New Options in Adjuvant Therapy for Early-Stage NSCLC

LUNGevity Foundation

Dr CarboneHistorically, surgery has been the most effective treatment for patients with early-stage non-small cell lung cancer (NSCLC). While technological improvements, such as the development of minimally invasive techniques (such as video-assisted thoracoscopic surgery or VATS), have made surgeries safer for patients, the ability to cure early-stage NSCLC patients hasn’t improved significantly in recent decades. Even after successful surgeries that completely remove the visible tumor, about half of these patients will face a recurrence with their cancer coming back within five years.  Researchers have been working to help these patients. Recently, there have been major successes in adjuvant therapies (treatments given after surgery) to help prolong life and improve outcomes for patients with early-stage NSCLC.

LUNGevity Foundation spoke to David Carbone, MD, PhD, director of the James Thoracic Oncology Center at the Ohio State University Comprehensive Cancer Center and member of LUNGevity’s Scientific Advisory Board, to learn more about these exciting advances in adjuvant therapy.

After surgery, what treatment options are available to patients with NSCLC?

Historically, all we’ve had was chemotherapy. Generally, adjuvant chemotherapy improves the 5-year survival by about 5%. Some studies show a little bit of a higher percentage, but really, it’s a small improvement for our patients. 

That is why it is exciting to have two new options to consider. Researchers have leveraged the recent progress in treating metastatic NSCLC and have conducted clinical trials to test new therapies in the adjuvant setting. 

One key area has been the focus on the targeted therapy, osimertinib, to treat EGFR-positive patients after surgery. The use of osimertinib for a subset of NSCLC patients in the adjuvant setting was approved by the Food and Drug Administration (FDA) in December of 2020. 

The other area of interest is the use of immunotherapy after surgery to provide a significant improvement for patients. This past October, atezolizumab was approved by the FDA for a subset of patients with early-stage NSCLC in the post-surgical setting.

Any advice to patients diagnosed with early-stage, resectable [able to be removed by surgery] NSCLC?

While there is still a lot to learn about adjuvant therapy, patients should be made aware that these options are available. Both options require biomarker testing of the tumor. Adjuvant immunotherapy requires a tumor’s PD-L1 expression to be greater than 1%, and adjuvant osimertinib requires a tumor to have one of two EGFR driver mutations (exon 19 deletion or exon 21 L858R substitution). Patients who are getting surgery should ask their surgeons or medical oncologists to have their tissue samples tested for biomarkers, just like patients with metastatic disease.  

What do you see as the future of adjuvant therapy?

Researchers collectively aim to use adjuvant therapy to improve upon patient outcomes from surgery alone. I am hopeful to see more cured patients. I hope to see people who are five years out from surgery who are not on adjuvant treatment anymore and are thriving. The most important goal to me is to have patients alive at 5 years who wouldn’t be alive if they didn’t have that adjuvant therapy.

There are signals that adjuvant immunotherapy is likely to hit that benchmark. We have seen now, with the PACIFIC clinical trial, that adding immunotherapy to chemo-radiation improves survival benefit at 5+ years, well beyond the completion of adjuvant therapy. Thus, the survival benefit seems to be maintained. 

In my mind, surgical adjuvant immunotherapy is very likely to show real and durable benefits to patients.

Adjuvant immunotherapy sounds promising. Why don’t we give it to everyone with resectable NSCLC?

In addition to the fact that it does not benefit everyone, there are two types of toxicities [harmfulness] to keep in mind here: physical toxicity and financial toxicity [problems related to the cost of treatment]. Immunotherapy is hugely expensive, especially compared to chemotherapy. Plus, there are potential lifelong toxicities of immunotherapy, such as hypothyroidism (reduced activity in the thyroid gland) and hypoadrenalism (reduced activity in the adrenal gland) and, occasionally, death, when they may not have needed the adjuvant therapy in the first place because half of our patients are cured with surgery alone. Therefore, there is a great need to identify patients who need adjuvant therapy and, if needed, who would benefit from immunotherapy.  These studies are ongoing.

How do we tell who needs adjuvant therapy? 

Each physician has to work with individual patients to set their treatment plans. We have to weigh the risks and the benefits. 
Generally, the benefits of adjuvant therapy are greater in the stage 3 patients than the stage 1 patients. If you have a patient who is elderly or has an autoimmune disease, adjuvant immunotherapy may not be a good idea. For patients who have had heart transplants or kidney transplants, adjuvant immunotherapy is pretty much contra-indicated in those cases. So, this must be a nuanced, individualized approach. 

Physicians should also be aware that the adjuvant data are immature and things will evolve as we learn more. It’s important for physicians to stay educated and get their patients tested for known biomarkers. If you don’t test, you don’t know. 

The lung cancer community needs to invest in developing better biomarkers. I would like to find better biomarkers to identify which patients need adjuvant therapy. And then, we also need to identify biomarkers to help us choose the best adjuvant treatments for each individual. I mean, just because you are at high risk for relapse doesn’t mean adjuvant immunotherapy will be effective for you. 

What are key considerations of targeted therapies in the adjuvant setting? 

Here, again, we need to consider financial toxicity.  One trial used three years of daily osimertinib, an EGFR targeted therapy. This cost hundreds of thousands of dollars in a setting where many people are cured using surgery alone. We need to develop biomarkers to help us find the people who are not likely to be cured by surgery alone.

To me, even more concerning is while the progression-free survival benefit is exceptional, I am not seeing data suggesting that there will be an overall survival benefit. One study of an EGFR targeted therapy in the adjuvant setting had 8-year survival data, and showed significant improvement of progression-free survival while taking the drug in the first few years after surgery, similar to what we are seeing with osimertinib.  However, once the adjuvant treatment was stopped, the progression-free survival benefit was lost, and the overall survival was exactly the same. It may be that adjuvant osimertinib improves progression-free survival while the patient is on the drug, but once treatment stops, everyone who is going to relapse will still relapse. You may not actually be getting improvements in overall survival. You may just be pushing the relapse point back, and with effective treatment at relapse there may not be a difference in overall survival. 

There are instances, in breast cancer for example, where patients stay on adjuvant therapy for 10 years to push the relapse back, but then the patient is exposed to the treatment toxicities for a long time and their quality of life can suffer. There are many risks and benefits to try to keep in balance.

What are some of the other open questions in adjuvant therapy for NSCLC?

There is a lot of room to conduct meaningful research in the field. 

For example, several huge adjuvant studies are ongoing, combining chemotherapy and immunotherapy. Most of these studies plan to use adjuvant therapy for a year after surgery, but we don’t know if a year of treatment is enough or too much. It could actually be six months or three months – we just don’t know. 

Some researchers are trying to identify residual disease after surgery by looking at circulating tumor DNA. They are trying to determine if a simple blood test to analyze circulating tumor DNA (DNA shed from the tumor) may be a good way to identify patients who would benefit from adjuvant therapy. 

The other question researchers are asking is: Does everyone need chemotherapy? In some of the neoadjuvant (treatment given prior to surgery) research conducted by my team and others, a significant number of people had complete pathological responses to surgery after being treated with immunotherapy alone. So, more research is needed to clarify the role of chemotherapy in adjuvant and neoadjuvant immunotherapy settings.

There are lots of unanswered questions, but it’s exciting to have lots of tools at our disposal to help increase the number of patients cured from early-stage NSCLC. 

What can LUNGevity, and other nonprofits, do to help improve outcomes for patients considering adjuvant therapy?

Education is key. Just keep doing what you have done in other areas of lung cancer treatments. Put out information in patient-friendly language. Help people understand state-of-the-art lung cancer research and treatment options. Don’t just discuss the positive aspects, but also the potential drawbacks of alternatives. Continue to get patients together to discuss and debate whether these treatments are right for them. And then, of course, keep funding research to answer the questions I’ve been posing and many others.  LUNGevity has done all of these things well in the past, and I’m sure LUNGevity and others will continue to help us make progress in the fight against lung cancer. 

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