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Jonathan Riess, MD, MS, discusses ongoing research with PARP inhibitors in lung cancer and potential biomarkers for this class of agents.
Jonathan Riess, MD, MS
Clinical findings have indicated that presence of BRCA1/2 mutations, SLFN11, and high loss of heterozygosity (LOH) may be biomarkers for patients with lung cancer who could respond to PARP inhibitors, explained Jonathan Riess, MD, MS.
“[PARP inhibitors] have been looked at in non—small cell lung cancer (NSCLC) and small cell lung cancer (SCLC) to see if we could translate some of the successes in other tumor types to lung cancer. It's had a mixed track record of success over the years,” said Riess, an associate professor at the University of California (UC) Davis Comprehensive Cancer Center. “There are certain clinical trials that have shown either no benefit or modest benefit, [and] there have been some intriguing advances showing that PARP inhibitors may have a role in lung cancer.”
For example, results of one study evaluating the combination of temozolomide plus the PARP inhibitor veliparib in patients with relapsed-sensitive or refractory SCLC showed that there was no clear benefit in progression-free survival (PFS) in the overall population. The 4-month PFS rates for temozolomide plus veliparib were 36% and 27% with temozolomide alone (P = .19). The median OS was 8.2 months and 7.0 months (P = .50), respectively.
In those with elevated SLFN11, however, the median PFS was 5.7 months with the combination and 3.6 months with temozolomide alone (P = .009). Likewise, OS was 12.2 months versus 7.5 months in SLFN11-positive patients, respectively (P = .014).
Moreover, the phase II SWOG S1900A trial (NCT03845296), which is part of the ongoing Lung Master Protocol (Lung-MAP) trial, is examining the effect of the PARP inhibitor rucaparib (Rubraca) on patients with stage IV NSCLC who have deleterious BRCA1/2 mutations and elevated LOH.
In an interview with OncLive, Riess discussed ongoing research with PARP inhibitors in lung cancer and potential biomarkers for this class of agents.
OncLive: What rationale do we currently have to explore PARP inhibitors in lung cancer?
Riess: PARP inhibitors are a class of drugs that induce cancer cell death via inhibition of DNA repair pathways. At its most basic, PARP inhibitors inactivate basic excision repair, allowing single-strand breaks to progress to double-strand breaks. There are certain mutations in many cancers, such as BRCA1/2 and other DNA repair proteins, that induce synthetic lethality and lead to cancer cell death. These drugs have been approved for patients with BRCA-mutant breast cancer as well as ovarian cancer. They are used in other BRCA-mutant tumors as well.
We are testing [SLFN11] in the Lung Master Protocol (Lung-MAP) SWOG S1900A, looking at a PARP inhibitor called rucaparib. That's given in patients who have BRCA1/2 mutations and high LOH, which we think is a phenotypic biomarker of homologous repair deficiency (HRD). This is taken from the ovarian cancer literature, where this drug is approved in the maintenance setting. There's a companion diagnostic that looks at high LOH and BRCA1/2 mutations as being potential biomarkers of increased activity of this drug.
What recent studies have evaluated PARP inhibitors in lung cancer?
We recently presented another arm of the Lung-MAP S1400G trial, which looked at the PARP inhibitor talazoparib (Talzenna) in patients with lung squamous cell carcinoma who have select DNA repair mutations. It showed a modest response rate of 4%. Unfortunately, it did not meet the efficacy threshold to proceed to accrue further patients. We're hoping that looking at additional biomarkers, such as LOH, may be a way forward in order to pick out more patients who will preferentially respond to PARP inhibition.
In 2018, in SCLC, a clinical trial was published looking at temozolomide in combination with the PARP inhibitor veliparib. It was a randomized trial between temozolomide alone and in combination with veliparib. There was an increased response rate of about 39% compared with 14%, which was statistically significant. It did not meet its primary efficacy endpoint. PFS was not significantly improved, but they found that an elevated immunohistochemistry marker and a protein called SLFN11, which is a DNA helicase protein.
In patients whose SCLC was high, [presence of SLFN11] looked like a signal of PFS and OS benefit. That is an intriguing biomarker to take forward in future trials with PARP inhibitors in SCLC.
What are some of the next steps regarding PARP inhibitors research?
The next steps for researching PARP inhibitors are finding the appropriate biomarker where there may be preferential benefit. The SWOG S1900A in Lung-MAP is looking at rucaparib, BRCA1/2 mutations, and the LOH biomarker. If the LOH biomarker is high, it may be a good phenotypic biomarker for HRD-deficient tumors that may be preferentially sensitive to PARP inhibitors. If SLFN11 is elevated and shows a signal of benefit in patients who have SCLC with elevated immunohistochemistry levels of this DNA helicase protein, SLFN may a good marker to take forward in future clinical trials.
How do you determine what patients are eligible for PARP inhibitors?
At UC Davis, we're part of the Lung-MAP SWOG S1900A, so we are screening patients [for enrollment eligibility]. Now, it's open to patients with squamous cell lung carcinoma and lung adenocarcinoma. We've screened patients through that trial and if they have high LOH tumors or BRCA1/2 mutations, they would be eligible for that trial.
How will PARP inhibitors affect the sequencing of therapies?
Right now, PARP inhibitors are not approved for treating patients with NSCLC or SCLC. In terms of where it fits in the pathway, it's definitely following progression on a prior line of treatment, whether it is chemoimmunotherapy or targeted therapy. Those have more of a proven track record at this point, but we'll see how these biomarker-driven trials play out in the future.
There are several other trials that are in the process of looking at SCLC and NSCLC, specifically with the combination of chemotherapy and immunotherapy followed by maintenance PARP inhibitions with immunotherapy. There is some preclinical activity and some rationale that potentially [PARP inhibitors] may be good in combination with immunotherapy.
Pietanza MC, Waqar SN, Krug LM, et al. 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. J Clin Oncol. 2018;36:2386-2394. doi: 10.1200/JCO.2018.77.7672.