Phase II Study on Biweekly Combination Therapy of Gemcitabine plus Carboplatin for the Treatment of Elderly Patients with Advanced Non‐Small Cell Lung Cancer

Abstract

Lessons Learned

• The biweekly GEM plus CBDCA dose and schedule showed satisfactory efficacy with mild toxicities in elderly patients with advanced NSCLC.

• The biweekly GEM plus CBDCA regimen could be considered an alternative to the 3‐week regimen in NSCLC.

Background

The gemcitabine (GEM)‐carboplatin (CBDCA) combination is widely used for non‐small cell lung cancer (NSCLC) and has some efficacy in elderly patients; however, a high incidence of thrombocytopenia is observed, and the optimal dosage and administration schedules are unknown. This multicenter phase II trial evaluated the efficacy and tolerability of GEM‐CBDCA for elderly patients with chemotherapy‐naive NSCLC.

Methods

Patients with chemotherapy‐naive performance status 0–1 and with stage IIIB/IV NSCLC were administered chemotherapy biweekly (GEM 1,000 mg/m² with CBDCA area under the blood concentration‐time curve (AUC) 3 on days 1 and 15 every 4 weeks). The primary endpoint was the objective response rate (ORR), and the secondary endpoints were progression‐free survival (PFS), overall survival (OS), and safety.

Results

Forty‐eight patients were enrolled. Median age was 76 years (range, 70–83); 35 patients were men (73%), and 27 patients had adenocarcinoma (56%). The ORR was 29.2% (95% confidence interval [CI], 17.0–44.1). The median PFS, median OS, and 1‐year survival was 5.9 months (95% CI, 4.1–6.6), 13.3 months (95% CI, 8.3–23.5), and 58%, respectively. Grade ≥3 hematological toxicities included neutropenia (29.2%), thrombocytopenia (4.2%), and anemia (20.8%). The incidence of grade ≥3 nonhematological toxicities was <5%.

Conclusion

This GEM‐CBDCA combination administered biweekly showed satisfactory efficacy with mild toxicities in elderly patients with advanced NSCLC.

Discussion

The incidence of lung cancer increases with age 1. More than 45% of patients with lung cancer are diagnosed at ≥75 years 2, and this proportion is likely to increase. In patients with advanced NSCLC, chemotherapy improves survival, disease‐related symptoms, and quality of life, and combination chemotherapy involving newer agents is now considered the standard first‐line treatment 3. However, combination chemotherapy causes increased hematologic and neuropsychiatric toxicity in older patients 4, 5, and >90% of elderly patients experience grade ≥3 toxicity when treated with platinum‐based combination chemotherapy 6. Therefore, single‐agent chemotherapy is considered the standard treatment for elderly patients with advanced NSCLC 7, 8, 9. An effective, less toxic therapy might be beneficial for a greater proportion of older patients.

The phase III JCOG0803/WJOG4307L trial, which included elderly patients, compared weekly CDDP‐docetaxel (DTX) and DTX alone. An interim analysis showed that combination therapy did not outperform monotherapy (OS 13.3 months vs. 14.8 months, hazard ratio [HR], 1.18; 95% CI, 0.83–1.69) 10. The IFCT0501 trial, which also included elderly patients, compared CBDCA‐weekly paclitaxel (PTX) with GEM or vinorelbine (VNR) and found a significantly prolonged PFS (6.0 months vs. 2.8 months; HR, 0. 51; 95% CI, 0.42–0.62, p < .0001) and OS (10.3 months vs. 6.2 months; HR, 0.64; 95% CI: 0.52–0.78, p < .0001) with combination therapy. However, this outcome is not greatly superior to that observed with monotherapy, and the rate of treatment‐related death in the combination group was 4.4% 11.

The combination of GEM and CBDCA is already widely administered as standard therapy for NSCLC in Europe and America, and some usefulness in the elderly is also reported 12. In Japan, the phase II randomized WJTOG‐0104 trial examined GEM‐CBDCA (3 weeks) and GEM‐VNR in younger patients (<75 years) with advanced NSCLC. GEM‐CBDCA had a good effect, with an ORR of 20.3% (GEM‐VNR, 21.0 %), a median survival time (MST) of 14.2 months (GEM‐VNR, 12.6 months), and a 2‐year survival rate of 38.3% (GEM‐VNR, 22.4%) 13. However, a high incidence of thrombocytopenia was observed in the GEM‐CBDCA group, and, therefore, the optimal dosage and administration schedules must still be defined. Our group has previously conducted a clinical trial of biweekly CBDCA‐PTX, which resulted in a more favorable hematologic toxicity profile, and we considered that this biweekly administration schedule may be useful for the GEM‐CBDCA combination in view of the differences in thrombocytopenia incidence between GEM and CBDCA, and an improvement in the acceptability of this administration schedule can be expected 14. Therefore, we conducted a phase II study of biweekly administration of GEM‐CBDCA to establish a highly acceptable and useful treatment for elderly patients with NSCLC.

This phase II study was developed with the intent of reducing toxicity without lowering efficacy compared with the standard 3‐week regimen in elderly patients in which chemotherapy is administered on days 1 and 8 of a 21 day cycle. The ORR was 29.2% (3‐week regimen in WJTOG‐0104 trial, 21.0 %). The median PFS was 178 days (95% CI, 122–198), and the median OS was 398 days (95% CI, 248–704; 3‐week regimen in WJTOG‐0104 trial, 14.2 months). The toxicity profile was generally mild and tolerable. On the basis of these results, the biweekly GEM‐CBDCA regimen—administered on days 1 and 15 of a 28 day cycle—could be considered an alternative to the 3‐week regimen for NSCLC.

Trial Information

Disease

Advanced cancer

Disease

Lung cancer–NSCLC

Stage of Disease/Treatment

Metastatic/advanced

Prior Therapy

None

Type of Study – 1

Phase II

Type of Study – 2

Single arm

Primary Endpoint

Overall response rate

Secondary Endpoint

Progression‐free survival

Secondary Endpoint

Overall survival

Secondary Endpoint

Safety

Additional Details of Endpoints or Study Design

 

The sample size was calculated at an α error of 0.05 and β error of 0.2. The expected response rate and threshold response rate are determined to be 25% and 10%, respectively. The estimated minimum sample size was 43, and considering the potential patient dropout, we planned to enroll 48 patients.

 

Investigator's Analysis

Active and should be pursued further

Drug Information

Drug 1

 

  Generic/Working Name

Carboplatin

  Drug class

Platinum compound

  Dose

AUC 3 mg/mL × minute

  Route

IV

  Schedule of Administration

Carboplatin AUC of 3 mg/mL × minute biweekly, on days 1 and 15 of each 28‐day cycle

Drug 2

 

  Generic/Working Name

Gemcitabine

  Dose

1,000 mg per m²

  Route

IV

  Schedule of Administration

Gemcitabine 1,000 mg/m² biweekly, on days 1 and 15 of each 28‐day cycle

Patient Characteristics

Number of Patients, Male

35

Number of Patients, Female

13

Stage

IIIB/IV

Age

Median: 76

Number of Prior Systemic Therapies

0

Performance Status: ECOG

0 — 13

1 — 35

2 — 0

3 — 0

Unknown — 0

Cancer Types or Histologic Subtypes

Adenocarcinoma, 27

Squamous cell carcinoma, 11

Large cell carcinoma, 3

Not otherwise specified, 7

Primary Assessment Method

Title

OS

Number of Patients Enrolled

48

Number of Patients Evaluable for Toxicity

48

Number of Patients Evaluated for Efficacy

48

Evaluation Method

RECIST 1.0

Response Assessment CR

n = 0 (0%)

Response Assessment PR

n = 14 (30%)

Response Assessment SD

n = 25 (52%)

Response Assessment PD

n = 5 (10%)

Response Assessment OTHER

n = 4 (8%)

(Median) Duration Assessments OS

398 days, 95% CI, 248–704

Kaplan‐Meier Time Units, Days

Time of scheduled assessment and/or time of event	No. progressed (or deaths)	No. censored	Percent at start of evaluation period	Kaplan‐Meier, %	No. at next evaluation/no. at risk
33	1	0	100.00	97.92	47
49	1	0	97.92	95.83	46
78	1	0	95.83	93.75	45
137	1	0	93.75	91.67	44
144	1	0	91.67	89.58	43
154	1	0	89.58	87.50	42
157	1	0	87.50	85.42	41
159	1	0	85.42	83.33	40
182	1	0	83.33	81.25	39
188	1	0	81.25	79.17	38
198	1	0	79.17	77.08	37
200	1	0	77.08	75.00	36
205	1	0	75.00	72.92	35
220	1	0	72.92	70.83	34
230	1	0	70.83	68.75	33
239	0	1	68.75	68.75	32
241	1	0	68.75	66.60	31
248	1	0	66.60	64.45	30
288	0	1	64.45	64.45	29
297	1	0	64.45	62.23	28
312	0	1	62.23	62.23	27
326	1	0	62.23	59.93	26
334	0	1	59.93	59.93	25
361	1	0	59.93	57.53	24
361	0	1	57.53	57.53	23
364	0	1	57.53	57.53	22
364	0	1	57.53	57.53	21
378	0	1	57.53	57.53	20
381	1	0	57.53	54.65	19
384	1	0	54.65	51.78	18
398	1	0	51.78	48.90	17
416	1	0	48.90	46.02	16
420	0	1	46.02	46.02	15
421	1	0	46.02	42.95	14
446	0	1	42.95	42.95	13
472	0	1	42.95	42.95	12
492	1	0	42.95	39.38	11
524	1	0	39.38	35.80	10
537	0	1	35.80	35.80	9
545	0	1	35.80	35.80	8
575	0	1	35.80	35.80	7
636	0	1	35.80	35.80	6
651	0	1	35.80	35.80	5
704	1	0	35.80	28.64	4
714	0	1	28.64	28.64	3
733	0	1	28.64	28.64	2
776	0	1	28.64	28.64	1
986	0	1	28.64	0.00	0

Kaplan‐Meier plot for overall survival. The median survival time was 398 days (95% confidence interval, 248–704 days).

Primary Assessment Method

Title

PFS

Number of Patients Enrolled

48

Number of Patients Evaluable for Toxicity

48

Number of Patients Evaluated for Efficacy

48

Evaluation Method

RECIST 1.0

Response Assessment CR

n = 0 (0%)

Response Assessment PR

n = 14 (30%)

Response Assessment SD

n = 25 (52%)

Response Assessment PD

n = 5 (10%)

Response Assessment OTHER

n = 4 (8%)

(Median) Duration Assessments PFS

178; 95% CI, 122–198

Kaplan‐Meier Time Units, Days

Time of scheduled assessment and/or time of event	No. progressed (or deaths)	No. censored	Percent at start of evaluation period	Kaplan‐Meier, %	No. at next evaluation/no. at risk
14	1	0	100.00	97.92	47
20	1	0	97.92	95.83	46
33	1	0	95.83	93.75	45
52	1	0	93.75	91.67	44
62	1	0	91.67	89.58	43
63	1	0	89.58	87.50	42
76	1	0	87.50	85.42	41
78	1	0	85.42	83.33	40
86	1	0	83.33	81.25	39
92	1	0	81.25	79.17	38
93	1	0	79.17	77.08	37
95	1	0	77.08	75.00	36
112	2	0	75.00	70.83	34
113	1	0	70.83	68.75	33
118	1	0	68.75	66.67	32
122	1	0	66.67	64.58	31
129	1	0	64.58	62.50	30
143	1	0	62.50	60.42	29
154	1	0	60.42	58.33	28
155	2	0	58.33	54.17	26
174	1	0	54.17	52.08	25
178	3	0	52.08	45.83	22
179	1	0	45.83	43.75	21
189	1	0	43.75	41.67	20
190	1	0	41.67	39.58	19
197	1	0	39.58	37.50	18
198	1	0	37.50	35.42	17
206	1	0	35.42	33.33	16
208	1	0	33.33	31.25	15
211	1	0	31.25	29.17	14
212	1	0	29.17	27.08	13
221	1	0	27.08	25.00	12
235	1	0	25.00	22.92	11
240	1	0	22.92	20.83	10
245	1	0	20.83	18.75	9
248	1	0	18.75	16.67	8
254	1	0	16.67	14.58	7
307	1	0	14.58	12.50	6
312	0	1	12.50	12.50	5
316	1	0	12.50	10.00	4
343	1	0	10.00	7.50	3
364	0	1	7.50	7.50	2
371	1	0	7.50	3.75	1
378	0	1	3.75	0.00	0

Kaplan‐Meier plot for PFS. The median PFS time was 178 days (95% confidence interval, 122–198 days).

Adverse Events

All Cycles
Name	NC/NA	1	2	3	4	5	All Grades
Hemoglobin	2%	21%	46%	27%	4%	0%	98%
Leukocytes (total WBC)	22%	19%	38%	21%	0%	0%	78%
Neutrophils/granulocytes (ANC/AGC)	16%	25%	23%	21%	15%	0%	84%
Platelets	29%	48%	17%	6%	0%	0%	71%
AST, serum glutamic oxaloacetic transaminase	61%	33%	6%	0%	0%	0%	39%
ALT, serum glutamic pyruvic transaminase	50%	44%	4%	2%	0%	0%	50%
Alkaline phosphatase	58%	42%	0%	0%	0%	0%	42%
Creatinine	92%	8%	0%	0%	0%	0%	8%
Fatigue (asthenia, lethargy, malaise)	88%	8%	4%	0%	0%	0%	12%
Fever (in the absence of neutropenia, where neutropenia is defined as ANC <1.0 × 109/L)	98%	2%	0%	0%	0%	0%	2%
Rash: acne/acneiform	86%	4%	10%	0%	0%	0%	14%
Pruritus/itching	98%	0%	2%	0%	0%	0%	2%
Constipation	88%	8%	2%	2%	0%	0%	12%
Anorexia	79%	13%	8%	0%	0%	0%	21%
Nausea	92%	6%	2%	0%	0%	0%	8%
Vomiting	96%	2%	2%	0%	0%	0%	4%
Flushing	98%	2%	0%	0%	0%	0%	2%
Hair loss/alopecia (scalp or body)	96%	4%	0%	0%	0%	0%	4%
Mucositis/stomatitis (clinical exam)	98%	2%	0%	0%	0%	0%	2%
Hiccoughs (hiccups, singultus)	96%	4%	0%	0%	0%	0%	4%
Dyspnea (shortness of breath)	98%	2%	0%	0%	0%	0%	2%
Left ventricular systolic dysfunction	98%	0%	0%	2%	0%	0%	2%
Cholecystitis	98%	0%	2%	0%	0%	0%	2%
Thrombosis/thrombus/embolism	98%	0%	0%	2%	0%	0%	2%
Ulcer, GI	98%	0%	0%	2%	0%	0%	2%
Potassium, serum‐high (hyperkalemia)	98%	0%	2%	0%	0%	0%	2%

The grade 3 or higher adverse events in 10% or more cases were leukopenia (20.8%), neutropenia (35.4%), and anemia (31.3%). Dose reduction was necessary in 8.3% (4/48) of the patients.

Abbreviations: AGC, absolute granulocyte count; ALT, alanine aminotransferase; ANC, absolute neutrophil count; GI, gastrointestional; NC/NA, no change from baseline/no adverse event; WBC, white blood cell.

Assessment, Analysis, and Discussion

Completion

Study completed

Investigator's Assessment

Active and should be pursued further

In elderly patients, assessment of the degree of progression of lung cancer and predictors of response to treatment (e.g., driver oncogenes, such as epidermal growth factor receptor [EGFR] mutation and ALK fusion gene, and tumor programmed death‐ligand 1 expression), as well as assessment and prediction of an individual's ability to tolerate treatment, are critical. In drug development trials, young people with good performance status tend to be clustered as the major population, and immediate application of the results to the elderly may not be appropriate. For this reason, clinical trials in the elderly have been conducted in Japan and overseas 8, 10, 15, 16, 17. These trials have had several important findings. First, compared with best supportive care, single‐agent cytocidal anticancer therapy prolongs survival. Second, as monotherapy, vinorelbine, and gemcitabine (GEM) are the first‐line drugs in Europe, and docetaxel (DTX) is the first‐line drug in Japan. All of these treatments are used in both Europe and Japan, but the recommended dosage is lower in Japan than in Europe and in the U.S. In Japan, there is much evidence of DTX, which is often the first choice of treatment. In contrast, the use of vinorelbine tends to be less frequent in the U.S. Third, clinical trials comparing split‐dose cisplatin plus DTX versus DTX monotherapy in Japan showed that the primary endpoint, survival, was not prolonged with combination therapy. Currently, the Japanese Lung Cancer Practice Guidelines recommend single‐agent treatment with DTX and other third‐generation anticancer drugs for patients aged 75 years or older with stage IV non‐small cell lung cancer (NSCLC) and a negative or unknown driver oncogene or EGFR mutation, ALK translocation, or ROS1 translocation. In the present study, the response rate was 29.2% (95% confidence interval [CI], 17.0–44.1), and the primary endpoint was met. This was more favorable than the response rates of single‐agent DTX or single‐agent tegafur‐gimeracil‐oteracil (S‐1), with confirmed noninferiority to single‐agent DTX [17]. The median progression‐free survival was 178 days (95% CI, 122–198), the median overall survival was 398 days (95% CI, 248–704), and the 1‐year survival was 57.5%. These results are comparable to the results of previous clinical studies in the elderly. Toxicity was generally mild, with grade 3 or greater neutropenia occurring in 29.2% of patients and thrombocytopenia in 4.2%. We conclude that this treatment regimen is appropriate for a validation group in phase III trials.

Pemetrexed (PEM), which is incorporated into standard therapy in nonelderly patients with non‐squamous cell carcinoma, is also a promising drug for the treatment of the elderly, but there is insufficient evidence for this. Recently, a phase III trial in Japan comparing DTX monotherapy with CBDCA + PEM in non‐squamous cell carcinoma patients aged 75 years or older found that the median overall survival was 15.5 months (95% CI, 13.6–18.4) in the DTX monotherapy group and 18.7 months (95% CI, 16.0–21.9) in the CBDCA‐PEM therapy group, with a stratified hazard ratio of 0.850 (95% CI, 0.684–1.056). The upper limit of the 95% CI of the p value, 1.056, was below 1.154, thus proving the noninferiority of CBDCA‐PEM therapy. The progression‐free survival favored CBDCA‐PEM therapy, with a hazard ratio of 0.739 (95% CI, 0.609–0.89). Response rates were also higher in the CBDCA‐PEM arm; DTX monotherapy had a response rate of 28.2% and CBDCA‐PEM therapy a response rate of 36.8% (p = .0740). In Japan, we recently obtained marketing approval for the use of necitumumab, an antimonoclonal antibody against EGFR, for unresectable advanced and recurrent squamous cell NSCLC. Since necitumumab is administered concomitantly with GEM plus platinum, the regimen in this study may also be applicable to treatment with necitumumab.

The results of this study met the criteria for the primary endpoint. Combination chemotherapy with CBDCA and GEM was found to be effective and well‐tolerated in elderly patients with NSCLC. These results warrant further evaluation of this combination in phase III trials.

Disclosures

Koichi Takayama: Chugai‐Roche Co., Ono Pharmaceutical Co. (RF), AstraZeneca, Chugai‐Roche Co., MSD‐Merck Co., Eli Lilly Co., Boehringer‐Ingelheim Co., DaiichiSankyo Co. (H); Junji Uchino: AstraZeneca, Eli Lilly Japan K.K. (RF). The other authors indicated no financial relationships.

(C/A) Consulting/advisory relationship; (RF) Research funding; (E) Employment; (ET) Expert testimony; (H) Honoraria received; (OI) Ownership interests; (IP) Intellectual property rights/inventor/patent holder; (SAB) Scientific advisory board