Pradnya D. Patil, MD, FACP, discusses the implications of these trials and the growing role of immunotherapy in lung cancer.
Pradnya D. Patil, MD, FACP
Following the transformation of frontline treatment for patients with advanced squamous non—small cell lung cancer (NSCLC) to include immunotherapy, research efforts should now focus on identifying biomarkers to predict response, as well as determining mechanisms of resistance, explained Pradnya D. Patil, MD, FACP.
These next steps follow pivotal data of immunotherapy and chemotherapy combinations in this patient population. For example, the final results of the phase III IMpower131 trial demonstrated a significant overall survival (OS) benefit with atezolizumab (Tecentriq) in combination with chemotherapy for patients with treatment-naïve, stage IV squamous NSCLC who also had high PD-L1 status. In this subgroup, the median OS was 23.4 months with the combination versus 10.2 months with chemotherapy alone (HR, 0.48; 95% CI, 0.29-0.81).1
However, in the intent-to-treat population, there was not a statistically significant OS benefit with the combination; the median OS was 14.2 months with atezolizumab/chemotherapy versus 13.5 months with chemotherapy alone (HR, 0.88; 95% CI, 0.73-1.05; P = .1581).
In the phase III KEYNOTE-407 study, pembrolizumab (Keytruda) in combination with chemotherapy was compared with chemotherapy alone in previously untreated patients with advanced squamous NSCLC. The median OS was 15.9 months with pembrolizumab/chemotherapy versus 11.3 months with chemotherapy alone, respectively (HR, 0.64; 95% CI, 0.49-0.85; P <.001).2 The immunotherapy/chemotherapy combination showed a survival benefit regardless of PD-L1 status.
“It was interesting to see a significant OS benefit beyond the intention-to-treat population,” expressed Patil. “When we looked across PD-L1—expression subgroups, even patients who had absolutely no PD-L1 expression seemed to derive benefit. We had not seen that previously with immunotherapy, so it is exciting to see a therapeutic option for patients who had either low or no PD-L1 expression.”
Based on the KEYNOTE-407 data, the FDA approved pembrolizumab in combination with carboplatin and either paclitaxel or nab-paclitaxel in October 2018 for the treatment of patients with metastatic squamous NSCLC.
“There are many unanswered questions as to why there was not OS benefit seen in [the IMpower131] particular trial,” Patil explained. “What is the difference between the two trials that led to OS difference? Some experts mentioned the control arm performed slightly better in IMpower131 compared with KEYNOTE-407, but whether that impacted the ultimate results is hard to say. Cross-trial comparisons are always tricky.”
Still, Patil is optimistic about the utilization of immunotherapy for this patient population, mentioning patient selection as another key issue to tackle in research.
In an interview during the 2019 OncLive® State of the Science Summit™ on Non—Small Cell Lung Cancer, Patil, hematology and oncology fellow at the Taussig Cancer Institute, Cleveland Clinic, discussed the implications of these trials and the growing role of immunotherapy in lung cancer.
OncLive: Could you discuss the emergence of immunotherapy into the paradigm and its shift into the frontline setting?
Patil: CheckMate-017 was the first trial that looked at the use of immunotherapy in the second-line setting, and it led to the approval of nivolumab (Opdivo). Subsequently, we saw more immunotherapeutic options introduced to the second-line setting. Just like other cancer drugs, once there is an efficacy signal of any particular drug, there is a move to try and see how it compares with frontline therapies. That is what happened with immunotherapies.
Over the last 3 years, and now with KEYNOTE-024, KEYNOTE-042, and KEYNOTE-407, we have seen these therapies move into the frontline setting. It is exciting because our patients do very well, even in the upfront setting, and have very durable responses.
This is an exciting time in squamous NSCLC where we haven't seen much progress in the past. For the patients who do not have an obvious contradiction, immunotherapy should be considered in the frontline setting as either monotherapy for a very select [group of] patients or in combination with chemotherapy.
What did the IMpower131 trial examine and what results were found?
The IMpower131 trial looked at the combination of atezolizumab plus chemotherapy compared with a control arm of carboplatin and nab-paclitaxel (Abraxane) in patients with advanced, untreated squamous NSCLC.
The interim analysis showed a PFS benefit in patients in the atezolizumab/chemotherapy arm; however, there was no OS benefit with the combination. Unfortunately, the final OS analysis presented at the 2019 World Congress for Lung Cancer, similarly, did not show any OS benefit.
What other pivotal data have been presented recently or are you excited about?
I was personally excited to see long-term, follow-up data from some trials, such as the CheckMate-017 trial. The 5-year OS rate in the nivolumab arm was about 13% compared with about 2% in the docetaxel arm. That is impressive, considering these are patients who were treated in the second-line setting or in subsequent lines of therapy. Now, we may have patients who are long-term survivors—maybe they are even cured.
What are some key challenges that remain in this space?
One of the major challenges has always been primary and acquired resistance to immunotherapy. We know that less than half of patients who receive these treatments derive clinical benefit, but we are just starting to understand why that is.
The gut microbiome plays a role, and there are extrinsic factors that may also be influencing these responses. As we understand more about what influences responses, and we study different combinations with the intention to overcome resistance, hopefully, in the future, we will have more therapeutic options when it comes to treating patients with advanced NSCLC.
Aside from exploring mechanisms of resistance, where should future research focus?
The other challenge that remains is patient selection. We don't yet understand what we should be using for patient selection. PD-L1 has been a biomarker that has been consistent for most trials; however, it is far from perfect. The same goes for tumor mutation burden which again, is imperfect as a biomarker by itself. Discovery of biomarkers that can allow us to select patients who are more likely to benefit from these therapies is much needed in this field.