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H. Daga
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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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MINI15.08 - A Phase II Study of Pemetrexed plus Carboplatin Followed by Maintenance Pemetrexed in Elderly Patients with Advanced Non-Squamous NSCLC (ID 2453)
16:45 - 18:15 | Author(s): H. Daga
- 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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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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MINI31.09 - Association of Crizotinib Toxicity with Pharmacokinetics and Pharmacogenomics in Non-Small Cell Lung Cancer Harboring ALK Fusion Gene (ID 464)
18:30 - 20:00 | Author(s): H. Daga
- Abstract
- Presentation
Background:
Crizotinib, a standard care for advanced ALK-positive NSCLC, is a substrate for ABCB1-encoded P-glycoprotein, and is primarily metabolized by CYP3A4/5. The most common adverse events (AEs) are visual disorder, gastrointestinal disorders, and elevated transaminase levels. Serious AEs such as grade (Gr) ≥ 3 elevated transaminase levels and interstitial lung disease (ILD) occasionally develop.
Methods:
ALK-positive NSCLC patients were enrolled in cohort A (enrollment before starting crizotinib therapy) or cohort B (enrollment during crizotinib therapy). Trough concentrations of crizotinib at steady state were measured using LC/MS/MS and ABCB1 polymorphisms were analyzed. We evaluated clinically significant AEs, defined as Gr 4 hematological toxicity, Gr ≥ 3 non-hematological toxicity, or any ILD. AEs during 8 weeks were also evaluated prospectively on the patients enrolled in cohort A.
Results:
A total of 78 patients at 17 institutions were enrolled. In cohort A (n = 47), AEs which occurred in more than 40% of patients during 8 weeks were ALT increased (75.0%), visual disorder (47.2%), anorexia (45.5%), nausea (45.5%), and AST increased (43.2%). In both cohorts (n = 75), 26 clinically significant AEs (n = 25) were observed: Gr ≥ 3 elevated transaminase level (14.7%), ILD (4.0%), Gr 4 neutropenia (4.0%), Gr 3 thromboembolic event (4.0%), Gr 3 esophagitis (2.6%), and Gr 3 QTc prolongation (2.6%). There was one treatment-related death (1.3%) due to ILD. Clinically significant AEs tended to occur more frequently in females than males, albeit without significance (38.4% vs. 19.2%, respectively; p = 0.09). Blood samples for trough concentrations of crizotinib at steady state were collected from 63 patients. The geometric mean of trough concentrations were 396 (95% CI, 325-483) ng/ml in male and 395 (95% CI, 329-474) ng/ml in female, respectively (p=0.569, Mann-Whitney U test). No clinical factors including gender, weight, body surface area, and age which influenced trough concentrations or AEs of crizotinib were identified. Moreover, the trough concentration of crizotinib was not significantly different between patient with clinically significant and without (429 [95% CI, 361-509] ng/ml vs. 378 [95% CI, 313-456] ng/ml, respectively [p=0.365]).
Conclusion:
In this multicenter study, we observed crizotinib AEs as previously reported. Clinically significant AEs tended to occur more frequently in females than males, albeit without significance. Furthermore, we will present the association of clinically significant AEs and trough concentration with ABCB1 polymorphism.
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P3.06 - Poster Session/ Screening and Early Detection (ID 220)
- Event: WCLC 2015
- Type: Poster
- Track: Screening and Early Detection
- Presentations: 1
- Moderators:
- Coordinates: 9/09/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
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P3.06-009 - Evaluation of Bone Metastasis Using Serial Measurements of Serum NTx in Patients with Lung Cancer: A Prospective Study (ID 1648)
09:30 - 17:00 | Author(s): H. Daga
- Abstract
Background:
The bone resorption biomarkers cross-linked N-telopeptide of type I collagen (NTx) have been shown to aid in the diagnosis of metastatic bone disease from lung cancer (MBDLC). Patients with MBDLC are often treated with zoledronic acid (ZA). ZA reduces the levels of NTx and also lowers the risk of skeletal adverse events in patients with MBDLC.
Methods:
Patients with MBDLC at initial diagnosis were included in this study. Serum NTx (sNTx) was measured once a month using the OSTEOMARK[TM] sNTx assay (Alere Medical). MBDLC was assessed by monthly physical examinations and bone scintigraphy every 3 months for 12 months. Progression of bone metastases during the follow-up period was defined as when the number of bone metastases as assessed by bone scintigraphy had increased from the previous follow-up measurement. The optimal cut-off value of sNTx levels indicative of progression of bone metastasis was evaluated by performing a receiver operating characteristic (ROC) curve analysis. In this ROC analysis, we evaluated the change rate of sNTx per month. The change rate per month was defined as “The change rate of sNTx between at the minimum levels of NTx and at the worsening bone metastasis / the number of month from the minimum levels of sNTx to the worsening bone metastasis’’
Results:
Twenty patients were enrolled between June and December 2010. The sNTx concentration at baseline was 19.8 ± 5.8 nmol bone collagen equivalents (nM BCE)/L. In the 16 patients receiving ZA, the levels of sNTx showed a significant decrease after the first month of treatment (baseline vs. 1 month of treatment: 21.3 ± 5.5 vs. 13.6 ± 2.7 nM BCE/L; p < 0.01). During the follow-up period, 13 of the patients treated with ZA experienced worsening bone metastasis. There were statistically significant differences in the levels of sNTx at baseline (20.3 ± 4.8 nM BCE/L), at the lowest levels after the administration of ZA (11.8 ± 2.9 nM BCE/L vs. baseline; p < 0.001), and at the point of measurable disease progression (14.1 ± 4.6 nM BCE/L vs. baseline; p < 0.05). In the ROC analysis, the optimal change rate of sNTx per month was 4.0% (sensitivity: 53.8%, specificity: 100%, area under the curve = 0.564).
Conclusion:
The administration of ZA significantly decreased the levels of sNTx within one month of the initiation of therapy. However, the levels of sNTx was slightly elevated when the bone metastasis has been aggravated during ZA treatment. The serial measurements of sNTx might prove to be useful in selecting drug treatment and evaluating drug efficacy for bone metastasis.
