Chemotherapy Remains Backbone in Non-Driver Lung Adenocarcinoma

Over the past few years, there has been an explosion of therapeutic advances for patients with non—small cell lung cancer (NSCLC) with molecular abnormalities or high levels of PD-L1 expression.

However, most patients with NSCLC do not have these targets, leaving platinum-based chemotherapy doublets—often in combination with angiogenesis inhibitors, such as bevacizumab (Avastin)—as standard treatment.

“The big thing is to not forget your chemotherapy backbones,” says Mary Jo Fidler, MD. “It is easy to jump to some of the immunotherapies or try to apply targeted agents but really, for the patient without a driver mutation and without the high expression of PD-L1, chemotherapy is the best option for them.”

OncLive: You spoke about patients with stage IV lung adenocarcinoma without driver mutations. What is important to highlight about these patients?

In what ways are we improving upon platinum-doublet therapy?

Fidler, an associate professor of Medicine at Rush University Medical Center, discussed this patient population during the 2017 OncLive^® State of the Science Summit on Advanced Non—Small Cell Lung Cancer. In an interview at the meeting, she shared insight on research aiming to improve platinum-based doublet therapy and the role of chemotherapy for non-driver adenocarcinoma in the future.Fidler: This talk was about systemic treatment of NSCLC in patients without drivers and without a high expression of the PD-L1 protein, which are still the bulk of patients who are coming through the door. We focused on how we got to platinum-doublet therapy as a cornerstone and ways to improve upon it. There were also studies on maintenance strategies, adding angiogenic agents, and studies adding EGFR-targeted therapies to the backbone of chemotherapy. If you look at the survival comparisons between 1 platinum doublet and another, we have made little progress and survival curves are overlapping. However, there are some subtleties and toxicities [between them], and there may be some subtleties in patient selection.

What do we see with the addition of angiogenesis inhibitors?

For example, nab-paclitaxel (Abraxane) may have a higher response rate in squamous cell patients. We hear a little bit about why these platinum doublets are not equal and how can we tease them out a little bit. People have tried to improve upon the platinum-doublet regimen, and the first big improvement was published several years ago, which was adding bevacizumab to carboplatin/paclitaxel. That made great news at the time and generated great excitement, because the addition of the antiangiogenic/anti-VEGF agent improved the median overall survival (OS), progression-free survival, the 1-year OS, and we saw numbers with a median survival of greater than 1 year which we had not seen in these studies.

Bevacizumab was the first successful strategy to improve upon the platinum-based doublet. Other strategies included adding other agents targeting the blood vasculature, another monoclonal antibody targeting the VEGF-2 receptor, and a small molecular tyrosine kinase inhibitor (TKI) targeting angiogenic pathways.

Bevacizumab is a drug with promise across multiple tumor types. What impact have you seen it have in lung cancer?

For patients who are EGFR wild-type, targeting EGFR has been a strategy applied in NSCLC. We have some modest activity with TKIs and we have 1 drug that is FDA approved, which is a monoclonal antibody targeting the EGFR receptor. In general, angiogenesis is a valid pathway. One of the challenges with getting big improvements is that we don’t have a biomarker, so we don’t have a way to select patients for it.

Is there any logic to exploring the combination of bevacizumab and erlotinib (Tarceva) in these patients?

What research has been conducted regarding maintenance strategies?

The second challenge is that there is a lot of redundancy in the angiogenic pathway. By bevacizumab targeting VEGF, we know that it improves outcomes with the addition of paclitaxel/carboplatin. We know it can be safely used with the addition of pemetrexed/carboplatin. For patients who want exposure to all agents, it is reasonable to expose them to an angiogenic agent at some point. There have been strategies to combine angiogenic agents and anti-EGFR agents. Cetuximab (Erbitux), which is another monoclonal antibody targeting EGFR, has been added to carboplatin/paclitaxel and bevacizumab. Cetuximab hasn’t gotten FDA approval based on the published data we have so far. There have been probably more maintenance strategies tested than people realize. The most commonly tested, large phase III trial maintenance strategy would be the addition of pemetrexed after platinum-doublet chemotherapy. Bevacizumab on its own, however, is a maintenance strategy. When that is added to carboplatin/paclitaxel, bevacizumab is continued as maintenance therapy.

What are the biggest challenges with this patient population?

Will chemotherapy forever be part of the treatment paradigm?

There have also been studies adding bevacizumab with pemetrexed as a maintenance component, and smaller studies with gemcitabine and EGFR TKIs in NSCLC. We need to get to that personalized medicine [approach]. Picking out the patient who is going to respond to their chemotherapy with a greater than 75% likelihood would be a huge milestone. We need to continue to decrease the toxicity of the agents that we have, and cost is going to be a big challenge in the future as more agents come through. It is great for patients, but it does add to the healthcare bill.I don't foresee chemotherapy going away. It could be 10 to 15 years from now when we learn how to manipulate the immune system so well that that is the first [drug to go away], and we are able to eradicate cancer. That would be fantastic.

However, with the immune system, the redundancy in cancer, and the ability to mutate, change, and acquire resistance will still leave chemotherapy with an active role in patients with lung cancer.