Window-of-Opportunity Strategies Continue to Make Headway in Lung Cancer

Paul A. Bunn, Jr, MD

The administration of neoadjuvant treatment in patients with lung cancer can not only provide deeper information on an individual tumor, but it could potentially lead to improved survival, explained Paul A. Bunn Jr., MD, stressing the need for window-of-opportunity trials.

“These are small pilot trials and haven't yet proven [if] we actually improved the cure rate, but they've led to larger, ongoing randomized trials where people are randomized to get chemoimmunotherapy or just chemotherapy before surgery,” said Bunn, Distinguished Professor, James Dudley Chair in Lung Cancer Research, Division of Medical Oncology, University of Colorado Denver, and a 2014 Giant of Cancer Care^® in Lung Cancer.

In an interview with OncLive during the 20th Annual International Lung Cancer Congress, Bunn highlighted the benefits of preoperative window-of-opportunity studies, specifically with immunotherapy in lung cancer.

OncLive: Could you discuss the rationale for preoperative window-of-opportunity studies in lung cancer?

Bunn: The goal of any cancer therapy is to cure patients. Surgery cures a certain number of patients with early-stage disease, but most of the failures after surgery occur in systemic sites. The questions are, “Should we combine systemic therapy with surgery? What type of systemic therapy? And, when should we give this systemic therapy?”

The systemic therapy, if you have a molecular driver, might be an [oral] TKI. If you have no driver, it might be chemotherapy or it might be chemotherapy combined with immunotherapy. There are a lot of advantages of giving systemic therapy first before surgery because you're treating disease at the earliest time point. Additionally, you can tell how well it works. After surgery, you can decide if you should give [more of] the same treatment or switch to another treatment.

The preliminary data with neoadjuvant immunotherapy or neoadjuvant chemotherapy plus immunotherapy shows much higher complete response and pathologic response rates and than with chemotherapy alone. The hope is that because response rates seemed much higher with chemoimmunotherapy versus chemotherapy alone, the cure rates will be higher.

What window-of-opportunity studies are currently ongoing?

One of the things about immunotherapy is that it doesn't work [for all patients]. For patients who have never smoked or have molecular drivers, such as EGFR, ALK, TRK, and so on, [oral TKIs] have a much higher response rate. The best approach is to exclude those patients who have molecular drivers from the neoadjuvant immunotherapy trials because they are less likely to benefit and there's something else that may benefit them more.

For patients with molecular drivers who we give TKIs to before surgery, we can learn why some of the cells persist after surgery. In stage IV disease, TKIs don't cure the disease. They kill a couple logs of cancer cells, but the rest remain even though they all have the same molecular abnormality. We don't know why that is, so we can't develop rational combinations. In these neoadjuvant trials with TKIs for specific drivers, we can look to see why those cells are persisting at the time of surgery and hopefully develop new novel therapies that will improve the cure rate.

What are the challenges with window-of-opportunity studies?

Often, patients want to get their cancer out as soon as possible. Surgeons also often want to get the cancer out as soon as possible because they want to schedule patients for surgeries. However, in many countries with more socialized systems, such as Canada and the United Kingdom, patients often wait 90 days to be scheduled for their surgeries. We don't really have any evidence that a 6-week delay in surgery is detrimental to patients.

Some [oncologists] say that when you give systemic therapy [before surgery], some patients will develop metastatic disease and then they [cannot undergo] surgery, However, that's actually an advantage because if those patients have systemic disease, they would have had surgery and recurred soon after. The surgery [wouldn’t] do those patients any benefit.

What is the key takeaway message for those who are weary to enroll their patients in these trials? How can physicians incorporate these studies into their practice?

The hope is that more patients will enroll. The reality is only 2% or 3% of patients with lung cancer of any stage go on a clinical trial. The only way to make advances is to have clinical trial results. The goal is to put as many early-stage patients on trials as possible—hopefully more than 2%. Most trials are with agents that are already approved, so you don't need an experimental pharmacy; many of these trials are available at community sites as well as academic sites. The hope is that community physicians will participate in those clinical trials.

You are also giving a presentation on small cell lung cancer (SCLC) at this meeting. Could you highlight the immunotherapy combinations of interest for this patient population?

Lung cancers are not all the same. We divide them primarily into 4 groups based on their histologic appearance: adenocarcinoma, squamous carcinoma, small cell carcinoma, and large cell differentiated. SCLC has several features that distinguish it from the others besides the histologic appearance. Almost all patients are former smokers; smoking is a very strong stimulus for SCLC. They also tend to spread sooner, so more patients have metastatic disease and fewer have surgically operable disease. Systemic therapy has always been a mainstay of SCLC treatment because almost all the patients develop disseminated disease.

Until recently, the only approved systemic therapy for these patients was chemotherapy. Immunotherapy was first tested in people who had failed chemotherapy, and a number of them benefitted. The idea was to move immunotherapy sooner and combine it with chemotherapy.

The first randomized trial that was completed was a trial of etoposide/carboplatin with or without atezolizumab (Tecentriq). That trial showed that patients who received atezolizumab with chemotherapy had better survival than those who received standard chemotherapy. That was the first survival improvement in SCLC in 20 years. Chemotherapy with immunotherapy with atezolizumab, given concurrently, rapidly became the standard care for extensive-stage SCLC.

Recently, another checkpoint inhibitor, durvalumab (Imfinzi), announced in a press release that they had a similar trial with chemotherapy with or without a checkpoint inhibitor and the primary endpoint was survival. It was announced that it met the survival endpoint; the data have not been released, so we don't know if it looks very similar to atezolizumab or better. About two-thirds of patients will have extensive-stage disease, meaning it spread to some other organ. One-third of patients will have disease confined to their chest, which is what we called limited-stage disease. The standard [for this population] is chemotherapy and radiation therapy, but we need to know whether adding immunotherapy will improve survival as well. In adenoid and squamous lung cancer, the addition of checkpoint inhibitors has improved survival. The hope is that those trials will be positive, showing that patients with limited-stage SCLC should get chemotherapy, immunotherapy, and radiation, but those trial results are not known yet for limited-stage disease.

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