What Is Neoadjuvant Immunotherapy, and How Is It Changing Cancer Treatment?

What This Article Covers

For decades, immunotherapy for solid tumors was something patients received after surgery, as insurance against recurrence. That sequence is now being rewritten. In a cluster of practice-changing trials across lung cancer and melanoma, giving checkpoint inhibitors before surgery — "neoadjuvant" therapy — has produced some of the most encouraging survival data immunotherapy has delivered in these diseases, backed by three separate FDA approvals since 2022. This article walks through the biological logic, the actual trial numbers, where the FDA has and hasn't signed off, and the real risks that come with treating before, rather than after, the tumor is removed.

Why Timing Matters Biologically

The rationale is intuitive once you see it. When surgery happens first, the primary tumor — and much of the antigen material that could teach the immune system what to attack — is gone before any drug is given, leaving the immune system less to learn from. According to the National Cancer Institute's reporting on the melanoma trial SWOG S1801, the tumor is still present, so "the immune system has already recognized" it as a threat; a checkpoint inhibitor given at that point can amplify an existing, tumor-specific T-cell response while there's still a target for those cells to be trained against. Those T cells then continue circulating after the tumor is surgically removed, in principle able to hunt down microscopic disease that has already spread beyond the surgical field — the same disease that causes most cancer recurrences. Giving the same drug only afterward, the researchers note, carries "the legitimate risk that there isn't much left for the immune system to respond to." It's an elegant hypothesis — and unusually, for oncology, the randomized data have largely backed it up.

Lung Cancer: Three FDA-Approved Regimens, Three Strong Readouts

Non-small cell lung cancer (NSCLC) has become the proving ground for this approach, and the results here are genuinely striking. CheckMate 816, a Bristol Myers Squibb-sponsored phase 3 trial published in the New England Journal of Medicine, gave neoadjuvant nivolumab plus chemotherapy to patients with resectable stage IB–IIIA NSCLC. The pathologic complete response rate — meaning no viable tumor left at surgery — jumped to 24% with nivolumab added, versus just 2.2% with chemotherapy alone. Event-free survival followed suit: a median of 31.6 months with nivolumab versus 20.8 months without (hazard ratio 0.63, p=.0052). The FDA approved this regimen in March 2022, its first-ever approval of a neoadjuvant therapy for early-stage lung cancer.

Two more regimens have since followed it into the clinic. KEYNOTE-671 (Merck, phase 3), testing perioperative pembrolizumab in roughly 800 patients with resectable stage II–IIIB NSCLC, found that median event-free survival was not yet reached in the pembrolizumab arm versus 17 months with placebo (hazard ratio 0.58) — a sizable gap — earning FDA approval in October 2023. Most recently, the AEGEAN trial (AstraZeneca, phase 3, 802 patients) paired durvalumab with chemotherapy and reported a pathologic complete response rate of 17% versus 4.3% for placebo, with median event-free survival not reached versus 25.9 months (hazard ratio 0.68, p=.0039); the FDA approved this regimen in August 2024. Having three independently positive phase 3 trials, from three different manufacturers, converge on the same directional result is about as reassuring as oncology evidence gets — though none of these trials has yet shown a mature overall-survival benefit large enough to change how "cure" is defined for these patients, and longer follow-up is still needed to know how durable the effect is.

Melanoma: A Smaller Trial, a Striking Signal — Not Yet an FDA Approval

The melanoma data, from the NCI-sponsored phase 2 trial SWOG S1801 (313 patients with resectable stage III–IV disease), are worth sitting with for a moment before moving to the caveats. Patients randomized to three cycles of neoadjuvant pembrolizumab before surgery, followed by adjuvant pembrolizumab, had a 2-year event-free survival rate of 72%, compared with 49% for patients who went straight to surgery and received pembrolizumab only afterward (hazard ratio 0.58, p=.004). Recurrence during follow-up occurred in just 9 of 154 neoadjuvant-arm patients versus 44 of 159 in the adjuvant-only arm — the kind of gap that reshapes how a field thinks about sequencing. About 21% of patients in the neoadjuvant arm achieved a pathologic complete response.

That said, this is a single, relatively small phase 2 trial, and unlike the lung cancer regimens above, neoadjuvant pembrolizumab does not currently carry an FDA approval specifically for this melanoma indication — it has changed how many oncologists sequence treatment for high-risk resectable melanoma, but formally remains outside the approved label for that timing. Overall survival data are also not yet mature enough to say whether the event-free survival advantage translates into more patients cured long-term.

The Real Risks: Progression, Immune Toxicity, and Non-Response

Neoadjuvant immunotherapy is not free of downside, and the trials are candid about it. The most consequential risk is disease progression during the pre-surgical window: in SWOG S1801, 42 of 154 patients in the neoadjuvant arm had their melanoma grow while on treatment, and 12 of them were ultimately unable to have surgery at all — a scenario that simply cannot happen with a surgery-first approach. Researchers note that some of these cases likely reflected disease that was never going to respond to any treatment, but the possibility of losing the surgical window is real and is part of what oncologists must weigh with each patient.

Checkpoint inhibitors also carry their well-documented risk of immune-related adverse events — inflammation that can affect the thyroid, lungs, colon, liver, or skin, occasionally severe enough to delay or complicate planned surgery. And response is far from universal: a majority of patients even in the positive trials above did not achieve a pathologic complete response, meaning residual tumor was still found at surgery. Neoadjuvant immunotherapy is a real advance for the patients who respond, not a treatment that transforms outcomes for everyone who receives it.

Bottom Line

Across three separate FDA-approved regimens in lung cancer and one strongly positive (though not yet FDA-approved for this specific timing) trial in melanoma, giving checkpoint inhibitors before surgery has produced some of the clearest, most reproducible immunotherapy gains oncology has seen in resectable solid tumors — and the biological rationale for why timing matters is unusually well-supported by the clinical data. But this remains a treatment with real trade-offs: a meaningful minority of patients progress before they can get to surgery, immune-related toxicity is a genuine consideration, and not every eligible patient benefits. Patients should discuss with a multidisciplinary oncology team whether their specific cancer type, stage, and biomarker status match an evidence base that, so far, is strongest in lung cancer and melanoma — and still developing elsewhere.