Expert Explains Approaches in Non-Driver NSCLC

Lyudmila A. Bazhenova, MD

The angiogenesis inhibitor bevacizumab (Avastin) has remained a go-to standard for patients with non-driver, nonsquamous non—small cell lung cancer (NSCLC), which comprises nearly one-quarter of the overall lung cancer population. PD-1/PD-L1 inhibitors have also demonstrated promising outcomes as monotherapy and in combination with chemotherapy.

An ongoing clinical trial is combining bevacizumab with immunotherapy, hoping to propel patients into deeper responses. The randomized, open-label phase III IMpower150 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).

OncLive: What is the prevalence of patients with non-biomarker driven nonsquamous lung cancer?

In an interview with OncLive, Lyudmila A. Bazhenova, MD, medical oncologist, professor of medicine, UC San Diego Health, discussed the non-driver NSCLC population, the treatment strategies available for them, and challenges physicians continue to face with this subgroup of patients.Bazhenova: The data behind 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 KRAS mutation. It is a very prevalent mutation but, at this point, we really cannot target that mutation.

Please discuss the variation in treatment approach between patients with driver mutations versus those without.

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 in about 5%. Then, you have much rarer mutations, like ROS1, which is in about 1% to 2%. Then, you go even smaller populations like BRAF, HER2, and others. 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 is the patient’s expression of PD-L1. If you have a patient with PD-L1 expression of more than 50%, the treatment of choice would be pembrolizumab (Keytruda), based on the randomized study comparing pembrolizumab versus chemotherapy that showed improvement in patients who were randomized to pembrolizumab.

Let’s discuss bevacizumab. What impact have you seen the angiogenesis inhibitor have on the non-driver NSCLC population?

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 [standard-of-care EGFR tyrosine kinase inhibitors, either erlotinib or gefitinib] to look for an improvement in outcomes of those patients. Bevacizumab has been 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 (PFS), and overall survival.

What is the utility of immunotherapy in this population?

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 clotting history. [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, as more than 50% of the tumor cells expressing PD-L1. Pembrolizumab improves outcomes.

At this point, for those patients, I will use pembrolizumab. There is another study that has been recently presented, which is cohort G of KEYNOTE-021. This was a randomized phase II trial which 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. What are some ongoing trials with therapies for non—biomarker-driven lung cancer? 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, nivolumab (Opdivo), and pembrolizumab.

We have been investigating with CTLA-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 immune-oncology drugs versus chemotherapy versus monotherapy of PD-L1 inhibitors.**

What are the challenges that still remain for the non-driver NSCLC landscape? What does the future of treatment look like to you?

People are also looking for other checkpoint inhibitors, such as LAG3 and Tim-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 patients de novo who haven’t been exposed to immunotherapy. But also, even more important, 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. 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.

I’m hoping that we will be able to use more combination immunotherapy treatments. Additionally, I’m also hoping that we will be able to target KRAS mutations or have approved drugs for, let’s say, HER2-insertion mutations or other rarer mutations in lung cancer.

*This interview took place prior to an announcement from AstraZeneca that the phase III FLAURA trial had met its primary endpoint, with frontline osimertinib significantly improving PFS versus standard of care in patients with locally-advanced or metastatic EGFR-positive NSCLC. **AstraZeneca announced in July that in the phase III MYSTIC trial, frontline durvalumab (Imfinzi), either in combination with tremelimumab or as a single agent, did not improve PFS in patients with stage IV metastatic NSCLC compared with standard platinum-based chemotherapy.