Maintenance Talazoparib Plus Atezolizumab for Patients With SLFN11-Positive Extensive-Stage Small Cell Lung Cancer

Nagla Abdel Karim, MD, PhD, Inova Schar Cancer Institute, Fairfax, Virginia, discusses phase 2 study results which demonstrated that the addition of talazoparib to maintenance atezolizumab improved survival outcomes for patients with SLFN11-positive extensive-stage small cell lung cancer. 

Transcript: 

Hi, my name is Dr Nagla Abdel Karim and today I'll be speaking about our study, S1929. It's a phase 2 randomized study of maintenance atezolizumab versus atezolizumab plus talazoparib in patients with Schlafen-11 (SLFN11)-positive extensive-stage small cell lung cancer. 

Just to summarize, the title of this or what it is all about, patients with extensive-stage small cell lung cancer, the standard of care is that they get treated first with chemotherapy, chemotherapy plus immunotherapy. What is extensive-stage small cell lung cancer? That is a type of malignancy that would be very aggressive and when we say extensive, means it's metastatic or it's spread outside one area or one side of the lung. The standard of care is to give chemotherapy, which is carboplatin and etoposide plus immunotherapy, most likely atezolizumab or durvalumab. 

In that study, patients were treated first with carboplatin, etoposide, and atezolizumab as the standard of care induction treatment and after that, as long as they get to have any response or at least are not progressing on the initiation of the therapy, patients could have received prophylactic cranial radiation or consolidation thoracic radiation, but they were tested during that time with one of the markers, it's called Schlafen-11. The reason we tested those patients for Schlafen-11 is because we do know that Schlafen-11-positivity tells us that this patient population will respond better to a group of medications, they're called the PARP inhibitors, which do have activity in this type of the tumor. Patients were tested for the Schlafen-11, and positive Schlafen-11 patients were randomized to receive either standard of care, atezolizumab versus atezolizumab plus talazoparib, which is a PARP inhibitor, and that was given until disease progression. We had patients that submitted their Schlafen-11 status, 79% of those patients were positive for Schlafen-11 in our study. Earlier studies showed that it was 50% in small cell lung cancer in general. Our study showed they're a little bit more about 79% with Schlafen-11 -positive, and the good news is that their testing came back in around 7 days, the median time to receive the Schlafen-11 testing was 7 days. 

This study was positive in terms that early on in the 5 months cut off, which was presented at ASCO 2023, we had data of atezolizumab plus talazoparib, they had median time before the disease progressed after this experimental approach, they had 4.2 months median progression-free survival compared to only 2.8 months in the atezolizumab standard of care option.

However, we continued to follow the patients and at 1 year, which was just published in the Journal of Thoracic Oncology, it's still a positive study however not that huge of a difference, but still shows a difference. Atezolizumab plus talazoparib, they had median progression-free survival of 2.9 months, that's closer to 3 months before they progressed. Atezolizumab was 2.4 months. That's still positive, but showing there is benefit but we still need improvement in our novel agent and in the predictive biomarkers.

The overall survival did not have statistical significance however, it was showing little bit of increase of course in the survival, in the most recent it was 9.7 median overall survival compared to 9.3 months in the 1-year cut off for the Journal of Thoracic Oncology citation. Having said that, it basically still shows that there could be feasibility of using Schlafen-11 as a predictive biomarker, but we need to improve the predictive biomarker and we need more potent PARP inhibitors. Now [it] looks like there are ongoing third-generation PARP inhibitors that will be in use. 

We had also sub-analysis or meta-analysis for a subgroup of patients, showing that patients who received radiation had even a better survival and better progression-free survival, even though it's a small number of patients around only 13 patients. The median progression-free survival was 5.5 months compared to only 3 months in that early study and the overall survival was not reached in the subgroup of patients who received radiation therapy, thoracic radiation, compared to those who had only standard of care was 8.5 months. The toxicity was mainly that of anemia or thrombocytopenia, as expected with the talazoparib or the PARP inhibitors in general and the other toxicities of elevated liver functions or all the other non-hematologic toxicities were sort of equal between the arms. The hematologic toxicity was more on the PARP inhibitor arm. 

There are more studies that are ongoing now to look into the PARP inhibitors in small cell lung cancer, however, now in progress there is another study, also a SWOG study, that was based on the success of our study, of the S1929, but that study will utilize subtypes of small cell lung cancer together with the Schlafen-11 positivity to offer those patients PARP inhibitor in addition to the immunotherapy but just augmenting the predictive biomarker with using the subtype, subtype A and at the same exact time that they are looking at a more potent PARP inhibitor, which would be a third-generation PARP inhibitor, with of course the immunotherapy. 

Having said that, I would say that the success of this study also can show us that small cell lung cancer can still have the success of personalized approach therapy so that patients in the future can get benefit of having what type of small cell lung cancer that they would have, possible that some drugs would work better in a subgroup compared to another subgroup of patient population.

Source: 

Karim NA, Miao J, Reckamp KL, et al. Phase II randomized study of maintenance atezolizumab (A) versus atezolizumab + talazoparib (AT) in patients with SLFN11 positive extensive stage small cell lung cancer. J Thorac Oncol. Published online: November 3, 2024. doi: 10.1016/j.jtho.2024.10.021