A phase I trial of temsirolimus and pemetrexed in patients with advanced non-small cell lung cancer

Abstract

Background

Pemetrexed is an anti-folate chemotherapeutic agent approved for use in non-small cell lung cancer. Mammalian target of rapamycin (mTOR) pathway is implicated in lung cancer development, and is inhibited by temsirolimus.

Methods

We performed a phase I study evaluating the combination of pemetrexed and temsirolimus in advanced non-squamous non-small cell lung cancer (NSCLC).

Results

Eight patients were enrolled in this study. The dose limiting toxicities included grade 4 thrombocytopenia, grade 3 leukopenia and grade 3 neutopenia. The maximum tolerated dose was determined to be pemetrexed 375 mg/m² intravenously on day 1 and temsirolimus 25 mg intravenously on days 1,8 and 15. No objective responses were noted, and 3 patients had stable disease as the best response.

Conclusion

The combination of pemetrexed and temsirolimus is feasible and well tolerated. This combination may be further evaluated in patients with mTOR pathway activation, particularly in patients with TSC1 or STK11 mutations.

INTRODUCTION

Lung cancer remains the leading cause of cancer-related death in the United States, accounting for more deaths than breast cancer, colon cancer and pancreatic cancer combined.¹ Non-small cell lung cancer accounts for 87% of lung cancer, and approximately 40% of patients present with metastatic disease treated with palliative systemic therapy.^2,3 Platinum-containing chemotherapy regimens have been shown to improve survival and quality of life in patients with good performance status.⁴ Small molecule inhibitors of the epidermal growth factor receptor (EGFR) gene and anaplastic lymphoma kinase (ALK) gene are used in patients with activating EGFR mutations and ALK gene rearrangements, respectively.^5–7 For patients with poor performance status, no targetable molecular alterations or tumor progression after front-line platinum-doublet therapy, treatment options are limited, with single agent chemotherapy recommended for eligible patients with good performance status.⁸

Pemetrexed is a folate antagonist approved for the treatment of patients with metastatic non-squamous lung cancer. The activity of pemetrexed is comparable to approved second line agents. In a randomized trial comparing pemetrexed to docetaxel, although there were no significant differences in median overall survival (OS), the toxicity profile favored pemetrexed with less. Grade 3 or 4 toxicities including neutropenia (5.3% vs 40.2%), febrile neutropenia (1.9% vs 12.7%), neutropenia with infections (3.3% vs. 0%), hospitalizations with neutropenic fever (13.4% vs. 6.4%), use of granulocyte colony-stimulating factor support (2.6% vs 19.2%), and all grade alopecia (6.4% vs 37.7%).^9,10

Activation of the mammalian target of rapamycin (mTOR) pathway has been implicated in the development of several malignancies, including lung cancer.^11,12 Temsirolimus is an inhibitor of the mTOR kinase and has demonstrated anti-proliferative and anti-angiogenic activity in multiple tumor types. Temsirolimus is generally well-tolerated with observed grade 3 or 4 toxicities including hyperglycemia (17%), hypophosphatemia (13%), anemia (9%), and hypertriglyceridemia (6%).^13,14 In a phase II study of multiple dose levels of temsirolimus, the 25 mg dose was found to be equally efficacious as higher doses, and was therefore chosen as the optimal dose for monotherapy.¹⁵. In the phase II study reported by Ruengwetwattana and colleagues, 55 patients with untreated NSCLC received temsirolimus 25 mg intravenously on a weekly basis.¹⁶ The clinical benefit rate was 35% with a partial response in 4 patients and stable disease for 8 weeks or more in 14 patients.

Pemetrexed and temsirolimus target different cellular pathways and may have synergistic activity when given in combination.^17,18 In a preclinical study, rapamycin and pemetrexed had synergistic effects in inhibiting the proliferation of NSCLC cells through downregulation of thymidylate synthase by rapamycin, increasing the activity of pemetrexed.¹⁷ Pemetrexed has also been shown to inhibit mTOR through the accumulation of ZMP, a substrate of the secondary target aminoimidazoecarboxamide ribonucleotide formyltransferase (AICART).¹⁸ Furthermore, temsirolimus is well-tolerated and has non-overlapping toxicities with pemetrexed. In a phase I study including 24 patients treated with pemetrexed and everolimus, administered either daily or weekly, there were 3 partial responses.¹⁹ The combination was considered safe although the frequency and severity of adverse events was higher than expected for each drug alone. The most common grade 3 and 4 toxicities were neutropenia, thrombocytopenia and dyspnea. Therefore we conducted a phase I study temsirolimus in combination with pemetrexed to establish the safety.

METHODS

Patients with histologically or cytologically confirmed advanced non-squamous NSCLC were enrolled on this study. Eligibility criteria allowed prior therapies, as long as treatment was completed at least 4 weeks prior to study entry. Patients who had not received prior therapy were eligible if they were not candidates for platinum-based chemotherapy. Other eligibility criteria included an ECOG performance status of 0–2, age ≥18, adequate marrow function (ANC ≥1500 cells/mm³; hemoglobin ≥9g/dl; platelets ≥ 100000/mm³; hepatic function (total bilirubin ≤1.5 mg/dL; AST/ALT ≤ 2.5 times the upper limit of normal or ≤ 5 times upper limit of normal for patients with liver metastasis); and renal function (creatinine <2.0 mg/dL and/or creatinine clearance ≥60 mL/min). Patients were required to have serum cholesterol <350 mg/dL and serum triglycerides < 300 mg/dL. The washout period for prior chemotherapy or surgery was 4 weeks, and 2 weeks for radiation therapy. Key exclusion criteria included prior treatment with pemetrexed, severe acute or chronic medical conditions and symptomatic brain metastasis. Written informed consent was obtained from all patients, and the trial was approved by the Washington University Human Research Protection Office.

The starting dose (dose level 1) of pemetrexed was 500 mg/m² administered on day 1 of each 21 day cycle over 10 minutes intravenously and temsirolimus 15 mg administered intravenously over 30 minutes on days 1, 8 and 15 of each cycle (Table 1). Patients were premedicated with IV steroids (dexamethasone 10 mg or equivalent), 5 HT3 receptor antagonists (palonosetron 0.25 mg or equivalent), and antihistamines (diphenhydramine 50 mg or equivalent) prior to treatment on days that included both pemetrexed and temsirolimus. Patients were premedicated with diphenhydramine 50 mg IV on the days that temsirolimus alone was administered. Routine supportive care was permitted. However, patients were recommended to avoid potent CYP3A4 inhibitors and inducers.

Table 1.

Dose escalation schema

Cohort	Pemetrexed (mg/m2) on day 1 every 3 weeks	Temsirolimus (mg) weekly on days 1,8,15
−1	375	15
1	500	15
2	500	20
3	500	25

A modified Fibonacci dose escalation scheme with a minimum of 3 patients per cohort was used.²⁰ Dosing began at dose level 1 and was escalated or de-escalated as appropriate. If a DLT occurred in 1 out of the first 3 patients, an additional 3 patients were accrued at the same dose level. If more than two patients in a given cohort experienced a DLT, the cohort would have exceeded the maximum tolerated dose (MTD) and a minimum of 6 patients were accrued at the next lower dose level.

All toxicities were graded according to the NCI CTCAE v.3.0. The MTD was defined as the dose level immediately below the dose at which 2 patients of a cohort experienced DLT. DLT was defined as any of the following during the first cycle of treatment: grade 4 neutropenia for greater than 7 days, neutropenic fever, grade 4 anemia, grade 3 or greater thrombocytopenia, grade 3 or greater toxicity determined to be reasonably related to protocol therapy, or any toxicity requiring a delay of protocol therapy greater than 14 days during the first cycle of therapy (6 weeks). Patients had weekly complete blood count and toxicity assessments performed during the first cycle of therapy to evaluate for DLT. Physical exams were performed every three weeks during the first cycle of therapy.

Patients were evaluated for response radiographically every 2 cycles. Treatment continued until progression of disease, DLT, or if the patient chose to withdraw from study therapy. Patients who experienced DLTs were removed from study and not evaluated for response but were evaluable for toxicity. Response was defined by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.0 criteria.

RESULTS

Between December 2009 and February 2011, 8 patients were enrolled in this study, of which 6 were men and 2 were women. The median age of these patients was 58.5 years (49–76). One patient had a performance status of 0, 6 patients had a performance status of 1 and one patient had a performance status of 2. Five patients had received one prior line of systemic platinum doublet therapy, while 3 patients were treatment naïve. Five patients had received prior radiation therapy, including whole brain radiation in 2 patients and thoracic radiation in 3 patients. Patients were treated on two dose levels: 2 patients received treatment on dose level 1, 6 patients received treatment on dose level -1. Patients received a mean of 2 cycles (6 weeks) of therapy.

At the first dose level, one patient completed 1.5 cycles and experienced a DLT of grade 4 thrombocytopenia, grade 3 leukopenia and grade 3 neutopenia (Table 2). A second patient treated at this dose level also developed grade 3 leukopenia and so the decision was made to decrease to dose level -1, comprising of pemetrexed 375 mg/m² on day 1 and temsirolimus 15 mg IV weekly on days 1,8, and 15. In dose level -1, no DLTs were observed and it was declared the MTD.

Table 2.

Toxicity profile

Toxicity	Cohort 1 (N=2)			Cohort -1 (N=6)
	Any	Grade 3	Grade 4	Any	Grade 3	Grade 4
Hematologic
Anemia	2	1		5	1
Leukopenia	2	2		6	2
Neutropenia	2	1		3	1	1
Lymphopenia	2			6	1	1
Thrombocytopenia	2		1	4
Non-hematologic
Fatigue	1			2	1
Anorexia	3
Nausea	1			3
Vomiting				2
Diarrhea				1
Constipation				1
Pain	1			3
Skin rash	1			2
Dyspnea				2	2
Hypoxia				1	1
Headache	1			1
Insomnia				2
Depression				1
Confusion	1
Creatinine elevation				2
Hyperglycemia	1			4	3
Hyponatremia				2
Hypocalcemia	2			2
Hypomagnesemia				1
Hypertriglyceridemia				1
Hypoalbuminemia	2			4
Hyperbilirubinemia	1
Elevated AST				5	1
Elevated ALT				3	1
Proteinuria	1
Watering eyes				1

Four patients were not evaluable for response. One patient in cohort 1, who experienced DLT of grade 4 thrombocytopenia, grade 3 leukopenia and grade 3 neutropenia was removed from study per investigator discretion. An additional patient was removed from trial by the treating physician, and two patients with poor performance status expired prior to week 6 scans, although no DLTs were observed in them. Four patients were evaluable for anti-tumor activity. Two of these patients had stable disease of 12 weeks duration, one patient had stable disease of 4 weeks duration, and one patient experienced disease progression. There were no responses observed.

DISCUSSION

The combination of pemetrexed and temsirolimus in patients with metastatic non-small cell lung cancer enrolled in this trial, with the maximum tolerated dose of pemetrexed 375 mg/m² on day 1 and temsirolimus 15 mg IV weekly. The lack of responses is not surprising in this small patient cohort, comprising mostly of patients who had failed prior platinum doublet therapy, and included a patient with PS 2. Patients with poor performance status remain a challenging group to treat, and more clinical trials are needed for this patient population, geared to filling this unmet need. Future trials should examine the activity of this combination in patients with mTOR pathway activation in NSCLC, in particularly for those with TSC1 or STK11 mutations, as these genomic alterations have been associated with response to mTOR inhibitor therapy.^21,22