Preoperative Immunotherapy in Oncology

Background: Immune checkpoint inhibitors (ICI) are in standard use for the treatment of many kinds of metastatic tumor. Their use before surgery to prolong event-free and overall survival (EFS, OS) has been studied in recent years.

Methods: This review is based on clinically relevant studies published since 2018 on the preoperative use of ICI for four tumor entities: breast cancer, non–small cell lung cancer (NSCLC), colorectal cancer, and esophagogastric adenocarcinoma. The studies were identified by a selective search in PubMed. In addition, abstracts from international conference presentations were evaluated.

Results: The approved, standard perioperative treatment of triple-negative breast cancer of stage IIa and above is with durvalumab (an ICI) combined with chemotherapy for one year. This improved the 5-year EFS by 9% (81.2% vs. 72.2%; HR = 0.65) and the overall survival rate by 5% (86.6% vs. 81.7%; HR = 0.66). In NSCLC, the addition of an ICI to preoperative chemotherapy increased 2-year EFS by approximately 11% in stage II or III (63.3% vs. 52.4%; HR = 0.68), according to the largest trial that has been published to date. The addition of durvalumab to perioperative chemotherapy for stage II or III esophagogastric adenocarcinoma increased the 2-year EFS by 8% (67% vs. 59%; HR = 0.71). Approval for this indication is expected. In colorectal carcinoma with microsatellite instability, neoadjuvant ICI therapy for 1–6 months often led to clinical and/or histological complete remission. In view of the high remission rates (50%–100%), patients with rectal carcinoma may be spared surgery and the particular risks it entails.

Conclusion: For some types of tumor, neoadjuvant ICI therapy is standard and/or about to be approved. Special care must be taken in managing ICI toxicity. In view of the adverse effects and cost of ICI, it will be important to identify biomarkers for a higher likelihood of benefit.

Cite this as: Hofheinz RD, Lorenzen S, Sebastian M, Bölükbas S, Fichtner-Feigl S, Loibl S: Preoperative immunotherapy in oncology. Dtsch Arztebl Int 2026; 123: 46–52. DOI: 10.3238/arztebl.m2025.0209

Immunotherapy was first approved in Germany in 2011. In that year, ipilimumab—an immune checkpoint inhibitor (ICI) that targets cytotoxic T-lymphocyte antigen 4 (CTLA-4) on T cells—was approved for metastatic melanoma. Since then, a total of 15 ICIs have been authorized in Germany.

The Figure depicts the target structures and mechanisms of action of ICIs. The following parameters are used as biomarkers for the efficacy of ICIs:

• PD-L1 protein expression in the tumor material
• the presence of a deficient mismatch repair system or high microsatellite instability (MSI) in the tumor tissue, due to either a genetic defect, as in Lynch syndrome, or sporadic occurrence
• a high tumor mutation burden (TMB) as is typical, for example, for melanoma.

Figure

Simplified overview of the mechanisms of action of CTLA-4, PD-1, and PD-L1 inhibitors. T cell-mediated antitumor activity is enhanced either by blocking CTLA-4 receptor–mediated T-cell deactivation by antigen-presenting cells (left) or by blocking PD-1 and PD-L1 inhibitory checkpoints between T-cells and tumor cell (right).

The latter two markers are linked with a large number of tumor neoantigens, which is associated with greater efficacy of ICI therapy. ICIs are therefore administered for melanoma without requiring biomarker confirmation. Adverse events from ICIs include autoimmune reactions, which can affect any organ system (immune-related adverse events, irAEs). These types of irAEs occur in 86 to 96% of patients. Earlier studies involving high-dose ICI combination therapies have reported severe and life-threatening irAEs (grade ≥ 3) in up to 59% of patients (1, 2, 3). In the trials outlined below, the rate of irAEs with a grade three or higher ranges from 10 to 15%. The symptoms of irAEs are different from side effects resulting from chemotherapy. Table 1 lists common irAEs and their severity grades as reported in two selected studies. Treatment of these irAEs should be initiated immediately and follow recommendations from organizations such as the European Society for Medical Oncology (ESMO) (4).

Table 1

Immune-mediated adverse events from two clinical trials (2, 3) examining ICI monotherapies (nivolumab and ipilimumab) versus their combination

In recent years, ICIs have also increasingly been investigated in perioperative or neoadjuvant settings—i.e., before and/or after surgery—with the aim of improving prognosis. The present article provides an overview of the current state of neoadjuvant ICI therapy for selected solid tumors. Discussions before the German Federal Joint Committee regarding this added benefit remain largely outstanding. Monthly therapy costs for ICIs range from 6000 to 7000 Euros.

Methods

A selective literature search was conducted in PubMed for articles published between January 2018 and August 2025. The following search terms were used: “immunotherapy” or “checkpoint inhibitors” and “neoadjuvant”/“preoperative,” as well as the tumor entities discussed below – breast cancer, non-small cell lung cancer (NSCLC), colorectal cancer, and gastroesophageal adenocarcinoma. In addition, abstracts from international conference presentations were also reviewed. Prospective phase II and III trials examining clinical endpoints were taken into account. Preclinical data and case reports were not included.

Results

Breast cancer

Neoadjuvant ICI therapy as part of preoperative treatment for breast cancer, combined with postoperative therapy, is currently standard of care only for triple-negative breast cancer (TNBC). TNBC refers to tumors that are negative for estrogen, progesterone, and HER2 receptors and account for approximately 25% of cases. Research data on the use of ICI are also available for HER2-positive breast cancer (approximately 15% of cases) and for hormone receptor-positive, HER2-negative tumors (approximately 60%).

Treatment of TNBC stage IIa and above comprises neoadjuvant therapy with the PD-1 antibody pembrolizumab combined with standard chemotherapy (carboplatin/taxane followed by Adriamycin/cyclophosphamide). The KEYNOTE-522 trial showed that disease-free and overall survival are prolonged (5, 6, 7). The risk of dying from the disease was reduced by 34% (5-year survival: 86.6% versus 81.7%) (Table 2). The pathologic complete remission rate (pCR)—i.e., the proportion of patients in whom no residual tumor is found in the breast at the time of surgery—was slightly higher in the pembrolizumab group (55.6% with chemotherapy, 63% with the addition of pembrolizumab). However, the association between pCR and survival is weaker for immunotherapies, thus rendering pCR unsuitable as a primary study endpoint. In the KEYNOTE-522 trial, patients with residual tumor after chemotherapy did not receive any further treatment with capecitabine as recommended for TNBC, so there is no evidence available on the combination of capecitabine and pembrolizumab. Nor was olaparib—which is standard post-neoadjuvant therapy for patients with a germline BRCA1 or BRCA2 mutation and residual tumor after neoadjuvant chemotherapy—included in the KEYNOTE-522 trial. Nevertheless, guidelines recommend the postoperative combination of olaparib and pembrolizumab because both agents have been shown to improve survival after surgery (8).

Table 2

Immune checkpoint inhibitors as part of preoperative therapy for triple-negative breast cancer: results of randomized phase II/III trials

The phase III NSABP B-59/GeparDouze trial, previously reported at conferences, combined a comparable chemotherapy regimen with the PD-L1 inhibitor atezolizumab and showed a non-relevant extension of event-free survival (EFS) – 4-year EFS: 85.2% with atezolizumab versus 81.9% (HR = 0.81; 95% CI: [0.62; 1.03]) (9). Overall survival was around 90% in both treatment arms. Other studies of atezolizumab (IMpassion031; NeoTRIP, Table 2) also showed no significant improvement in EFS (10, 11, 12). A phase II trial involving durvalumab demonstrated improved survival; however, the drug has not been approved for this indication (13).

Therefore, the gold standard for primary TNBC is currently neoadjuvant and adjuvant pembrolizumab administered in the combination mentioned above in patients with a tumor size greater than 2 cm or axillary lymph node–involvement. Selection of patients according to biomarkers is not required. Adjuvant therapy or post-neoadjuvant therapy alone without prior neoadjuvant therapy with an ICI is not indicated.

The IMpassion050 trial yielded no improvement in pCR and no extension of survival by the addition of atezolizumab to neoadjuvant standard therapy for HER2-positive breast cancer (14).

HER2-negative, hormone receptor-positive carcinoma is treated without the addition of ICI, because trials involving this patient population have reported only pCR data and survival data are still outstanding. These phase III trials, KEYNOTE-756 and CheckMate-7FL, evaluated the addition of pembrolizumab and nivolumab, respectively, to neoadjuvant standard therapy in patients with high-risk, HER2-negative, hormone receptor–positive breast cancer (15, 16). Both analyses showed that the addition of ICI significantly increases pCR statistically and clinically (pCR in KEYNOTE-756: 24.3% versus 15.6%; p = 0.00005; pCR in CheckMate 7FL: 24.5 % versus 13.8 %; p = 0.0021).

In summary, neoadjuvant ICI therapy as part of preoperative management combined with postoperative (adjuvant) therapy is standard care only for TNBC stage IIa and above. Survival data for HER2-negative breast cancer, on the other hand, are still pending. The trials on perioperative ICI therapy yielded no positive effects for HER2 -positive breast cancer.

Non-small cell lung cancer

Neoadjuvant systemic treatment in early-stage NSCLC has so far only been included in treatment algorithms for locally advanced stage III disease. Registration trials have compared neoadjuvant chemoimmunotherapy with chemotherapy alone (17, 18, 19, 20, Table 3). Some of these trials included an additional twelve-month phase of postoperative ICI maintenance therapy (17, 19, 20). The following presents efficacy of neoadjuvant chemoimmunotherapy in operable stage II and III NSCLC.

Table 3

Immune checkpoint inhibitors as part of preoperative therapy for non-small cell lung cancer: results of randomized phase III trials

Surrogate endpoints, such as pCR and EFS, were selected for early assessment of efficacy. Further analyses of clinical trials are required to demonstrate whether these endpoints correlate sufficiently with the clinically relevant endpoint of overall survival.

The neoadjuvant treatments included platinum-based chemotherapy combined with a second cytostatic agent (doublet), supplemented with an ICI. The control arm received chemotherapy alone. Treatment duration was nine to 12 weeks. Around 80% of those receiving neoadjuvant therapy went on to surgery, with no differences between the treatment arms.

The addition of ICI resulted in a significant improvement in pCRs. Major pathologic response (mPR), defined as less than or equal to 10% viable tumor cells in the resected tissue, was also significantly higher. EFS was prolonged by a clinically relevant and statistically significant degree with additional ICI therapy across all registration trials. The AEGEAN trial, for example, showed a two-year EFS increase from 52.4% to 63.3% with the addition of durvalumab (17).

Final overall survival data have so far been reported only for the KEYNOTE-671 trial, which demonstrated a significant survival benefit in patients treated with the addition of pembrolizumab (20). However, this group was administered not only neoadjuvant ICI therapy but also adjuvant pembrolizumab.

The study results demonstrate the potential of ICIs in the neoadjuvant setting. However, this picture is marred by a significant number of patients who underwent surgery too late or not at all due to disease progression (4.6% to 6.8%) or because of adverse events (1.1% to 6.3%) during ICI treatment (17, 18, 19, 20). Good patient selection is essential for preoperative ICI therapy to minimize this risk. The decision regarding the resectability of a tumor should be made before treatment by a multidisciplinary tumor board at experienced centers. The authors of the present article recommend presentation at a lung cancer center certified by the German Cancer Society. Only patients with potentially resectable disease should be offered neoadjuvant therapy. Node-negative tumors benefit less from neoadjuvant chemo-ICI therapy. The same applies to patients whose tumors are negative for PD-L1 immunohistochemistry. The evidence base for patients with tumors harboring an ALK or EGFR driver alteration is uncertain as only the KEYNOTE-671 (20) and AEGEAN (17) trials have included this patient population. Patients who had never smoked also had an, at best, minimal benefit from immunotherapy across all studies.

In summary, neoadjuvant platinum-based chemo-ICI therapy with neoadjuvant or pembrolizumab has been approved for patients with tumors in resectable clinical stages II and III. An interdisciplinary tumor board should make the selection for this form of therapy, while involving all diagnostic and therapeutic disciplines.

Esophageal and gastric adenocarcinomas

Locally advanced gastroesophageal adenocarcinoma is treated using a multimodal strategy with curative intent. Guidelines recommend perioperative chemotherapy with FLOT (5-fluorouracil, leucovorin [folinic acid], oxaliplatin, and docetaxel) (21, 22). Nevertheless, prognosis is poor, with a median overall survival of 50 months (23). The addition of ICIs to chemotherapy is standard care in the first-line treatment of metastatic tumors with confirmed PD-L1 expression in tumor cells. Trials are currently assessing the extent to which the addition of ICIs to chemotherapy improves outcomes in the perioperative setting. Data is now available from one randomized phase II trial (DANTE) and two phase III trials (KEYNOTE-585, MATTERHORN) (Table 4).

Table 4

Immune-checkpoint inhibitors as part of preoperative therapy for esophageal and gastric adenocarcinoma: results of randomized phase II/III trials

The results of the DANTE phase II trial showed that the addition of atezolizumab to the FLOT regimen achieved a higher pCR than FLOT alone (24% versus 15%) (24). MSI tumors and tumors with high PD-L1 expression (combined positivity score [CPS] ≥ 10) showed the greatest benefit.

Patients in the KEYNOTE-585 trial who received pembrolizumab in addition to perioperative chemotherapy achieved a significantly higher pCR rate (12.9% versus 2.0%; p <0.0001) (25). Chemoimmunotherapy, however, prolonged only the co-primary endpoint EFS in a clinically relevant but not statistically significant manner (median: 44.4 versus 25.3 months; HR = 0.81; p = 0.0198). Median overall survival was comparable (60.7 and 58.0 months, respectively). A significant and clinically relevant EFS benefit from the addition of pembrolizumab was observed in patients with a CPS ≥ 10 (HR = 0.68).

The MATTERHORN phase III trial also demonstrated a significant improvement in pCR (19% versus 7%) in patients who had received durvalumab in addition to FLOT (26). The trial is particularly relevant because, unlike the KEYNOTE-585 trial, it only allowed FLOT as the chemotherapy regimen. The proportion of patients who underwent resection (87% versus 84%) and the R0 resection rates (86% in both treatment arms) did not differ. However, EFS was significantly and clinically relevantly prolonged (median not achieved versus 32.8 months; HR = 0.71; p <0.001). The addition of durvalumab to FLOT improved two-year EFS, regardless of PD-L1 expression (59% versus 67%). Overall survival was also significantly prolonged (median not achieved versus 47.2 months; HR = 0.78; p = 0.0025).

Patients with MSI tumors (around 8% of locally advanced tumors) demonstrate exceptionally high pCRs with ICI treatments. Two smaller single-arm phase II studies have been published on this issue. The NEONIPIGA trial (n = 32) reported a pCR rate of 58.6% after neoadjuvant ICI combination therapy with nivolumab and ipilimumab (27). These results were confirmed in the INFINITY trial (n = 36): neoadjuvant therapy with tremelimumab and durvalumab for three months resulted in a pCR rate of 60% (28).

In summary, preoperative chemoimmunotherapy results in a significant improvement in pCRs and EFS. Approval for durvalumab combined with FLOT is anticipated. The neoadjuvant use of ICI in patients with MSI tumors could replace perioperative chemotherapy. One notable feature in this patient population is the avoidance of surgery among patients achieving clinical complete remission (cCR). This strategy is currently being assessed in several studies.

Colorectal cancer

Until a few years ago, neoadjuvant radiotherapy (RT) or radiochemotherapy (RChT) was standard treatment for locally advanced rectal tumors (tumors situated 0–16 cm from the anal verge). Treatment options have meanwhile broadened, and therapy has now become risk-adapted to include RT/RChT, neoadjuvant chemotherapy, and primary resection. In patients with a very high risk of recurrence, neoadjuvant RT/RChT is supplemented with an additional 3- to 4.5-month neoadjuvant chemotherapy regimen (total neoadjuvant therapy, TNT). Organ-preserving approaches are also being adopted more frequently, i.e., deferral of surgery in patients with a cCR after RT/RChT or TNT (29).

Patients with colon cancer have so far undergone primary surgery. Only in recent years has neoadjuvant chemotherapy been reported as a treatment option (30). In stages II and III colon cancer, approximately 15 to 20% of tumors present MSI. In previous years, several preoperative phase II trials have been conducted for MSI colon cancer, most of which examined the primary endpoint pCR. These studies reported very high pCRs. The largest of these analyses, the NICHE-2 single-arm trial, treated patients preoperatively with nivolumab and ipilimumab for four weeks (31, 32). Primary endpoints were safety and disease-free survival (DFS) at three years. Of 115 patients, 113 (98%) were operated on within the planned timeframe. None of the patients terminated treatment due to adverse events. Of 111 evaluable patients, 95% achieved an mPR (≤ 10% residual viable tumor) and 75 (68%) a pCR. All patients were still alive at 36.5 months follow-up, and there were no recurrences. These results were confirmed in three additional trials (33, 34, 35) involving other ICIs (Table 5).

Table 5

Immune checkpoint inhibitors as part of preoperative therapy for colon cancer: results of phase II trials for MSI/dMMR tumors

In one study on MSI tumors (only 2 to 4% of patients) a different endpoint was selected for rectal carcinoma: organ sparing management. This endpoint is more relevant in rectal cancer than in colon cancer due to the complexity of rectal cancer surgery and its implications for patient-relevant endpoints, such as continence, sexual function, etc. In this single-arm study involving 49 patients, dostarlimab was administered as monotherapy for six months (36). All patients achieved cCR. The primary endpoint (sustained complete remission for at least 12 months from completion of treatment) has been achieved in 37 evaluable patients to date. Long-term data is not yet available.

Data from randomized studies have also been reported for the addition of ICIs to TNT in microsatellite-stable (MSS) rectal cancer (37, 38, 39). The studies presented in the eTable demonstrated very high pCR rates of 40 to 55%, particularly for protocols that used short-course radiotherapy (5 x 5 Gy) followed by consolidation chemotherapy combined with preoperative ICI administration (32, 33). Follow-up of these studies will determine whether this significant improvement in the pCR also results in improvements in DFS and overall survival. Moreover, future studies should investigate the extent to which integrating ICIs into TNT protocols improves the likelihood of organ preservation.

eTable

Immune checkpoint inhibitors as part of preoperative total neoadjuvant treatment of rectal carcinoma: results of randomized phase II/III trials in predominantly microsatellite-stable tumors

In summary, preoperative ICI therapy in colorectal cancer is particularly effective in MSI tumors and shows high pCRs and, in rectal cancer, a greater chance of organ preservation; however, no approval has been granted to date.

Conflict of interest statement

RDH received counseling and lecture fees from AstraZeneca, BeOne, BMS, GSK, and MSD. He also received travel expense support and conference fee reimbursement from AstraZeneca, BeOne, BMS, and MSD.

SL received counseling and lecture fees from AstraZeneca, BMS, Daiichi-Sankyo, GSK, JAZZ, MSD, Servier, and Takeda, and travel expense support and conference fee reimbursement from Daiichi-Sankyo.

MS received counseling and lecture fees from Pfizer, AstraZeneca, Takeda, Gilead, Daiichi-Sankyo, Regeneron, and Boehringer. He received travel expense support and conference fee reimbursement from Pfizer, Daiichi-Sanko, and Merck.

SB received lecture fees from AstraZeneca, Bristol Myers Squibb, Roche, and Johnson&Johnson. He is treasurer of the European Society of Thoracic Surgeons.

SFF declares that no conflict of interest exists.

SL received professional fees and research funding (all to the institution) from AstraZeneca, Abbvie, Agendia, Amgen, BionTech, Celgene, BMS, Cellcuity, DSI, Exact Science, Gilead, GSK, Incyte, Lilly, Medscape, Molecular Health, MSD, Novartis, Pierre Fabre, Pfizer, Relay, Roche, Sanofi, Seagen, Stemline/Menarini, Olema, Bayer, Bicycle, JAZZ Pharma, and BeiGene. She received support for travel costs and conference fees from DSI, ESMO, SGBCC, ASCO, and the Breast Commission of the Gynecologic Oncology Working Group (AGO). She holds, or has applied for, the following patents: EP14153692.0 / EP21152186.9 / EP18209672 / EP24210258. She has received royalties from VM Scope.

Manuscript received on April 29, 2025, revised version accepted on November 4, 2025

Translated from the original German by Dr. Grahame Larkin

Corresponding author:
Prof. Dr. med. Ralf-Dieter Hofheinz

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