Interestingly, studies evaluating adjuvant immunotherapy alone after surgery have produced mixed results, with some succeeding and others failing, whereas trials incorporating preoperative (neoadjuvant) immunotherapy have shown remarkably consistent positive outcomes [Table]. What explains this difference?

The Key Question Raised at ASCO 2026: Is the Problem Not the Drug, but the Timing?

Serving as the discussant for the EA5142 study, Professor Mariano Provencio of Spain offered a particularly striking interpretation. He suggested that administering an immune checkpoint inhibitor as monotherapy only after surgery and completion of all other treatments may be “too little, too late.”

His argument is highly compelling from an immunological perspective. Immune checkpoint inhibitors do not primarily generate new antitumor immune responses; rather, they amplify pre-existing ones. By the time surgery has been completed, however, the tumor has already been removed. With the tumor gone, the quantity of tumor-specific antigens and neoantigens is dramatically reduced. In addition, opportunities for immune-cell activation through tumor-draining lymph nodes are diminished. In other words, immunotherapy is being administered at a time when the very target the immune system must learn to recognize has largely disappeared.

Provencio characterized EA5142 not as a failed study, but as an “informative negative trial”—one that did not confirm its hypothesis but nevertheless raised important questions.

Why Does Preoperative Immunotherapy Work?

In contrast, a common feature of recently successful studies is that all incorporated immunotherapy before surgery.

Prior to surgery:

• The tumor remains present.
• Tumor-specific antigens are abundant.
• Tumor-draining lymph nodes remain intact.

Under these conditions, tumor-reactive T cells can be activated much more effectively. Jamie Chaft, the presenter of the EA5142 study, similarly noted that “a much stronger tumor-specific immune response can be generated when both the tumor and the draining lymph nodes are present.”

Many immunologists describe this phenomenon as “in situ vaccination.” The tumor itself functions as a vaccine that educates and primes the immune system. Recent successful perioperative studies have provided clinical evidence supporting this immunological hypothesis.

Does This Mean Postoperative Immunotherapy Is No Longer Needed?

For medical oncologists in daily clinical practice, the decision is not simply about treatment sequencing. It directly affects both recurrence risk and quality of life.

First: Patients Who Have Not Yet Undergone Surgery

For these patients, clinical practice is increasingly moving toward prioritizing perioperative immunotherapy, based on the results of studies such as KEYNOTE-671 and CheckMate 77T. Current evidence strongly suggests that inducing an immune response before surgery may be a more effective strategy.

Second: Patients Who Have Already Undergone Surgery

The negative results of EA5142 and BR.31, both conducted in completely resected patients, do not necessarily invalidate the concept of adjuvant immunotherapy. Rather, they call for a reassessment of its magnitude of benefit and the populations most likely to benefit.

The positive outcomes observed in IMpower010 and KEYNOTE-091 may, in reality, have been driven by specific patient subgroups. At present, however, it remains difficult to clearly identify which patients are the true beneficiaries of postoperative immunotherapy.

This uncertainty may help explain why contemporary lung cancer treatment strategies have increasingly shifted their emphasis from adjuvant immunotherapy toward perioperative approaches.

Third: Patients Who Have Already Received Preoperative Immunotherapy

All successful perioperative studies to date have demonstrated the efficacy of an entire treatment package consisting of preoperative immunotherapy, surgery, and postoperative immunotherapy.

The contribution of preoperative immunotherapy is now relatively clear. The unresolved question concerns the incremental value of postoperative immunotherapy.

In particular, it remains uncertain whether patients who achieve a pathologic complete response (pCR) or have undetectable circulating tumor DNA (ctDNA) should still receive one full year of maintenance immunotherapy. Future clinical trials will need to address this important question.

The Questions and Message of ASCO 2026

The question in the past was straightforward:

“Can postoperative immunotherapy reduce recurrence?”

IMpower010 and KEYNOTE-091 provided an affirmative answer for at least some patients, establishing the rationale for adjuvant immunotherapy.

However, with the successive successes of perioperative immunotherapy trials, the focus has shifted from whether immunotherapy should be given before or after surgery to a more nuanced question.

The more important question now is:

“Which patients truly need postoperative immunotherapy?”

As Provencio emphasized, EA5142 was not merely a negative study. It highlighted the limitations of a one-size-fits-all postoperative treatment strategy.

Going forward, early-stage lung cancer research is likely to move away from simply adding treatment for every patient. Instead, biomarkers such as pCR, ctDNA, and minimal residual disease (MRD) will increasingly be used to identify which patients can safely receive less treatment and which require more intensive therapy.

Ultimately, ASCO 2026 demonstrated that the central question is no longer whether to use immunotherapy, but rather who should receive it, when it should be administered, and for how long.

Source: The Bio (https://www.thebionews.net)