Ellis, Peter M. MD, PhD*†; Jungnelius, Ulf MD‡; Zhang, Jennie PhD‡; Fandi, Abderrahim MD, PhD‡; Beck, Robert BSc‡; Shepherd, Frances A. MD§¶
Small-cell lung cancer (SCLC) represents approximately 15% of all lung cancers.1 SCLC is associated with rapid tumor doubling and early metastatic spread. SCLC is highly responsive to chemotherapy and radiotherapy; however, most patients relapse within 2 years of treatment and die from recurrent disease.1 There has been little improvement in survival for SCLC in recent decades, despite the evaluation of multiple new agents and approaches.2 The addition of biological and targeted agents has also been unsuccessful.3,4
An analysis of historical randomized studies in SCLC revealed a median survival of 7.0 months in studies performed from 1972 to 1981, whereas those performed from 1982 to 1990 reported a median survival of 8.9 months (p = 0.001).2 This modest improvement is likely because of the introduction of the cisplatin+etoposide regimen as a standard therapy in the early 1980s,2 and this outcome has remained consistent over the past two decades. Currently, median survival ranges between 9 and 11 months, with less than 5% of patients surviving beyond 2 years.1
Immunomodulatory drugs (IMiDs) improve survival among patients with multiple myeloma, and combination regimens including IMiDs and chemotherapeutic agents have demonstrated efficacy in relapsed or refractory disease.5 Pomalidomide (CC-4047; Celgene Corporation, Summit, NJ) is an immunomodulatory compound with potent antiangiogenic and tumoricidal effects.6–10 Pomalidomide has been shown to inhibit proangiogenic factors, vascular endothelial growth factor, and basic fibroblast growth factor,7–9 which promote tumor cell proliferation and migration and are associated with poor prognosis in lung cancer.11,12 Pomalidomide has demonstrated antitumor activity and tolerability in combination with gemcitabine in metastatic pancreatic cancer13 and has been evaluated in another study in patients with various solid tumors.14
The aim of this study was to determine the maximum-tolerated dose (MTD) and safety profile of pomalidomide administered with cisplatin+etoposide in chemotherapy-naive patients with extensive-stage (ES) SCLC.
PATIENTS AND METHODS
Chemotherapy-naive patients aged 18 years and older with histologically or cytologically confirmed ES SCLC were eligible, if they had an Eastern Cooperative Oncology Group performance status (ECOG PS) of 0, 1, or 2. Written informed consent was obtained from all the patients. The study was approved by each institution’s Research Ethics Board. Screening for protocol eligibility was conducted within 4 weeks of treatment initiation.
Study Design and Treatment Schedule
This was a multicenter, phase I, open-label, dose-escalation study (www.ClinicalTrials.gov: NCT00537511) designed to determine the MTD of pomalidomide in combination with cisplatin+etoposide chemotherapy (Fig. 1).
Eligible patients were enrolled into cohorts of three patients. Chemotherapy consisted of intravenous (IV) cisplatin 25 mg/m2 and etoposide 100 mg/m2 on days 1 to 3 of each 21-day cycle. Pomalidomide was administered orally at doses of 1, 3, or 5 mg/day on days 1 to 14. Dose escalation followed a standard phase I 3+3 design. If MTD was exceeded at 3- or 5-mg pomalidomide, the next dose levels would be reduced by 1 mg; if MTD was exceeded at 1 mg, the next dose level would be 0.5 mg.
Adverse events (AEs) were graded in accordance with the National Cancer Institute Common Toxicity Criteria for AEs (NCI CTCAE) version 4.0. The MTD, determined during cycle 1, was defined as the highest dose level at which no more than one of six patients experienced a dose-limiting toxicity (DLT). Six additional patients were assigned to receive pomalidomide at the MTD with cisplatin+etoposide. Patients experiencing a DLT during cycle 1 were allowed to continue on study, at the investigator’s discretion. Patients without DLT or progressive disease at the end of cycle 1 could receive up to six treatment cycles (extension period). Patients without disease progression after six cycles of pomalidomide plus cisplatin+etoposide could continue with pomalidomide alone. Three weeks after the last chemotherapy, the pomalidomide dose was increased to 5 mg daily (days 1–14 of each 21-day cycle) for this maintenance period.
Response was assessed every three cycles, using Response Evaluation Criteria in Solid Tumors.15 For patients continuing pomalidomide after chemotherapy, response was assessed every three cycles.
Hematopoietic growth factors as prophylaxis or managing of hematologic toxicities were not allowed in cycle 1. However, subsequent use of hematopoietic growth factors was allowed.
The primary objective was to identify the MTD of pomalidomide administered with cisplatin+etoposide in patients with ES SCLC. Secondary objectives included safety, investigator-determined overall response rate (ORR), response duration, and overall survival (OS).
A 3+3 design was used to determine the MTD during cycle 1 and was defined as the highest dose level at which no more than one of six patients experienced a DLT. Response, on the basis of Response Evaluation Criteria in Solid Tumors version 1.0, was assessed by the investigators and was summarized by treatment cohort for the intent-to-treat population.15
Baseline Characteristics and Treatment
Twenty-two patients with ES SCLC were enrolled; median age was 64.5 years (range, 49–77 years), 81.8% were men, and 27.3% had an ECOG PS of 2 (Table 1).
Four dosing cohorts of pomalidomide were evaluated: 1 mg/day (6 patients), 3 mg/day (4 patients), as well as 5 mg/day and 4 mg/day (6 patients each). All patients received at least one pomalidomide dose. Four patients discontinued because of AEs, two died, and one received growth factors for neutropenia during cycle 1 and was therefore withdrawn in accordance with the eligibility criteria. One patient was not evaluated while on treatment for unknown reasons.
DLTs per dose are summarized in Table 2. At the pomalidomide 5-mg dose level, two DLTs were observed (transient ischemic attack/cerebrovascular accident and neutropenic infection); therefore, pomalidomide was de-escalated to 4 mg daily. The median treatment duration with pomalidomide for all patients was 20.5 weeks; median durations were longer in the 1- and 3-mg cohorts than in the 4- and 5-mg cohorts (17.9 and 17.0 weeks versus 14.0 and 13.0 weeks, respectively). Nine patients did not receive all the six treatment cycles during phase I of the study (5 patients received 1 cycle, 1 received 2 cycles, and 3 received 4 cycles). Reasons for discontinuation were AEs, death, withdrawal of consent, progression of disease, and others. Overall, four DLTs were observed among three patients for which a relationship with pomalidomide and cisplatin+etoposide was suspected. One patient in the 1-mg pomalidomide cohort had grade 4 cerebral ischemia and grade 3 convulsions and died of sepsis. In the 5-mg cohort, one patient had a grade 4 transient ischemic attack and another experienced fatal neutropenic infection. In both patients, treatment with pomalidomide and cisplatin+etoposide had been withdrawn.
The MTD of pomalidomide was established as 4 mg on days 1 to 14 with cisplatin+etoposide. In this cohort, three patients (50%) required a dose delay of cisplatin (n = 2), etoposide (n = 1), and/or pomalidomide (n = 3); none of the patients required a dose reduction. Patients in the 5-mg cohort received fewer cycles of chemotherapy, suggesting that the addition of pomalidomide at this dose level compromised the ability to deliver standard doses of chemotherapy.
All 22 patients were included in the safety analysis, and all discontinued the study treatment: five during cycle 1, six during cycles 2 to 6, three during or at the end of cycle 7, and eight during the pomalidomide maintenance period. Most patients (13 of 22; 59.1%) discontinued the study treatment because of disease progression and four patients (18.2%) because of AEs; two patients (9.1%) died because of sepsis and pulmonary emboli.
Most AEs were grade 1 or 2; however, all patients experienced at least one AE of grade 3 or higher. The most common AEs of all grades were fatigue (95.5%), nausea (68.2%), constipation (54.5%), neutropenia (54.5%), anemia (40.9%), alopecia (54.5%), and rash (27.3%). Grade 1 to 2 renal dysfunction was observed in three patients. With the exception of nausea, constipation, and neutropenia, which occurred more frequently in the 4- and 5-mg cohorts, a relationship between the frequency of AEs and pomalidomide dose level was not suspected. The most common AEs (all grades) related to pomalidomide were fatigue (72.7%), nausea (45.5%), and neutropenia (40.9%).
Pomalidomide-related serious AEs were observed in 31.8% of patients, and 40.9% of patients experienced cisplatin- and/or etoposide-related serious AEs. Serious AEs of neutropenic infection, febrile neutropenia, cerebral ischemia, pulmonary embolism, sepsis, fatigue, convulsion, diverticular perforation, and increased blood creatinine were in most cases suspected to be related to the study treatment (pomalidomide and/or cisplatin+etoposide). Sixteen patients died during the study: most deaths (13 of 16; 81%) resulted from underlying disease and occurred more than 30 days after treatment discontinuation. Three subjects died of causes other than disease progression: central nervous system cerebrovascular ischemia (suspected to be related to both pomalidomide and cisplatin and/or etoposide), pulmonary emboli (suspected to be related to cisplatin and/or etoposide), and unknown cause (125 days after the last dose of pomalidomide).
The most common grade 3 or higher AEs were neutropenia (55%), thrombocytopenia (9%), and anemia (23%) (Table 3). Neutropenia of grade 3 and higher was seen more frequently with higher pomalidomide dose levels: 83.3% of patients in the 5-mg pomalidomide cohort versus 33.3% in the 1-mg cohort, and 50% in each of the 3- and 4-mg cohorts. The most common grade 3 to 4 nonhematologic AE was fatigue (18.2%). Other grade 3 to 4 AEs that occurred in at least two patients included anemia and cerebral ischemia. Grade 4 AEs were less frequent in the 1- and 3-mg cohorts compared with those in the 4- and 5-mg cohorts. Grade 5 AEs were observed in three patients and included sepsis (1-mg cohort), pulmonary embolism (4-mg cohort), and neutropenic infection (5-mg cohort).
Investigator-assessed ORR was 31.8%, with all responses (7 of 22 patients) being partial responses (PRs) (Table 4). Four patients (18.2%) had unconfirmed PR, listed in Table 4 as stable disease. Four patients (18.2%) had progressive disease. Of the remaining patients, six discontinued before the first postbaseline assessment and one was not evaluated for reasons unknown. There was no evidence of a dose–response effect for pomalidomide.
The median response duration for responding patients was 12.4 weeks (range, 0.1–19.4) (Table 4). There was one unconfirmed PR in the 5-mg group that lasted less than 4 weeks as the patient was hospitalized for diverticular perforation after cycle 4 and died from SCLC. In the remaining 10 responders, response duration varied from 4 to 19.4 weeks. At the time of study closure, four patients (18%) were censored for response duration because either their disease had not progressed or they had discontinued the treatment before progression was documented.
At the time of study closure, six patients (27%) were alive and were therefore censored for the OS analysis. The median OS was 49.6 weeks (95% confidence interval: 28.0–63.9).
As the observed ORR for pomalidomide and cisplatin+etoposide in this study was consistent with published data for cisplatin+etoposide alone, and the secondary endpoint for median OS had been reached, the study was terminated and phase II investigation canceled.
This phase I study demonstrated that the MTD of pomalidomide was 4 mg on days 1 to 14 in combination with IV cisplatin 25 mg/m2 and IV etoposide 100 mg/m2. Patients discontinued treatment primarily (59.1%) because of disease progression. The most common AE leading to treatment modification was grade 3 to 4 neutropenia, which in the majority of cases, was suspected to be related to both pomalidomide and cisplatin+etoposide. Neutropenia led to transient treatment interruption but not treatment discontinuation; furthermore, no change to the dose of pomalidomide or cisplatin+etoposide occurred after treatment interruption. This neutropenia rate is comparable with those reported in previous studies investigating cisplatin+etoposide in extensive disease SCLC.16–18 Neutropenia of grade 3 or higher seemed to be more frequent in the 5-mg cohort (83.3% versus 33.3% in the 1-mg cohort and with 50% in the 3- and 4-mg cohorts).
The AE profile of pomalidomide combined with cisplatin+etoposide was consistent with that observed in patients with ES SCLC who were treated with cisplatin+etoposide alone; notably, pomalidomide was not associated with any serious (grade ≥3), treatment-related renal toxicities.16–18 The AE profile for pomalidomide in this study was also consistent with that observed in trials of pomalidomide in multiple myeloma.19,20 Fatigue was one of the most common nonhematologic AEs of grade 3 or 4. Fourteen patients (63.6%) experienced at least one treatment-emergent AE (TEAE) that led to dose reduction or interruption of pomalidomide and 13 (59.1%) experienced one or more TEAEs that led to dose reduction or interruption of cisplatin and/or etoposide. However, patients in the 5-mg cohort seemed to receive fewer cycles of chemotherapy than patients in the 1- or 3-mg cohorts (median number of cycles 4 versus 6). This highlights the need for dose-escalation schedules to consider not only the toxicity experienced during cycle 1, but also the impact of toxicity in subsequent cycles of treatment. There was no relationship between chemotherapy dose reduction or interruption and pomalidomide dose.
The ORR for pomalidomide in combination with cisplatin+etoposide was consistent with published data for cisplatin+etoposide given alone.18,21,22 The addition of pomalidomide to cisplatin+etoposide did not seem to improve the ORR (32%) or survival compared with published data for cisplatin+etoposide alone.18,21,22 These results are disappointing because previous trials with thalidomide suggested a possible benefit for this agent. In one trial, 119 patients with ES SCLC, who had responded to two cycles of etoposide, cisplatin, cyclophosphamide, and 4′-epidoxorubicin (PCDE) received thalidomide 400 mg/day or placebo with their four subsequent chemotherapy cycles.23 Progression-free survival (PFS) and OS were longer in the thalidomide arm, although the differences were not significant (OS, p = 0.16; PFS, p = 0.015); however, the difference was significant in patients with an ECOG PS score of 1 or 2 (OS, p = 0.02; PFS, p = 0.02). Patients receiving thalidomide had an increased incidence of sensory neuropathy of grade 2 or higher. In another study, thalidomide 100 to 200 mg/day or placebo was combined with etoposide+carboplatin in patients with both limited-stage or ES SCLC.24 There was no difference in OS (10.1 versus 10.5 months) in the total patient population; furthermore, in ES patients, thalidomide was associated with worse OS compared with placebo (8.0 versus 9.1 months; p = 0.011). Thalidomide also led to a higher incidence of thrombotic events compared with placebo (19 versus 10%; p < 0.001).
In conclusion, although pomalidomide may be combined with cisplatin+etoposide chemotherapy for ES SCLC, it does not seem to improve the therapeutic index of cisplatin+etoposide alone. On the basis of these data, pomalidomide does not warrant further study in ES SCLC.
This study was funded by Celgene Corporation. Medical writing services were provided by Marlene Knippenberg, PhD, Ronald van Olffen, PhD, and Kim Grootscholten, MSc, of Excerpta Medica.
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Pomalidomide; Chemotherapy; Extensive-stage small-cell lung cancer; Phase I trial; First-line therapy