Should Immunotherapy Move Upfront in Unresectable Stage III NSCLC? (2025)

Flipping the script in unresectable stage III non-small cell lung cancer (NSCLC) by giving neoadjuvant chemoimmunotherapy followed by chemoradiation has the potential to improve outcomes for patients with this difficult-to-treat disease, a team of investigators asserts.

The current standard of care for stage III unresectable NSCLC is chemoradiation followed by consolidation with the immune checkpoint inhibitor (ICI) durvalumab (Imfinzi), based on results of the phase 3 PACIFIC trial.

However, Rajat Thawani, MD, and colleagues from the University of Chicago argue that upfront platinum-based chemotherapy with an ICI may help preserve the immune function of tumor-draining lymphatics. In contrast, immunotherapy administered concurrently with chemoradiation attenuates systemic immunity responses to checkpoint blockade, they say.

“Tumor-draining lymph nodes serve as the site for T-cell activation in mounting an antitumor immune response for a respective primary tumor. Furthermore, it is understood that PD-L1 blockade in the tumor-draining lymph node plays a critical role in subsequent clinical responses. Thus, these tumor-draining lymph nodes must be functional for checkpoint blockade to be effective,” the investigators write in the Journal of Clinical Oncology.

They state that the need to preserve tumor-draining lymph dendritic cell activation, and the ensuing immune response, suggests that “immunotherapy should be used before, not concurrent with, radiotherapy.”

“Our main argument is that we should be fully testing this in a randomized trial to see if we’re providing benefit to these patients as opposed to the PACIFIC regimen,” coauthor Aditya Juloori, MD, from the department of Radiation and Cellular Oncology at the University of Chicago Medical Center, told Oncology News Central (ONC).

Strong Evidence Base

Although the concept has yet to be formally tested in NSCLC, there are encouraging examples from clinical trials both in resectable NSCLC and in other solid tumors, Dr. Juloori noted.

As an example, he cited the KEYNOTE-689 trial, which included patients with resectable, locally advanced head and neck squamous cell carcinomas. As reported by ONC, the addition of perioperative pembrolizumab (Keytruda) to the standard of care – surgery and postoperative pathology-guided radiotherapy with or without cisplatin – resulted in significant improvement in event-free survival (EFS) and an increase in the percentage of major pathologic responses.

Further evidence to support the case for upfront immunotherapy comes from clinical trials of therapies for patients with resectable NSCLC that included chemoimmunotherapy in the neoadjuvant or perioperative setting. These trials, including CheckMate 816, the AEGEAN trial, KEYNOTE-671, and the NADIMII trial, all showed improvements in EFS and overall survival with chemoimmunotherapy compared with chemotherapy alone.

“The responses to chemoimmunotherapy that we see in these surgical trials – the treatment of distant micrometastatic disease, improvement in EFS, and local tumor treatment reflected in the major and complete pathologic response rates – should theoretically similarly be demonstrated with neoadjuvant chemoimmunotherapy in the unresectable setting,” the authors write.

Key Concerns Allayed

Dr. Juloori told ONC that those who may be concerned that upfront chemoimmunotherapy could delay definitive radiotherapy need to understand “that we’re not delaying therapy. When they start chemotherapy and immunotherapy, they’re starting their anticancer treatment.”

The improved pathologic complete responses and major responses from the trials mentioned above show that neoadjuvant systemic therapy may improve locoregional control, a principle that should apply to patients with unresectable disease as well as those with resectable tumors, he said.

Sandip P. Patel, MD, professor of medical oncology at the University of California San Diego, who was not involved in the study, told ONC that upfront chemoimmunotherapy makes good sense.

“Incorporation of immunotherapy or chemoimmunotherapy prior to initiation of concurrent chemoradiation followed by durvalumab (as per PACIFIC) is a very reasonable approach to be investigating in clinical trials, for multiple reasons. Preradiation use of systemic treatment can shrink tumor volumes, allowing for more tolerable radiation fields with potential reduced toxicity,” he said.

“Additionally, given the negative effects of immunotherapy during radiation, use of immunotherapy before and after concurrent chemoradiation allows for earlier introduction of immunotherapy, which may otherwise be negatively affected by concurrent lymph node irradiation with immunotherapy,” Dr. Patel added.

“I am excited by earlier integration of novel systemic approaches to optimize curative intent radiation in NSCLC,” he said.

Dr. Juloori reported a consulting or advisory role for Isoray, General Electric, AquaLung Therapeutics, AstraZeneca, DaiichiSanko, Regeneron, EMDSerrono, and GlaxoSmithKline; research funding from AstraZeneca; and travel, accommodations, and expenses from EMD Serono.

Dr. Patel reported various financial relationships.

Source: https://www.oncologynewscentral.com/nsclc/should-immunotherapy-move-upfront-in-unresectable-stage-iii-nsclc

Read More: NSCLC (non small cell lung cancer) series and Immunotherapy series.