A Personalized Approach to Combining Drugs and Surgery for NSCLC

Patients with non-small cell lung cancer (NSCLC) should have a team of clinicians working to decide how and when surgery fits in to their treatment plan, as well as what drugs should be given before or after resection, according to Dr. Erminia Massarelli.

Massarelli is a professor in the department of medical oncology and therapeutics research and division chief of thoracic oncology at City of Hope National Medical Center. At the CURE® Educated Patient® Lung Cancer Summit, she discussed treatment options for surgically resectable (meaning that the disease is eligible to be removed via surgery) NSCLC.

“It is very important for [patients with] lung cancer to be evaluated by a skilled thoracic surgeon and a multidisciplinary team that includes not only a thoracic surgeon, but also medical oncology and radiation oncology and also dedicated pathologists and molecular pathologists,” Massarelli said in the presentation.

Disease characteristics that are considered when determining if presurgical (neoadjuvant) or postsurgical (adjuvant) treatment is best include: disease stage, which describes how big the tumor is and if nearby lymph nodes are involved; and location of the tumor, as evaluated by a thoracic surgeon, according to Massarelli.

Clinicians may use targeted therapy (if applicable), immunotherapy and/or chemotherapy to treat patients with resectable NSCLC. But before deciding on an adjuvant drug, it’s important to know if the tumor has certain genetic mutations.

“We want to know upfront if that particular tumor that we are evaluating expresses gene alterations such as EGFR, ALK or some others, for example ROS1,” Massarelli said. “We know that immunotherapy is not very effective for EGFR-mutated cancer or ALK-mutated cancer.”

Immunotherapy

Treatment with immunotherapy is widely used in patients without EGFR-, ALK- or ROS1-mutant NSCLC, Massarelli said.

“Immunotherapy is largely used now either before surgery or after surgery,” Massarelli said.

In the presurgical setting, Massarelli cited the NADIM trial, which investigated Opdivo (nivolumab) plus chemotherapy compared with chemotherapy alone in patients with locally advanced potentially resectable stage 3A-3D NSCLC that did not have an EGFR or ALK mutation. After surgery, the Opdivo group received adjuvant Opdivo, while the chemotherapy-only group underwent observation.

Findings from NADIM showed that the pathologic complete response (pCR; no tumor cells detected in samples of the lung or lymph nodes) was 36.8% and 6.9% in the Opdivo and chemotherapy-only groups, respectively.

“It is very important to say that the pathologic complete response, which means basically complete disappearance of viable tumor in the tumor bed, correlates very well with survival. So, increasing the pathologic complete response is the key for these neoadjuvant treatments,” Massarelli said.

Further, the NEOSTAR trial showed that pCR was even better in patients with resectable stage 1 to 3A NSCLC who received both Opdivo and Yervoy (ipilimumab) in the presurgical setting. These trial findings showed that the pCR rates were 10% and 38% in the Opdivo-only and Opdivo plus Yervoy groups, respectively. However, combining the two drugs can increase side effects.

“This is paying the price with increased toxicity,” Massarelli said. “So, we don’t have this option [FDA-approved] yet to use [Yervoy] and [Opdivo] in the neoadjuvant space, but we definitely have the option of chemotherapy plus immunotherapy.”

Targeted Therapies

There are two tyrosine kinase inhibitors (TKIs) that are currently approved by the FDA in the postsurgical setting. These drugs — Tagrisso (osimertinib) and Alecensa (alectinib) — work by targeting specific genetic mutations (EGFR and ALK, respectively) that are involved in the formation and growth of cancer.

The ADAURA clinical trial compared Tagrisso to placebo (inactive drug) in patients with stage 1B, 2 or 3A NSCLC that has been surgically resected. Findings from the trial that were presented in 2022 showed that the 36-month disease-free survival (DFS; time patients live after treatment without signs or symptoms of cancer) rates were 79% in the Tagrisso group and 40% in the placebo group. Further, 2023 data of five-year overall survival (OS; time from treatment until death of any cause) rates were 88% and 78% in the Tagrisso and placebo groups, respectively.

“This [trial] is still ongoing, and we don’t have results yet,” Massarelli said.

Additionally, the ALINA trial evaluated Alecensa in patients with ALK-positive stage 1B to 3A NSCLC that has been surgically removed. Patients were randomly assigned to receive either adjuvant Alecensa or platinum-based chemotherapy. Findings from this study showed that Alecensa reduced the risk of disease progression or death by 76% compared to the chemotherapy regimen.

Now, the ongoing NEOADAURA trial is investigating the use of presurgical Tagrisso in patients with stage 2 to 3B EGFR-mutant NSCLC. Participating patients will be randomly assigned to one of three treatments: placebo plus chemotherapy; Tagrisso plus chemotherapy; or Tagrisso alone. All patients will then undergo surgery and then postsurgical treatment of the clinician’s choice.

Editor's note: This program was made possible with support from Daiichi Sankyo Inc.

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