The standard of care for patients with small-cell lung cancer (SCLC) has remained unchanged for several decades. Now, the findings of a phase II study reveal the potential of biomarker-guided use of temozolomide (TMZ) in combination with veliparib in patients with tumours expressing schlafen family member 11 (SLFN11), which promotes cell death following DNA damage.

In this trial, 104 unselected patients with relapsed and/or refractory SCLC were randomized to receive either TMZ plus placebo or TMZ plus the poly(ADP-ribose) polymerase (PARP) inhibitor veliparib. Patients in the TMZ plus veliparib group had no significant improvement in overall survival (8.2 months versus 7.0 months in the TMZ plus placebo group; P = 0.5). In a prespecified subgroup analysis, however, patients in the TMZ plus veliparib arm with SLFN11-positive tumours, as defined using immunohistochemistry (n = 12), had improved progression-free survival (5.7 months versus 3.6 months; P = 0.009) and overall survival (12.2 months versus 7.5 months; P = 0.014) relative to patients with SLFN11-negative tumours. PARP1 expression was detected in the majority of samples analysed (87%) and was not correlated with patient outcomes.

The addition of veliparib to TMZ resulted in an increased risk of several grade 3–4 haematological toxicities, including thrombocytopenia, neutropenia, and leukopenia. No notable differences in risk of grade 3–4 non-haematological toxicities were observed.

These findings, albeit only from a small subgroup of patients, provide prospective evidence that SLFN11 expression is a biomarker of responsiveness to PARP inhibition in patients with SCLC. The authors note that adjustments in the dose and/or type of PARP inhibitor used might confer further improvements in the outcomes of patients with SLFN11-positive SCLC.