Nonbiomarker NSCLC Population a Challenging Obstacle, Expert Says

Lyudmila A. Bazhenova, MD

The angiogenesis inhibitor bevacizumab (Avastin) has remained a go-to standard regimen for patients with nonbiomarker, nonsquamous non—small cell lung cancer (NSCLC), those who account for more than half of the overall lung cancer population. Parallel to the efficacious agent, programmed cell death protein-1 (PD-1) and programmed cell death-ligand protein-1 (PD-L1) inhibitors have also demonstrated promising outcomes as monotherapies and in combination with chemotherapy— specifically pembrolizumab (Keytruda) coupled with carboplatin/ pemetrexed, which was granted approval by the FDA in May 2017.

An ongoing clinical trial is looking to merge the 2 mechanisms of bevacizumab and immunotherapy and potentially propel patients into deeper responses. The randomized, open-label phase III IMpower 150 study is evaluating the safety and efficacy of atezolizumab (Tecentriq) in combination with carboplatin/paclitaxel with or without bevacizumab versus treatment with carboplatin/ paclitaxel plus bevacizumab in chemotherapy-naïve patients with stage IV nonsquamous NSCLC (NCT02366143). In the trial, patients will be randomized in a 1:1:1 ratio to atezolizumab plus carboplatin/paclitaxel (arm A), atezolizumab plus carboplatin/paclitaxel with bevacizumab (arm B), or carboplatin/paclitaxel plus bevacizumab (arm C).

In an interview withTargeted Oncology, Lyudmila A. Bazhenova, MD, medical oncologist, professor of medicine, University of California, San Diego Health, shared more details on the nondriver NSCLC population, the treatment strategies available for them, and challenges physicians continue to face with this subgroup of patients.

TARGETED ONCOLOGY:What is the prevalence of patients with nonbiomarker, nonsquamous lung cancer?Bazenhova:The data behind the prevalence of different targeted mutations in lung cancer comes from The Cancer Genome Atlas (TCGA). In this data, we see that approximately one-quarter of patients, about 25%, do not have any genetic mutations. In the TCGA database, we also see that maybe about 30% of patients with lung cancer have a mutation that is called KRAS. It is a very prevalent mutation, but at this point, we really cannot target that mutation.

If you look at the incidence of EGFR mutations in all patients with nonsquamous NSCLC, it is approximately 10% to 15%, and ALK mutations are about 5%. Then, you have much rarer mutations, like ROS1, which is in about 1% to 2%. Then, you go to even smaller populations, like BRAF, HER2, and others.

TARGETED ONCOLOGY:What are the differences between treatment strategies for patients with some of these driver mutations versus those without?

Bazenhova:When one decides what is the best thing to do for their patients with newly-diagnosed nonsquamous NSCLC, certain tests need to be done. You have to know what the patient’s EGFR, ALK, and ROS1 mutation status is and what the patient’s expression of PD-L1 is. If you have a patient with PD-L1 expression of more than 50%, the treatment of choice would be pembrolizumab, based on the randomized study comparing pembrolizumab versus chemotherapy that showed improvement in patients who were randomized to pembrolizumab.

For patients with ROS1-mutant lung cancer, I would be prescribing them crizotinib (Xalkori). For patients with EGFR-mutant lung cancer, you currently have 3 drugs that are FDA-approved, which are erlotinib (Tarceva), gefitinib (Iressa), and afatinib (Gilotrif). We are eagerly awaiting the release of the FLAURA study, which will be released at the 2017 ESMO Annual Congress. This is a study that compared osimertinib (Tagrisso) versus approved first- and second-generation ALK inhibitors to look for an improvement in outcomes of those patients.

TARGETED ONCOLOGY:Let’s discuss bevacizumab. What impact have you seen the angiogenesis inhibitor have on the nondriver NSCLC population and when do you use it?

Bazenhova:Bevacizumab [was] approved in lung cancer based on the ECOG E4599 study. In this study, patients were randomized to carboplatin/paclitaxel versus carboplatin/paclitaxel plus bevacizumab. The study showed an improvement in outcomes. There were improvements in response rate, progression-free survival, and overall survival. However, one has to remember that bevacizumab has contraindications. Number one, bevacizumab is contraindicated for patients with squamous cell carcinoma, contraindicated for patients with uncontrolled hypertension, and for patients with significant bleeding and a clotting history.

TARGETED ONCOLOGY:What is the utility of immunotherapy in this population?

Bazenhova:[It is generally] for patients with newly-diagnosed lung cancer—that is, metastatic stage IV—who have a high expression of PD-L1 on the tumor that is defined, at this point, at more than 50% of the tumor cells expressing PD-L1. Pembrolizumab improves outcomes [in this population].

At this point, for those patients, I will use pembrolizumab. There is another study that was recently presented, which is cohort G of KEYNOTE-021. This was a randomized phase II trial that looked at carboplatin/pemetrexed versus carboplatin/ pemetrexed plus pembrolizumab. The triplet arm showed an improvement in outcomes. Therefore, the FDA has approved a triplet combination of carboplatin/pemetrexed and pembrolizumab, so that could be another option for these patients.

TARGETED ONCOLOGY:What are some ongoing trials with therapies for nonbiomarker lung cancer?Bazenhova:Immunotherapy in lung cancer has been undergoing a tremendous explosion. We have a lot of new drugs that are being developed. We all know about PD-1/PD-L1 inhibitors, the so-called checkpoint inhibitors. We have 3 of these drugs currently approved for lung cancer, which are atezolizumab (Tecentriq), nivolumab (Opdivo), and pembrolizumab.

We have been investigating with CTLA-4 [cytotoxic T-lymphocyte-associated protein 4] inhibitors; one of the examples is ipilimumab (Yervoy). We have trials ongoing looking at comparisons of monotherapy with PD-1 inhibitors versus PD-1/CTLA-4 combinations versus a chemotherapy doublet. We have learned recently that the MYSTIC study will be presented at the 2017 ESMO Annual Congress. MYSTIC looked at the combination of immunooncology drugs versus chemotherapy versus monotherapy of PD-1 inhibitors. People are also looking for other checkpoint inhibitors, such as LAG3, Tim-3 [T-cell immunoglobulin and mucin-domain containing-3], and T-cell stimulants, such as 4-1BB, OX40, and GITR. I’m hoping that, in the future, we will see more options for our patient de novo who haven't been exposed to immunotherapy. But also, even more importantly, to [see more] patients who have responded to immunotherapy and then lost their response. I hope that we, eventually, will be able to figure out what is the right thing to do for those patients.

TARGETED ONCOLOGY:What are the challenges that still remain for the nondriver NSCLC landscape? What does the future of treatment look like to you?Bazenhova:The main challenge in managing stage IV patients with lung cancer is the fact that we still cannot cure them. Our treatments work, and they work pretty well, but they work for a limited time. I am hoping that new drugs, or new systemic treatments, will be developed that we can use sequentially after failure of previous treatments.