Emerging Treatments in SCLC: Targeting DNA Damage

Hossein Borghaei, DO, MS: Vivek, do we have some data on targeting DNA-damage pathways?

Vivek Subbiah, MD: Absolutely. We know that Temodar, or temozolomide, and PARP inhibitors are active in small cell lung cancer. The first study I’m going to discuss is a randomized double-blind phase 2 trial of temozolomide in combination with either a PARP inhibitor, veliparib, or placebo in patients with sensitive relapsed or refractory small cell lung cancer. This phase 2 randomized study evaluated whether the addition of a PARP inhibitor, veliparib, or temozolomide improves a 4-month progression-free survival [PFS]. They entered 104 patients with recurrent small cell lung cancer. They were randomly assigned 1:1 to either oral veliparib or placebo at 40 mg twice daily, days 1 through 7, and oral temozolomide 150 to 200 mg for days 1 through 5 of a 28-day cycle until disease progression.

Response was determined by imaging at week 4, week 8, and every 8 weeks thereafter. Improvement in PFS at 4 months was the primary end point. Unfortunately, no significant difference was seen in the 4-month PFS between temozolomide plus veliparib and temozolomide and placebo. The 4-month PFS was 36% and 27%, respectively. Unfortunately, median overall survival was not ultimately improved significantly with temozolomide and veliparib. However, they saw a signal with an objective response rate significantly higher in patients receiving temozolomide and veliparib when compared with placebo. Grade 3 and 4 thrombocytopenia and neutropenia were more common in the combination arm with Temodar and veliparib: 50% vs 9%, and 31% vs 7%.

The most important part of this interesting study was this biomarker analysis, which significantly prolonged the PFS at 5.7 vs 3.6 months, and the overall survival of 12.2 vs 7.5 months, when observed in a subset of patients with SLFN11-positive tumors treated with temozolomide and veliparib. Look for this biomarker. More is known right now about this biomarker, SLFN11-positive tumors, and there are more agents and trials that are going to be targeting this biomarker and similar biomarkers in this space.

The second study I was asked to look into was the clinical efficacy of a PARP inhibitor. The second 1 was olaparib as monotherapy or in combination with an ATR inhibitor. It’s an AstraZeneca agent called AZD6738, which is ceralasertib. Using these 2 small molecules that target the DNA-repair pathway—the PARP inhibitor olaparib in combination with the ATR inhibitor ceralasertib—the investigators evaluated the clinical efficacy of olaparib monotherapy or combination in patients with relapsed small cell lung cancer.

This is a part of a phase 2 biomarker-driven umbrella study in small cell lung cancer, the SUKSES study. Patients who failed prior platinum therapy were allocated based on their genomic alterations. Patients with mutations in the HR [hormone receptor] pathway mutation, but not limited to BRCA1 or BRCA2, ATM deficiency, or MRE11A mutations, were allocated to olaparib monotherapy, which is the SUKSES-B arm. Patients in a biomarker nonmatched arm in the group of unselected patients were also allowed to receive olaparib and the ATR inhibitor. It was called the SUKSES-N2 arm. The primary end point was objective responsive rate. Simon’s 2-stage design was used. What did they see? Unfortunately, both arms were terminated at stage I based on predefined protocol criteria. In the olaparib monotherapy arm, the objective response rate was 6.7%, and the disease control rate was 26.7%, with 1 partial response and 3 stable diseases. The median progression-free survival was 1.25 months, and the median overall survival was 8.56 months.

A patient was reported to have a confirmed partial response with a tumor volume decrease of 37% compared with baseline. Interestingly, a splicing side view vision of the BRCA2 was identified from deep target sequencing in this patient. In the combination arm, the objective response rate was 3.8%, the median PFS was 2.75 months, and the overall survival was 7.18 months. Unfortunately, 3 patients discontinued treatment because of grade 5 pneumonia and grade 3 drug-induced pneumonitis. Targeting DDR [DNA damage response] pathways with olaparib as a single agent, or in combination with this ATR inhibitor, demonstrated some early signal of activity in these patients. There wasn’t much, but we think there are definite signals of activity.

What did we learn from this trial? It’s important to note that this is the first biomarker-driven umbrella trial in small cell lung cancer. Targeting DDR pathways with olaparib as a single agent or in combination with an ATR inhibitor demonstrated some signal of activity in these patients. Unfortunately, it didn’t pan out in the big picture. But I personally advocate for further investigation of these drugs in combination with other agents, like an anti-VEGF agent, which are ongoing, like olaparib and bevacizumab, and olaparib and avelumab. We look forward to studies with multiple combinations in specific biomarker-driven subsets of this population.

What do we come back to? As we all know, small cell lung cancer has been treated as a single disease because the tumors all look similar under the microscope, even though they behave very differently. As Steve mentioned, the study from Carl Gay and Lauren Byers from [The University of Texas] MD Anderson [Cancer Center] provides a transformative new system to define the 4 major subtypes of small cell lung cancer. It’s 1 of the first avenues for personalized treatment for the second most common type of lung cancer, small cell lung cancer. We look forward to such elegant biomarker-defined studies in the future to guide us in further treatment.

Hossein Borghaei, DO, MS: Thank you. I appreciate it.

TRANSCRIPT EDITED FOR CLARITY