Phase II Study of Modified Carboplatin Plus Weekly Nab-Paclitaxel in Elderly Patients with Non-Small Cell Lung Cancer: North Japan Lung Cancer Study Group Trial 1301.

LESSONS LEARNED: Weekly nanoparticle albumin-bound-paclitaxel (75 mg/m2) in combination with carboplatin (area under the curve 6 mg/mL/min) in elderly patients with previously untreated, advanced non-small cell lung cancer showed favorable efficacy, was well tolerated, and showed less neuropathic toxicity.This modified regimen offers potential for the treatment of elderly patients.
BACKGROUND: The CA031 trial suggested weekly nanoparticle albumin-bound-paclitaxel (nab-PTX) was superior in efficacy to paclitaxel (PTX) once every 3 weeks when combined with carboplatin (CBDCA) for advanced non-small cell lung cancer (NSCLC) patients; a subgroup analysis of elderly patients looked promising. In a multicenter phase II trial, we prospectively evaluated the efficacy and tolerability of modified CBDCA plus weekly nab-PTX for elderly patients with untreated advanced NSCLC.
METHODS: Eligible patients received CBDCA (area under the curve [AUC] 6 mg/mL/min) on day 1 and nab-PTX (75 mg/m2) on days 1, 8, and 15 every 4 weeks. The primary endpoint was an overall response rate (ORR), and secondary endpoints were progression-free survival (PFS), overall survival (OS), and toxicity.
RESULTS: Of 32 patients (median age of 78 years), 84% were male, 56% had stage IV NSCLC, and 56% had squamous cell carcinoma. ORR and disease control rates were 50% (95% confidence interval (CI): 33-67) and 94% (95% CI: 85-100), respectively. Median PFS and OS were 6.4 months (95% CI: 4.8-8.0) and 17.5 months (95% CI: 11.9-23.1), respectively. Grade ≥3 toxicities were neutropenia (47%), leukopenia (38%), anemia (34%), thrombocytopenia (25%), and anorexia (9%). Febrile neutropenia and treatment-related deaths were not observed.
CONCLUSION: Modified CBDCA plus weekly nab-PTX demonstrated significant efficacy and acceptable toxicities in elderly patients with advanced NSCLC. © AlphaMed Press; the data published online to support this summary is the property of the authors.

Discussion

This prospective study was designed to investigate the efficacy and safety of modified CBDCA combined with weekly nab‐PTX as first‐line chemotherapy in elderly patients with advanced NSCLC. Socinski et al. analyzed the efficacy and toxicity of CBDCA combined with nab‐PTX in elderly patients (≥70 years old) in the CA031 study and revealed the ORR was 32% and the median OS was 19.9 months [1]. An ORR of 50% and an OS of 17.5 months in the present study are consistent with the CA031 study, although our study was intended for patients ≥75 years of age, and the median weekly dose intensity was less than that used in the CA031 study (45 mg/m2 vs. 73.4 mg/m2).

Tumor shrinkage by histological type. Blue bars: squamous cell carcinoma, n = 18. Orange bars: adenocarcinoma, n = 14.

Quoix et al. recently reported on IFCT‐0501, a phase III study comparing CBDCA (AUC 6 mg/mL/min on day 1 every 4 weeks) plus PTX (90 mg/m2 on days 1, 8, and 15 every 4 weeks) with monotherapy with vinorelbine or gemcitabine in elderly patients with advanced NSCLC [2]. The median OS was significantly longer in the doublet group than in the monotherapy group. Similar to the IFCT‐0501 trial, we previously demonstrated the high efficacy of CBDCA (AUC 6 mg/mL/min on day 1 every 4 weeks) plus weekly PTX (70 mg/m2 on days 1, 8, and 15 every 4 weeks) compared with single‐agent docetaxel for elderly patients with NSCLC [3]. We have also reported on a randomized phase II trial of weekly PTX combined with CBDCA (same as above) versus standard PTX combined with CBDCA (210 mg/m2 and AUC 6 mg/mL/min on day 1 every 3 weeks) for elderly patients with advanced NSCLC [4]. Regarding the efficacy of CBDCA plus nab‐PTX, the ORR and PFS (50%, 6.4 months) attained are consistent with the results achieved with a CBDCA plus weekly PTX regimen in our previous two studies (55%, 6.0 months and 54%, 6.6 months, respectively) [3], [4].

Regarding the toxicity of modified carboplatin plus weekly nab‐paclitaxel, its adverse event (AE) profile was tolerable. Nonhematological toxicities were acceptable, with the most frequent AEs being anorexia, alopecia, and nausea. Also, the relatively lower incidences of sensory neuropathy resulting in the discontinuation of treatment were similar to those seen in patients treated with CBDCA plus nab‐PTX in the CA031 study [1], [5]. Our data support the feasibility of a modified regimen of CBDCA plus a lower dose of nab‐PTX for elderly patients. In addition to fewer AEs, because nab‐PTX does not contain solvents, unlike PTX, it is not usually necessary to take premedications, such as H1 and H2 blockers and steroids, to prevent allergic reactions prior to the administration of nab‐PTX [6], [7], [8], [9]. Therefore, nab‐PTX may be a more acceptable drug option than PTX for elderly lung cancer patients.

Trial Information

Lung cancer – NSCLC

Metastatic/Advanced

None

Phase II

Single arm

Overall response rate

Progression free survival

Overall survival

Toxicity

Active and should be pursued further

Drug Information

Nanoparticle albumin‐bound‐paclitaxel

Abraxane

Taiho Pharma

Chemotherapy

Microtubule‐targeting agent

75 milligrams (mg) per square meter (m2)

IV

Day 1, 8, and 15 every 4 weeks

Carboplatin

Paraplatin

Bristol‐Myers Squibb

Chemotherapy

Platinum compound

AUC 6 mg/mL/min

IV

Day 1 every 4 weeks

Patient Characteristics for Phase II Control Arm

27

5

IIIb: 7

IV: 18

Postoperative recurrence: 7

Median (range): 78(75–86)

Median (range): 0

0 — 16

1 — 16

2 —

3 —

unknown —

Mutant: 2

Wild: 16

Unknown: 14

Adenocarcinoma: 14

Squamous cell carcinoma: 18

Primary Assessment Method for Phase II Control Arm

35

35

32

32

n = 1 (3.1%)

n = 15 (46.9%)

n = 14 (43.8%)

n = 2 (6.3%)

n = 0 (0%)

6.4 months, CI: 4.8–8.0

17.5 months, CI: 11.9–23.1

Assessment, Analysis, and Discussion

Study completed

Not Collected

Active and should be pursued further

Lung cancer is the most common cause of death from cancer in the elderly population. With many countries facing an aging population, the incidence of lung cancer in this age group is expected to increase. Consequently, it has become increasingly important to establish more effective treatments for elderly patients with advanced non‐small cell lung cancer (NSCLC). A recent IFCT‐0501 trial demonstrated that carboplatin (CBDCA) combined with weekly paclitaxel (PTX) would be advantageous, compared with vinorelbine or gemcitabine monotherapy, for elderly patients with previously untreated, advanced NSCLC [2]. Subsequently, the CA031 trial suggested that weekly nanoparticle albumin‐bound‐PTX (nab‐PTX) was superior in efficacy and safety compared with PTX once every 3 weeks when combined with CBDCA [1], [5]. In addition, a subgroup analysis of elderly patients in the CA031 trial yielded very promising data (a 34% overall response rate [ORR] and 8 months of progression‐free survival [PFS]), whereas in a Japanese subgroup analysis, many cases required the omission of treatments as well as a reduction in doses [10]. We therefore conducted this multicenter, nonrandomized, open‐label, phase II trial to prospectively evaluate the efficacy and tolerability of a modified CBDCA plus weekly nab‐PTX regimen for elderly patients with previously untreated, advanced NSCLC. The ORR met our primary endpoint and supported the favorable efficacy of this combination among an elderly population, as found in the CA031 trial [5].

We also evaluated the ORR by histologic type. Satouchi et al. reported that a Japanese subset analysis of the CA031 study showed more effectiveness in the squamous cell carcinoma subset than in nonsquamous cell carcinoma [10]. Although a similar tendency was shown in this study, because of the small sample size, a significant difference was not observed between adenocarcinoma and squamous cell carcinoma in terms of ORR and PFS. Recently, several studies have confirmed the effectiveness of nab‐PTX with CBDCA in patients with squamous cell carcinoma [11]. Further study is needed to determine the difference in effects for both histological types.

The present study had several limitations. First, this study used a small sample size and, for this reason, future phase III studies will be required to evaluate the effectiveness of this modified regimen, although promising results were obvious in this study. Concerning this limitation, the CAPITAL study, a randomized phase III trial of CBDCA plus nab‐PTX versus docetaxel for squamous NSCLC in the elderly, is ongoing in Japan. Second, the present study lacked a quality‐of‐life (QoL) assessment. Most elderly patients with advanced NSCLC do not have curative treatment options, and, therefore, the goal of therapy for such patients is a prolongation of survival without negatively impacting QoL. From this perspective, we plan to evaluate QoL in a future, randomized phase III trial of modified CBDCA plus nab‐PTX for elderly patients with advanced NSCLC.

In conclusion, weekly nab‐PTX (75 mg/m2) in combination with CBDCA (AUC 6 mg/mL/min) in elderly patients with previously untreated, advanced NSCLC showed favorable efficacy, was well tolerated, and showed less neuropathic toxicity. Therefore, nab‐PTX offers several distinct advantages over conventional PTX when combined with CBDCA. Based on our results, even if the high cost of nab‐PTX is considered, we believe that a modified CBDCA plus weekly nab‐PTX regimen should be used for elderly patients regarding efficacy and tolerability. Future phase III studies will be needed to further evaluate the role of weekly nab‐PTX in combination with CBDCA for such patients.