Reviewing Early-Stage NSCLC Treatments in 2025

Deepa Rangachari, MD Beth Israel Deaconess Medical Center

Key Points

• Staging each patient and evaluating eligibility for surgery are the first tasks when determining the correct treatment algorithm in early-stage NSCLC.

• Neoadjuvant chemotherapy with or without immunotherapy based on presence of actionable mutations is one of the primary approaches for surgery-eligible patients.

• For surgery-ineligible patients, concurrent chemoradiation followed by immunotherapy is the standard of care, though more data are needed for disease subgroups.

Drs. Rahul and Rohit Gosain, hosts of the Oncology Brothers podcast, spoke with Deepa Rangachari, MD, Beth Israel Deaconess Medical Center, to review the current treatment algorithms for patients with early-stage non-small cell lung cancer (NSCLC).

To start, it’s mandatory to thoroughly evaluate tumors with radiographic staging, positron emission tomography scanning, brain magnetic resonance imaging, pathologic nodal evaluation, genomics, and multidisciplinary approaches, Dr. Rangachari stated. Additionally, next-generation sequencing is required as there are two approved targeted therapies, osimertinib for NSCLC with common EGFR mutations and alectinib for NSCLC with ALK alterations.

After staging, Dr. Rangachari said the critical first question is always whether or not the patient is a candidate for surgical resection, as surgery is part of the standard treatment algorithm for all eligible patients. 

Treating Resectable Early-Stage NSCLC

In patients with stage IA NSCLC, surgery is the standard of care for eligible patients and stereotactic body radiation therapy is the standard for surgery-ineligible patients.

For surgery-eligible patients with stage IB-IIIA NSCLC without actionable mutations, “I think the field is moving towards favoring neoadjuvant chemotherapy with consideration of adjuvant or fully perioperative therapy depending on the outcome at the time of surgery,” Dr. Rangachari said. 

She referenced recent data from the CheckMate 816 trial that showed that patients who achieved a pathologic complete response (pCR) after neoadjuvant chemoimmunotherapy followed by surgery had a very high rate of event-free survival and overall survival.

Based on the existing data, Dr. Rangachari counsels patients to expect perioperative therapy, but if they achieve a pCR, she is comfortable having a discussion about the necessity of continuing adjuvant checkpoint inhibitor therapy.

Dr. Rahul Gosain asked if circulating tumor DNA (ctDNA) has a role in informing treatment decisions. “I think the field is evolving in that direction, but as of right now I would say this is really an investigational and exploratory tool,” Dr. Rangachari answered. She noted that using outcomes like pCR or ctDNA to adjust treatment is challenging because there are no adaptive strategies to switch to if those outcomes are not achieved.

For patients with actionable mutations, Dr. Rohit Gosain highlighted the variation in postsurgery chemotherapy. Data from the ADUARA trial do not support replacing chemotherapy with osimertinib in patients with common EGFR mutations. Conversely, findings from the ALINA study showed that adjuvant alectinib had a benefit over adjuvant chemotherapy. 

Despite the ALINA findings, Dr. Rangachari said many oncologists might still administer adjuvant chemotherapy prior to alectinib in ALK-mutated patients with high-risk features in the interest of further disease eradication.

Treatment Algorithm for Stage III Unresectable NSCLC

For surgery-ineligible patients with stage III disease, the standard of care is concurrent platinum-based chemotherapy and radiation therapy followed either by durvalumab, as in the PACIFIC trial, or by osimertinib in patients with EGFR-mutated disease, as in the LAURA trial.

Dr. Rangachari said it’s an open question as to what to follow chemoradiation with in the molecularly-defined subgroups that are similar to EGFR-mutated NSCLC, such as ALK or ROS, though she said she does not advise durvalumab. 

Further discussing the LAURA trial, Dr. Rahul Gosain questioned if the indefinite osimertinib regimen really represents a curative intent. From a pragmatic standpoint, data show that few patients with stage III NSCLC are fully cured, Dr. Rangachari said. She suggested that “there is a difference between curative intent and curative reality, and indefinite osimertinib is one way to translate curative intent to curative reality as long as patients are able to continue taking the medication.”

Managing Side Effects of Osimertinib and Alectinib in NSCLC

Rounding out the NSCLC discussion, the doctors briefly covered managing the different side effect profiles of osimertinib and alectinib.

Osimertinib is associated with cutaneous side effects that can present in a variety of ways, Dr. Rangachari said. She encourages patients to adopt a skin care routine that includes topical emollients twice a day, good sun protection, and topical clindamycin or cortisone as a spot therapy for focal patches of skin effects. 

She also suggested that physicians have a very low threshold for starting an oral tetracycline like doxycycline in patients that experience more diffuse skin toxicity. Additionally, diarrhea management may be more effective if patients build a schedule to take loperamide in a more anticipatory fashion rather than after side effects start to occur. 

While alectinib is associated with some relatively routine side effects like fatigue, nausea, and diarrhea, it can also involve some effects like lower-extremity cramping, heaviness, and edema that are more difficult to manage, Dr. Rangachari said. For these, she suggested the best way to manage may be a treatment pause or dose reduction.

Dr. Rahul Gosain noted more and more studies have shown that decreasing dose does not compromise good outcomes with these therapies, and encouraged physicians to not hesitate adjusting dose in order to balance treatment benefit and quality of life.

Ultimately, “the early-stage NSCLC landscape is moving fast, and it’s on us in the community settings to stay up to date to make sure we are providing the best care close to home for all of our patients,” Dr. Rahul Gosain concluded.