was at least 91.2% up to cycle 9. In the overall patient population, investigator-assessed disease control rate (DCR) was 77.1% and median duration of response (DOR) 9.7 months. Investigator-assessed whole-body DCR [95% confidence interval (CI)] in patients with and without baseline BrM was 74.0% [64.3, 82.3] and 85.0% [70.2, 94.3], respectively, while DOR [95% CI] was 9.2 [5.5, 11.1] and 10.3 [7.4, 16.6] months, respectively. Analysis of PROs data demonstrated that treatment with ceritinib improved lung cancer symptoms in patients with and without baseline BrM (Figure). QLQ-LC13 outcomes were broadly consistent with those of LCSS. In general, mean global quality of life (QLQ-C30) was maintained on treatment for both patient subgroups, with mean change from baseline in QLQ-C30 global health status ranging from -3.06 to +7.25 in patients without baseline BrM and -2.83 to +3.55 in those with baseline BrM. Figure 1
Conclusion:
In patients with ALKi-pretreated ALK+ NSCLC who received prior chemotherapy and ceritinib, clinical efficacy was demonstrated and cancer symptoms were mostly improved, with health-related quality of life generally maintained regardless of presence or absence of baseline BrM.
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ORAL 16 - Clinical Care of Lung Cancer and Advanced Biopsies (ID 115)
- Event: WCLC 2015
- Type: Oral Session
- Track: Treatment of Advanced Diseases - NSCLC
- Presentations: 1
- Moderators:J.W. Neal, Q. Zhou
- Coordinates: 9/08/2015, 10:45 - 12:15, Mile High Ballroom 2a-3b
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ORAL16.01 - Tyrosine Kinase Inhibitors (TKIs) for the Treatment of Brain Metastases (BMs) from Advanced Lung Cancer : A Large Retrospective Cohort Study (ID 2824)
10:45 - 10:56 | Author(s): L. Crinò
- Abstract
- Presentation
Background:
BMs are found in up to 30% of patients (pts) with advanced non small cell lung cancer (NSCLC), and are associated with a poor prognosis despite radiotherapy treatment, with a median survival of 6 months (mo). Several data are suggesting the potential brain activity of tyrosin kinase inhibitors (TKIs) alone in NSCLC pts with activating mutations. We retrospectively identified EGFR mutated and ALK rearranged NSCLCs with BMs, to evaluate the efficacy of TKIs and their role in the upfront setting.
Methods:
Out of a cohort of 270 never smoker (NS) NSCLC patients (pts) treated at our Institution from 2/2006 to 2/2015, 89 (32.9%) NSCLCs BMs were identified, synchronous in 27 pts (30.3%). 38 pts (42.7%) harboured an EGFR mutation, 33 pts (37.1%) were ALK rearranged, 18 pts (20.2%) negative for both, were used as a control cohort. Among the EGFR mutated, an in-frame deletion in exon 19 (mostly E746-A750) was found in 26 (68.4%) patients, while a point mutation in exon 21 (L858R) was detected in 10 (26.4%), 1 (2.6%) exon 18 mutation and 1 (2.6%) exon 20 insertion were identified. The majority of EGFR and ALK positive (+) pts with BMs were female (53.9%), median age 52, adenocarcinoma histology, and a good performance status.
Results:
Out of the 71 NSCLCs with BMs EGFR/ALK+, 58 pts (81.7%) received at least one line of chemotherapy, while 13 pts (18.3%) were only treated with TKIs. Of the entire series, 40 pts (56.3%) were treated with standard radiotherapy (WBRT or radiosurgery) prior to TKIs treatment, while 31 (43.7%) received a TKI upfront, distributed as follows: 13 pts (37.9%) were treated with an EGFR inhibitor (gefitinib/erlotinib/afatinib), while 18 pts (62.1%) with an ALK TKI (crizotinib/ceritinib/alectinib). All the pts in the molecular negative cohort, received WBRT and, at least, one line of chemotherapy. Within the entire series, Overall Intracranial Response Rate (OIRR: complete response CR + partial response PR) was evaluated: EGFR+ 31 pts (81.5%), ALK+ 28 pts (84.8%), control cohort 6 pts (33.3%) (p,0.003). Median [95% CI] overall survival (OS) for EGFR mutans, ALK + and EGFR/ALK negative was: 52 months (mo) (32.6-74.4),74 mo (not reached), 25 mo (9.4-40.03) (p,0.003). In the subgroup who received a TKI upfront, all EGFR+ achieved a PR, while all ALK+ obtained an objective response: 4 (22.2%) a CR and 14 (77.8%) a PR. No significant difference in OS between EGFR/ALK+ BMs treated with a TKI upfront versus further line.
Conclusion:
This retrospective study confirms that TKIs are strongly active in patients with BMs from NSCLCs harbouring a sensitive mutation. Brain disease control was achieved in an impressive 81.5% of the EGFR+ pts and 84.8% of the ALK+ subset. Of particular note, is the highest response rate in the TKI upfront arm, with 22.2% attaining a complete remission. We conclude that the use of TKIs in first line setting for BMs treatment may be a reasonable option for asymptomatic subgroup of patients with a long survival expectation, for whom WBRT may be postponed at a later disease stage.
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ORAL 33 - ALK (ID 145)
- Event: WCLC 2015
- Type: Oral Session
- Track: Treatment of Advanced Diseases - NSCLC
- Presentations: 1
- Moderators:S. Gadgeel
- Coordinates: 9/09/2015, 16:45 - 18:15, Mile High Ballroom 1a-1f
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ORAL33.05 - Pooled Analysis of CNS Response to Alectinib in Two Studies of Pre-Treated ALK+ NSCLC (ID 1219)
17:28 - 17:39 | Author(s): L. Crinò
- Abstract
- Presentation
Background:
The central nervous system (CNS) is a frequent site of progression in ALK+ NSCLC patients treated with crizotinib, thus good CNS efficacy is of crucial importance for new ALK inhibitors. Two recent phase II studies examined the efficacy and safety of alectinib in patients with ALK+ NSCLC who progressed after crizotinib; data from both studies were pooled to further examine the efficacy of alectinib in the CNS.
Methods:
Both phase II, single-arm, multicenter studies enrolled ALK+ NSCLC patients previously treated with crizotinib. One study was conducted in North America only (NP28761; NCT01871805), the other was global (NP28673; NCT01801111). All patients received 600mg oral alectinib twice daily. A primary endpoint of both studies was objective response rate (ORR) by independent review committee (IRC) and key secondary endpoints included CNS ORR by IRC and CNS duration of response (DOR). Response was determined according to RECIST v1.1. All patients underwent imaging at baseline to assess CNS metastases.
Results:
The pooled analysis population comprised 225 patients (n=87 from NP28761 and n=138 from NP28673); baseline characteristics were similar to each study population, with most patients being non-smokers, <65 years old with ECOG performance status 0/1. Median follow-up was 27.7 weeks. Fifty patients had measurable CNS disease at baseline (MD) while a further 85 had non-measurable disease (NMD) at baseline; both groups together (M+NMD) comprised 135 patients, 60% of the overall study population. In the MD group, 34 patients (68%) had received prior radiotherapy, but 24 of them had completed that radiotherapy >6 months prior to starting alectinib. For the M+NMD group, 94 patients (70%) had received prior radiotherapy, with 55 completing this >6 months prior to starting alectinib. In the MD group, 30/50 patients had a CNS response (60.0%; 95% CI 45.2–73.6%), with 7 complete responses (CR; 14.0%) and a CNS DCR of 90.0% (78.2–96.7%). In the M+NMD group, 22 additional patients had a CR (29/135; 21.5%), giving a CNS ORR of 38.5% (30.3–47.3%), with a CNS DCR of 85.2% (78.1–90.7%). Complete responses were seen in patients with and without prior radiotherapy. Median CNS DOR after only 17% of events in both groups was 7.6 months (5.8–7.6) in the MD group (n=30) and 7.6 months (5.8–10.3) in the M+NMD group (n=52), which is similar to the systemic DOR reported in both studies (Ou et al, ASCO 2015; Gandhi et al, ASCO 2015). Tolerability was also similar to the overall study population.
Conclusion:
Alectinib showed promising efficacy in the CNS in ALK+ NSCLC patients previously treated with crizotinib, achieving a complete response rate of 22% and a DCR of 85%, irrespective of prior radiotherapy. The CNS response was sustained for an equivalent duration to the systemic response, suggesting that alectinib could provide an effective treatment for patients with ALK+ NSCLC while actively targeting CNS metastases. The ongoing phase III clinical studies will assess the systemic and CNS efficacy of alectinib versus crizotinib as front-line therapy for ALK+ NSCLC patients.
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ORAL 38 - Liquid Biopsies (ID 147)
- Event: WCLC 2015
- Type: Oral Session
- Track: Biology, Pathology, and Molecular Testing
- Presentations: 1
- Moderators:M.S. Tsao, J. Wang
- Coordinates: 9/09/2015, 16:45 - 18:15, Mile High Ballroom 2a-3b
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ORAL38.07 - Quantification of EGFR Mutations in Plasma of NSCLC Patients: An Early Predictor of Clinical Response to Tyrosine Kinase Inhibitors (ID 2242)
17:50 - 18:01 | Author(s): L. Crinò
- Abstract
- Presentation
Background:
As DNA analytical methods have become more sensitive, attempts to develop accurate clinical tests to assess tumor mutation status by means of patient plasma samples are now being pursued. The potential to accurately quantify EGFR mutations in plasma from non-small cell lung cancer (NSCLC) patients would enable more rapid and more frequent analyses to assess disease status; however, the utility of such analyses for clinical purposes has only recently started to be explored.
Methods:
Plasma samples were obtained from 69 NSCLC patients with EGFR-mutated tumors and 21 negative control cases. EGFR mutations in plasma were analyzed by a standardized allele-specific polymerase chain reaction (PCR) test and ultra-deep next generation sequencing (NGS). A semi-quantitative index (SQI) was derived from dilutions of known EGFR mutation copy numbers. Clinical responses were evaluated by RECIST 1.1 criteria and expressed as percent tumor shrinkage.
Results:
The sensitivity and specificity of the PCR test and NGS assay in plasma versus tissue were 72% versus 100%, and 74% versus 100%, respectively. Quantitative indices by the PCR test and NGS were significantly correlated (P<0.001). EGFR testing at baseline and serially at 4–60 days during TKI therapy revealed a progressive decrease in SQI , starting from day 4, in 95% of cases. The rate of SQI decrease correlated with percent tumor shrinkage at 2 months (P<0.0001); at 14 days it was more than 50% in 70% of patients (rapid responders) (Fig.1A-B). In 2 patients with slow response (Fig.1B), an early increase in the circulating levels of the T790M mutation was observed. These patients were defined as early resistant (Fig.1C). No early T790M mutations were seen in plasma samples of rapid responders, suggesting that slow responders are more prone to develop early resistance.
Conclusion:
Quantification of EGFR mutations from plasma with a standardized PCR test is feasible. To our knowledge, this is the first study showing a strong correlation between the EGFR SQI during therapy and clinical response with relevant implications for patient management. With the strong correlation between EGFR SQI in plasma and clinical outcome, this study opens the way to prospectively design clinical trials to confirm these data and evaluate the diagnostic value of this test. Figure 1
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P1.04 - Poster Session/ Biology, Pathology, and Molecular Testing (ID 233)
- Event: WCLC 2015
- Type: Poster
- Track: Biology, Pathology, and Molecular Testing
- Presentations: 1
- Moderators:
- Coordinates: 9/07/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
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P1.04-002 - Protein Signaling Analysis of KRAS Mutant Lung Adenocarcionomas Reveals Variable MAPK and mTOR Pathway Activation (ID 2280)
09:30 - 09:30 | Author(s): L. Crinò
- Abstract
Background:
Despite the numerous efforts made to target KRAS directly, this protein is still undruggable. A number of therapeutics that target linked KRAS pathway members have been tested, but their efficacy in KRAS mutant lung adenocarcinoma is still controversial. Understanding the biochemically linked protein signaling network associated with a KRAS mutation may lead to the identification of therapeutic targets to identify patients that may benefit from a therapeutic agent targeting KRAS downstream substrates.
Methods:
Thirty-four archived samples from surgically-treated KRAS mutant adenocarcinomas were included in this study. Samples were collected at the H.Lee Moffitt Cancer Center & Research Institute (Tampa, FL) and at the Santa Maria della Misericordia Hospital (Perugia, Italy). Pure cancer epithelial cell subpopulations were isolated using Laser Capture Microdissection. The expression/activation level of 155 proteins was then measured by Reverse Phase Protein Microarray, a high-throughput semi-quantitative platform.
Results:
The protein activation level of ERK (as measured by phosphorylation of T202/Y204), a direct downstream substrate of KRAS activity, was highly variable across KRAS mutant samples. While a subgroup of patients showed, as expected, high activation of ERK, approximately 2/3 of the patients had a comparable ERK activation level to the wild-type counterpart previously analyzed. The activation level of the remaining protein signaling analytes was then compared between samples with high and low ERK activation. Tumors with high levels of ERK activation showed a significant increase in the signaling network of: 1) the MAPK proliferative pathway including Ras-GRF1 S916, Mek 1/2 S217/221, MSK1 S360, p38MAPKinase T180/Y182 (p=0.03, p<0.01, p=0.04, p<0.01 respectively), 2) the AKT-mTOR pathway including Akt S473, AMPKα1 S485, ATP Citrate Lyase S454, LKB1 S428, mTOR S2448, p70S6K T389, p70S6K T412, 4E-BP1 S65 (p<0.01, p<0.01, p<0.01, p<0.01, p<0.01, p<0.01, p=0.02, p=0.03 respectively).
Conclusion:
This analysis suggests that the signaling network of KRAS mutant lung adenocarcinomas, while manifesting expected ERK activation as a group, is highly variable. In fact a majority of KRAS mutant tumors had the same range of MEK-ERK activation as KRAS WT tumors. Analysis of high and low ERK activation in the KRAS mutant tumors revealed druggable protein signaling activation of a number of important targets. If validated in a larger study set, these data may have important clinical implication for the allocation of patients toward more effective and specific targeted treatments.
