Randomized, Double-Blind, Phase II Study of Temozolomide in Combination With Either Veliparib or Placebo in Patients With Relapsed-Sensitive or Refractory Small-Cell Lung Cancer

Abstract

Purpose Both temozolomide (TMZ) and poly (ADP-ribose) polymerase (PARP) inhibitors are active in small-cell lung cancer (SCLC). This phase II, randomized, double-blind study evaluated whether addition of the PARP inhibitor veliparib to TMZ improves 4-month progression-free survival (PFS). Patients and Methods A total of 104 patients with recurrent SCLC were randomly assigned 1:1 to oral veliparib or placebo 40 mg twice daily, days 1 to 7, and oral TMZ 150 to 200 mg/m²/day, days 1 to 5, of a 28-day cycle until disease progression, unacceptable toxicity, or withdrawal of consent. Response was determined by imaging at weeks 4 and 8, and every 8 weeks thereafter. Improvement in PFS at 4 months was the primary end point. Secondary objectives included overall response rate (ORR), overall survival (OS), and safety and tolerability of veliparib with TMZ. Exploratory objectives included PARP-1 and SLFN11 immunohistochemical expression, MGMT promoter methylation, and circulating tumor cell quantification. Results No significant difference in 4-month PFS was noted between TMZ/veliparib (36%) and TMZ/placebo (27%; P = .19); median OS was also not improved significantly with TMZ/veliparib (8.2 months; 95% CI, 6.4 to 12.2 months; v 7.0 months; 95% CI, 5.3 to 9.5 months; P = .50). However, ORR was significantly higher in patients receiving TMZ/veliparib compared with TMZ/placebo (39% v 14%; P = .016). Grade 3/4 thrombocytopenia and neutropenia more commonly occurred with TMZ/veliparib: 50% versus 9% and 31% versus 7%, respectively. Significantly prolonged PFS (5.7 v 3.6 months; P = .009) and OS (12.2 v 7.5 months; P = .014) were observed in patients with SLFN11-positive tumors treated with TMZ/veliparib. Conclusion Four-month PFS and median OS did not differ between the two arms, whereas a significant improvement in ORR was observed with TMZ/veliparib. SLFN11 expression was associated with improved PFS and OS in patients receiving TMZ/veliparib, suggesting a promising biomarker of PARP-inhibitor sensitivity in SCLC.

Trial registration: ClinicalTrials.gov NCT01638546.

Fig 1.

CONSORT diagram. A total of 104 patients were randomly assigned in a 1:1 fashion, stratified by sensitive disease or refractory disease and center. Four patients were not treated: three in the temozolomide (TMZ)/placebo arm (one each: withdrawal of consent, complications of disease, and concomitant therapy prohibitive to initiate study medication), and one in the TMZ/veliparib arm (complications of disease). Forty-six and 54 patients were evaluable for safety in the TMZ/placebo and TMZ/veliparib arms, respectively. In the TMZ/placebo arm, 44 patients were evaluable for response because two patients were removed for toxicity during the first cycle and before undergoing imaging, indicated by (*). In the TMZ/veliparib arm, five patients were removed from the study, indicated by (*), during the first cycle: registered ineligible (n = 1), clinical progression of disease (n = 3), and death due to treatment toxicity (n = 1). As such, 49 patients were evaluable for response. AE, adverse event; SCLC, small-cell lung cancer.

Fig 2.

Kaplan Meier curves for outcomes. (A) Progression-free (PFS) and (B) overall survival (OS) for the 104 patients with sensitive or refractory small-cell lung cancer in need of second- or third line-therapy.

Fig 3.

Tumor response. The best calculated percentage change in tumor size on the basis of measurable lesions for (A) 49 evaluable patients in the temozolomide (TMZ)/veliparib arm and (B) 44 evaluable patients in the TMZ/placebo arm. In the TMZ/veliparib arm, five patients were removed from the study during the first cycle and were not evaluable for response: registered ineligible (n = 1), clinical progression of disease (n = 3), and death due to treatment toxicity (n = 1). In the TMZ/placebo arm, two patients were removed for toxicity during the first cycle and before undergoing imaging; thus, they were not evaluable for response; one other patient’s tumor measurements were not available, although the patient developed progression of disease on the basis of the appearance of new nontarget lesions. CR, complete response; ORR, .overall response rate; PR, partial response.

Fig 4.

SLFN11 immunohistochemistry (IHC) predicts improved survival. (A) Example images of tumors with negative (neg) and positive (pos) SLFN11 by IHC (scale bar = 100 uM, 400× magnification). (B) Overall survival (OS) and progression-free survival (PFS) from date of randomization was improved in patients with SLFN11-positive disease in the temozolomide (TMZ)/veliparib treatment arm (PFS overall interaction log-rank P = .046; OS overall interaction log-rank P = .095). (C) OS from time of diagnosis trends toward increased survival in patients with SLFN11 positive (IHC score ≥ 1) disease. (D) Swim-plot of months on trial in the TMZ/veliparib treatment arm color coded by potential biomarker of response (time calculated from start of treatment to date of last follow-up). Blue indicates SLFN11 positive; (*)MGMT promoter methylation. (E) Summary of biomarker status (SLFN11; MGMT methylation; ATM, BRCA2, or CHEK2 mutation for patients with response data). Gray indicates biomarker assayed and not detected; white indicates no data. Best response to treatment in each treatment arm. ATM, ATM mutation; BRCA2, BRCA2 mutation; CR, complete response; Dx, diagnosis; mo, months; NA, not achieved; PD, progression of disease; PR, partial response; SD, stable disease.

Fig A1.

Tumor response in a patient treated with veliparib and temozolomide. A 57-year-old man with small-cell lung cancer metastatic to the brain, pancreatic tail, juxtaphrenic nerve, and subcutaneous tissue treated with the temozolomide (TMZ)/veliparib arm. (A) Sagittal T1-weighted magnetic resonance imaging scan with contrast shows a 1-cm metastasis (arrow) in the right frontal lobe at the time of enrollment in the study. (B) Sagittal T1-weighted magnetic resonance imaging scan with contrast demonstrates complete resolution of the brain lesion (arrow shows previous location) after therapy with TMZ/veliparib. (C) Axial computed tomography scan (CT) with contrast in narrow windows illustrates a 5-cm juxtaphrenic nodal mass (arrow) at the time that therapy was commenced. (D) Axial CT with contrast after therapy with TMZ/veliparib shows significant decrease in the lesion (arrow) compatible with response to therapy. (E) Axial abdominal CT with contrast shows a 5-cm heterogeneously enhancing lesion in the pancreatic tail (arrows). (F) Axial abdominal CT with contrast after therapy with TMZ/veliparib shows interval decrease in the pancreatic lesion to 3.5 cm. (G) Axial CT with contrast in narrow windows shows a 2.5-cm soft tissue implant (arrow) in the subcutaneous fat overlying the left gluteal muscles. Axial CT with contrast after treatment with the combination of veliparib and TMZ demonstrates a decrease in the size of the lesion (arrow). Importantly, there was significant pain associated with the lesion, which improved with temozolomide/veliparib therapy. Ao, aorta; C, colon; IVC, inferior vena cava; H, heart; K, kidney; L, liver; S, spleen.

Fig A2.

Poly (ADP-ribose) polymerase (PARP)-1 expression does not predict improved survival. (A) Progression-free survival (PFS) and (B) overall survival (OS) from date of randomization was not improved in patients whose tumors expressed PARP-1 by immunohistochemistry in the temozolomide (TMZ)/veliparib arm compared with the TMZ/placebo arm. IHC, immunohistochemistry; mo, months; NA, not achieved.

Fig A3.

SLFN11 expression does not predict improved response to treatment. Waterfall plots of best Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 response (%) in each treatment arm color coded by SLFN-11 immunohistochemistry (IHC) status (positive, negative, or unknown): (A) temozolomide (TMZ)/placebo and (B) TMZ/veliparib. Boxplot of RECIST 1.1 responses in each treatment arm by SLFN-11 IHC: (C) TMZ/placebo and (D) TMZ/veliparib; trend toward deeper responses among patients with SLFN11-positive disease receiving veliparib and TMZ combination. CR, complete response; NA, not available; PD, progression of disease; PR, partial response; SD, stable disease.

Fig A4.

MGMT promoter methylation did not predict improved survival. (A) Progression-free survival (PFS) and (B) overall survival (OS) from the date of randomization in patients with known MGMT promoter methylation status. mo, months; NA, not achieved; TMZ, temozolomide.

Fig A5.

Low circulating tumor cell (CTC) numbers were associated with improved outcomes. CTCs < 5 in 7.5 mL were associated with improved survival. (A) At baseline and (B) at the end of cycle 1, CTCs < 5 in 7.5 mL were associated with improved survival. mo, months; OS, overall survival.