Lung Cancer Awareness Month: Reducing the Risk of Recurrence of NSCLC

Benny Weksler, MD, MBA

Lung cancer care has been improved by the introduction of immunotherapy and targeted therapies in recent years. In addition to offering new treatment options in metastatic and recurrent disease where few options existed before, targeted and immunotherapies have had success in dramatically reducing the risk of recurrence of disease in patients who would have received surgical resection or chemotherapy for non­–small cell lung cancer (NSCLC).

Trials of patients with stage IB to IIIB disease have shown how new therapies can reduce risk of recurrence and improve survival for patients, according to Benny Weksler, MD, MBA. Adjuvant and neoadjuvant immunotherapy have shown potential to improve the outcomes following resection of lung tumors. Immunotherapy can also be combined with chemotherapy and radiation therapy in patients whose tumors cannot be resected.

While molecular targeted therapies have had the most application in stage IV disease, EGFR-targeted therapy has also proven effective in the adjuvant setting. This has highlighted the importance of biomarker testing in earlier-stage patients at diagnosis.

Weksler, professor of cardiothoracic surgery at Drexel University College of Medicine, system chief of thoracic surgery for Allegheny Health Network (AHN), and chief of the division of thoracic surgery in the department of cardiothoracic surgery at Allegheny General Hospital, discussed the key trials that have recently influenced the standard of care for patients with stage IB to IIIB NSCLC.

Targeted Oncology^TM: How has the field of NSCLC treatment changed in recent years?

The big change started with the PACIFIC trial [NCT02125461] of immunotherapy in patients with unresectable stage III disease, which is locally advanced disease. That trial included chemotherapy and radiation therapy followed with immunotherapy [with durvalumab (Imfinzi)]. It nearly revolutionized the care for these patients because the results were so good. The combination of immunotherapy with the standard of care, which was chemotherapy and radiation therapy, showed very impressive disease-free survival [DFS] and overall survival [OS], over what was considered standard of care.¹ This study came out in 2017, and it made a dent in the chemotherapy space and in the way we think of lung cancer.

There were previous trials of immunotherapy as single-agent therapy for stage IV disease, the most advanced disease stage with [distant] metastases. [Immunotherapy] has also shown great promise in keeping patients alive with the disease in check for many years. As a surgeon, I'm never that excited with diseases that that we can't cure, but the results for stage IV disease are impressive. In some patients who have lung cancer, it becomes like a chronic disease that is getting treated, and the cancer is in check. Now we see patients with stage IV disease surviving over 4 or 5 years, and that's something that never happened before. Before, 2 to 3 years survival was the norm for patients with stage IV disease.

What trials of targeted therapy have been impressive to you in this space?

The most exciting things in terms of trials with targeted therapy started in the last 2 or 3 years. The first was a trial of targeted therapy for patients with adenocarcinoma who have an EGFR mutation. The ADAURA trial [NCT02511106] had amazing results in keeping patients alive without recurrence for several years [with osimertinib (Tagrisso)]. OS for this trial is still lacking, but the DFS [for all patients at median follow-up of 22.1 months] was increased by 80% [99.12% CI, 0.14-0.30; P < .001].² So the risk of cancer coming back with this particular therapy is reduced by 80%, which is just incredible. That changed the way we do business in lung cancer because now all patients with adenocarcinoma, which are over 50% of patients, we test for this particular mutation. If they have the mutation, we recommend treatment for the next 3 years. The belief in the science is strong, that this will prevent the cancer from coming back.

The issue is that only about 20% to 23% of patients with adenocarcinoma have this mutation. You still have the rest of the population that is at risk. Usually, when we say at risk, we like to think of patients with later-stage disease. Usually, for this type of trial, we [treat] the population stage IB and above, which is still considered early stage, but not as early as IA.

Are there other trials that are relevant in NSCLC?

The 2 other very important trials that came in the last year are the IMpower010 [NCT02486718] and the CheckMate 816 [NCT02998528] trials, [both of] which AHN were part of. Those studies are slightly different in the sense that CheckMate 816 gives treatment before surgery, and IMpower010 gives treatment after surgery.

CheckMate 816 gave treatment including chemotherapy and immunotherapy [with nivolumab (Opdivo) plus ipilimumab (Yervoy) or nivolumab] before surgery. Follow-up in this study has shown amazing results in improving OS and DFS in patients with stage IB disease and above.³ The IMpower 010 trial treated patients who were not treated before surgery but had a higher stage after surgery [with chemotherapy plus atezolizumab (Tecentriq)], and it also showed very significant effects on DFS.⁴ What those studies have in common is the use of an immunotherapy agent, which makes our immune system fight the cancer.

When do you order biomarker testing for patients in this setting?

Today we know that that we need to test patients for EGFR, which is the mutation that we can address, and for the presence of a [PD-1/PD-L1] immune marker that shows better response to the immunotherapy drugs. We are moving into testing those on diagnosis, right when the patient had the biopsy. We want those tested now.

When patients have recurrent disease or stage IV disease, there is an indication for more comprehensive testing, [since] there are some mutations that we can address [with targeted therapies, though] they are not very common. At that time, we do more comprehensive testing.

What newer studies and efforts is AHN involved in for NSCLC?

We at AHN are going to participate in a large trial looking at multiple different potential targets, which is called the LCMC4 LCRF LEADER trial [NCT04712877] combined with the NAUTIKA study [NCT04302025]; those studies are interrelated. This is a national trial looking for targeted mutations that we can address with drugs to find out if targeting those mutations improves OS and DFS.

We are big in following the standard of care or [enrolling] patients in clinical trials. There is still so much for us to learn from this disease, that I'm always very enthusiastic about different trials that we have in patients that that can be operated. We are looking at one trial now [NCT01817192] in patients with very early-stage disease, trying to find out if we can change the risk of the cancer coming back, which still does in about 20% of patients, by doing a comprehensive genetic testing of the tumor. This study is open for us now, and it's something that I'm very enthusiastic about because I think if this is positive, we can start moving the needle even more, even in patients with very early-stage lung cancer.

What should community oncologists know about treating NSCLC that they might not already?

What community oncologists need to know is that, today, the care of lung cancer…now depends on careful multidisciplinary discussion because there are a lot of intricacies in the treatment of those patients. For example, a patient with adenocarcinoma may be qualified for treatment before surgery, but if that patient has an EGFR mutation, they probably shouldn't be treated before surgery. They need to be treated after surgery. There is a lot involved nowadays in the care of these patients, and a multidisciplinary discussion group like we have here at AHN every week is key to proper selection of treatment for patients with lung cancer.

_References:

_{1. Antonia SJ, Villegas A, Daniel D, et al. Durvalumab after chemoradiotherapy in stage iii non-small-cell lung cancer. N Engl J Med. 2017;377(20):1919-1929. doi:10.1056/NEJMoa1709937}

_{2. Wu YL, Tsuboi M, He J, et al. Osimertinib in resected EGFR-mutated non-small-cell lung cancer. N Engl J Med. 2020;383(18):1711-1723. doi:10.1056/NEJMoa2027071}

_{3. Forde PM, Spicer J, Lu S, et al. Neoadjuvant nivolumab plus chemotherapy in resectable lung cancer. N Engl J Med. 2022;386(21):1973-1985. doi:10.1056/NEJMoa2202170}

_{4. Felip E, Altorki N, Zhou C, et al. Adjuvant atezolizumab after adjuvant chemotherapy in resected stage IB-IIIA non-small-cell lung cancer (IMpower010): a randomised, multicentre, open-label, phase 3 trial. Lancet. 2021;398(10308):1344-1357. doi:10.1016/S0140-6736(21)02098-5}