Neoadjuvant Ipilimumab Research Articles

Tissue and Imaging Biomarkers of Response to Neoadjuvant Nivolumab or Nivolumab plus Ipilimumab in Patients with Resectable Hepatocellular Carcinoma

Introduction: Perioperative immunotherapy has shown promise in some patients with early-stage hepatocellular carcinoma (HCC). This study examined tissue and imaging biomarkers associated with pathologic response in a phase II clinical trial in patients with resectable HCC. Methods: Analysis included 18 patients with biopsy-proven resectable HCC treated with neoadjuvant nivolumab plus ipilimumab or nivolumab alone in a phase II clinical trial at MD Anderson Cancer Center (NCT03222076). Liver MRE (to measure tissue fibrosis) and biopsies (to evaluate immune activation markers) were obtained serially pretreatment and after completing neoadjuvant immunotherapy. A major pathologic response (MPR) was defined as tumor necrosis of more than 70%. Data comparing patients with MPR versus those without were summarized using descriptive statistics and compared using the Wilcoxon rank-sum test. Results: Patients with MPR after neoadjuvant immunotherapy tended to have larger tumors (mean 9.52 vs. 4.99 centimeters; p = 0.050). They had a significant reduction in tumor size posttreatment (14.67% reduction vs. 9.15% increase in size; p = 0.042) and a nonsignificant decrease in serum AFP (−24.20% vs. −14.00%; p = 0.085). Further, patients with MPR had a greater increase in intratumoral expression levels of CD8 (26.92% vs. −0.04%; p = 0.026), granzyme B (15.56% vs. −2.24%; p = 0.011), and PD-1 (20.17% vs. 0.40%; p = 0.048) but not PD-L1 (7.69% vs. 0.57%; p = 0.26). For imaging biomarkers, tumor and liver fibrosis were comparable before and after neoadjuvant therapy in patients with MPR versus nonresponders. Conclusion: Changes in tumor size, immune cell infiltration, and immune cell activation are candidate predictive markers of pathologic response to neoadjuvant immunotherapy in patients with resectable HCC.

1090P High concurrent interferon gamma signature expression in the primary tumor and lymph node metastasis is associated with superior outcome upon neoadjuvant ipilimumab + nivolumab in stage III melanoma

1090P High concurrent interferon gamma signature expression in the primary tumor and lymph node metastasis is associated with superior outcome upon neoadjuvant ipilimumab + nivolumab in stage III melanoma

Single-arm trial of neoadjuvant ipilimumab plus nivolumab with chemoradiotherapy in patients with resectable and borderline resectable lung cancer: the INCREASE study

BackgroundIn non-small cell lung cancer (NSCLC), chemoradiotherapy (CRT) yields pathological complete response (pCR) rates of approximately 30%. We investigated using ipilimumab plus nivolumab (IPI-NIVO) with neoadjuvant CRT in resectable, and...

Quality of life with neoadjuvant ipilimumab (IPI) and nivolumab (NIVO) versus adjuvant nivolumab in resectable stage III melanoma: 36-week data from the phase 3 NADINA trial.

LBA9584 Background: Neoadjuvant (neoadj) ipilimumab (IPI) + nivolumab (NIVO) showed improved event-free survival compared to adjuvant (adj) NIVO, but at the cost of increased immune related toxicity (irAEs). In the PRADO trial, impairment of health-related quality of life (HRQoL) was predominantly driven by the extent of the surgery and not by irAEs. To evaluate the effect of neoadj IPI+NIVO on HRQoL, we report the 36w HRQoL outcomes from the phase 3 NADINA trial. Methods: Eligible patients (pts) with resectable, macroscopic stage III melanoma were randomly assigned to receive 2 cycles of neoadj IPI+NIVO followed by a therapeutic lymph node dissection (TLND; w6) and only in partial- or non-responders, 1y of adj systemic treatment; or TLND (w0) followed by 12 cycles adj NIVO. EORTC QLQ-C30 questionnaires (qtn) were digitally collected at baseline, w6, w12 and thereafter q12w. The unadjusted HRQoL scores (scale 0-100) were assessed for pts who completed 39w of follow-up (FU) on January 12, 2024. Results: 261/423 randomized pts had 39w FU at data cutoff. 81% completed the qtn at BL, with thereafter an average compliance of 80%. QLQ-C30 data were available for 107 pts in the neoadj arm and 103 in the adj arm. Physical-, role-, emotional functioning, and pain were comparable between the neoadj and adj arm across all timepoints (Table), as were fatigue and the summary score. A numerical trend towards worsening of physical-, role functioning, and pain was seen at w6 for the adj arm and at w12 for the neoadj arm, representing the post-surgery QoL timepoints. Conclusion: Using fully digitalized data collection, this first HRQoL analysis of neoadj vs adj immunotherapy in stage III melanoma showed comparable results between the neoadj and adj arms. Physical-, role functioning, and pain were impaired in both groups at the first post-surgery timepoint. Clinical trial information: NCT04949113 . [Table: see text]

Neoadjuvant Immunotherapy in Locally Advanced Mismatch Repair–Deficient Colon Cancer

BackgroundMismatch repair–deficient (dMMR) tumors can be found in 10 to 15% of patients with nonmetastatic colon cancer. In these patients, the efficacy of chemotherapy is limited. The use of neoadjuvant immunotherapy has shown promising results, but data from studies of this approach are limited.MethodsWe conducted a phase 2 study in which patients with nonmetastatic, locally advanced, previously untreated dMMR colon cancer were treated with neoadjuvant nivolumab plus ipilimumab. The two primary end points were safety, defined by timely surgery (i.e., ≤2-week delay of planned surgery owing to treatment-related toxic events), and 3-year disease-free survival. Secondary end points included pathological response and results of genomic analyses.ResultsOf 115 enrolled patients, 113 (98%; 97.5% confidence interval [CI], 93 to 100) underwent timely surgery; 2 patients had surgery delayed by more than 2 weeks. Grade 3 or 4 immune-related adverse events occurred in 5 patients (4%), and none of the patients discontinued treatment because of adverse events. Among the 111 patients included in the efficacy analysis, a pathological response was observed in 109 (98%; 95% CI, 94 to 100), including 105 (95%) with a major pathological response (defined as ≤10% residual viable tumor) and 75 (68%) with a pathological complete response (0% residual viable tumor). With a median follow-up of 26 months (range, 9 to 65), no patients have had recurrence of disease.ConclusionsIn patients with locally advanced dMMR colon cancer, neoadjuvant nivolumab plus ipilimumab had an acceptable safety profile and led to a pathological response in a high proportion of patients. (Funded by Bristol Myers Squibb; NICHE-2 ClinicalTrials.gov number, NCT03026140.)

Neoadjuvant Nivolumab and Ipilimumab in Resectable Stage III Melanoma

BackgroundIn phase 1–2 trials in patients with resectable, macroscopic stage III melanoma, neoadjuvant immunotherapy was more efficacious than adjuvant immunotherapy.MethodsIn this phase 3 trial, we randomly assigned patients with resectable, macroscopic stage III melanoma to two cycles of neoadjuvant ipilimumab plus nivolumab followed by surgery or surgery followed by 12 cycles of adjuvant nivolumab. Only patients in the neoadjuvant group with a partial response or nonresponse received adjuvant treatment. The primary end point was event-free survival.ResultsA total of 423 patients underwent randomization. At a median follow-up of 9.9 months, the estimated 12-month event-free survival was 83.7% (99.9% confidence interval [CI], 73.8 to 94.8) in the neoadjuvant group and 57.2% (99.9% CI, 45.1 to 72.7) in the adjuvant group. The difference in restricted mean survival time was 8.00 months (99.9% CI, 4.94 to 11.05; P<0.001; hazard ratio for progression, recurrence, or death, 0.32; 99.9% CI, 0.15 to 0.66). In the neoadjuvant group, 59.0% of patients had a major pathological response, 8.0% had a partial response, 26.4% had a nonresponse (>50% residual viable tumor), and 2.4% had progression; in 4.2%, surgery had not yet been performed or was omitted. The estimated 12-month recurrence-free survival was 95.1% in patients in the neoadjuvant group who had a major pathological response, 76.1% among those with a partial response, and 57.0% among those with a nonresponse. Adverse events of grade 3 or higher that were related to systemic treatment occurred in 29.7% of patients in the neoadjuvant group and in 14.7% in the adjuvant group.ConclusionsAmong patients with resectable, macroscopic stage III melanoma, neoadjuvant ipilimumab plus nivolumab followed by surgery and response-driven adjuvant therapy resulted in longer event-free survival than surgery followed by adjuvant nivolumab. (Funded by Bristol Myers Squibb and others; NADINA ClinicalTrials.gov number, NCT04949113.)

The MARIANE-trial: Multicenter phase 1b/2 trial testing safety and efficacy of neoadjuvant intradermal ipilimumab and nivolumab in high-risk stage II melanoma.

TPS9615 Background: Adjuvant anti-PD1 (nivolumab or pembrolizumab) has been shown to improve relapse free survival for patients with high-risk stage II melanoma (IIB-C). However, this therapy probably won’t be reimbursed as standard of care in most European countries due to high costs, and the benefit-risk-ratio. For macroscopic stage III melanoma, neoadjuvant ipilimumab (IPI; anti-CTLA4) plus nivolumab (NIVO; anti-PD1) has been shown to induce high pathologic response rates in the resected lymph nodes, long-term event free survival, and this schedule is currently being compared to adjuvant NIVO in a phase 3 study (NCT04949113). This combination schedule, however, is unsuitable for earlier disease stages, due to high costs and clinical toxicity. In preclinical models, a local tumor draining lymph node directed delivery of anti-PD-1 plus anti-CTLA-4 has been demonstrated to outperform systemic administration on induction of T-cell proliferation and tumor control. In patients, local delivery of anti-PD-1 or anti-CTLA-4 has been suggested to be equally effective in tumor control with a reduction of adverse events. These data have formed the rationale for testing intradermal injections at the excision site of the primary tumor with IPI and NIVO prior to the re-excision and sentinel node procedure in high-risk stage II melanoma patients. Methods: This multicenter, dose-escalating phase Ib/II trial, using a Simon’s two-stage design, is the first trial to test feasibility and efficacy of intradermal IPI plus NIVO in high-risk stage II melanoma patients. In total 21 to 80 patients, diagnosed with a stage T3-4 cutaneous melanoma with ≥ 50% chance of positive sentinel node, naïve for re-excision, sentinel node surgery and immunotherapy, will be included in this trial. Patients will receive 2 cycles of intradermal IPI 0.5 mg + NIVO 1 mg at the excision site of the primary melanoma (every 3 weeks; arm A); 6 cycles intradermal IPI 0.5 mg + NIVO 1 mg (every week; arm B); 2 cycles intradermal IPI 10 mg + NIVO 20 mg (every 3 weeks, arm C); or 2 cycles of intravenous nivolumab 240 mg every 3 weeks combined with the most optimal intradermal regimen of IPI + NIVO (based on the results of arm A, B or C) in arm D. In week 6, patients will undergo sentinel node surgery, whereafter only patients with a non-MPR (&gt;10% vital tumor) will be treated with adjuvant anti-PD1 according to current standard of care. We expect the first patient to be enrolled in March 2024and to be accruing for 1-1.5 years. Clinical trial information: NCT06240143 .

Analysis of neoadjuvant nivolumab and ipilimumab for clinical stage III melanoma using the SWOG S1801 event-free survival definition.

e21563 Background: Perioperative pembrolizumab to advanced melanoma, as shown SWOG S1801 trial, was associated with a longer event-free survival (EFS) than those who received adjuvant pembrolizumab (EFS at 2y: 72% vs 49%, respectively). EFS, as defined in this trial, encompasses important factors related to neoadjuvant therapy in clinical practice. So far, there is no data of EFS rate for melanoma patients(pts.) treated with neoadjuvant nivolumab and ipilimumab, which is associated with more response rate but also more toxicity. Methods: We conducted a retrospective analysis of pts. with clinical stage III melanoma treated with neoadjuvant nivolumab 3mg/kg + ipilimumab 1 mg/kg (N3+I1) for two cycles followed by surgery and adjuvant therapy at AC Camargo Cancer Center. We applied the SWOG S1801 EFS definition (which includes inability to receive surgery, to start adjuvant therapy, melanoma recurrence and death) to this cohort. Results: Between Jan 2019 and Jan 2024, 37 pts. with clinical stage III melanoma treated with neoadjuvant N3+I1 were identified. Gender: 25 males (67%), median age (years): 58 (range: 31-78), BRAFV600 mut: 25(67%), Stage AJCC 8th edition: IIIB = 23 (62%), IIIC = 12 (32%), IIID = 2(6%). G3/G4 immune-related adverse events (irAE): 11 patients (30%). Two out 37 pts. did not complete the programmed neoadjuvant cycles due to toxicity (1 = colitis, 1 = myositis). Three pts. (8%) were unable to receive surgery: irAE = 1, metastatic disease = 2. All pts. who underwent surgery (n = 35) achieved R0 resection and started adjuvant therapy within 84-days after the procedure. Major pathological response (MPR) = 23 pts(66%) and non-MPR = 12 pts.(34%). There were 4 melanoma relapses after starting adjuvant therapy (11%). The total number of events was 7 (19%). In a median follow-up of 16.1 months(range:13.9-25), the landmark analysis of EFS at 2 years was 73% (95%CI, 49 to 87). Relapse-free survival(RFS) for MPR at 2 years: 96%. Conclusions: Neoadjuvant N3+I1 seems to have similar EFS compared to SWOG S1801, but numerically more MPR rate and fewer events of progression, relapse and/or death. [Table: see text]

Neoadjuvant immunotherapy in sarcomatoid mesothelioma (Alliance A082101).

TPS8125 Background: Sarcomatoid mesothelioma is the most aggressive form of pleural mesothelioma and is associated with the worst prognosis of the histologic variants of this disease. In the Checkmate 743 clinical trial the patients with sarcomatoid mesothelioma who received ipilimumab and nivolumab had survival outcomes that were similar to those of patients with epithelioid mesothelioma. In comparison, the patients with sarcomatoid mesothelioma who received chemotherapy had the worst outcomes in this trial, highlighting the known limited efficacy of chemotherapy against this histologic variant. Checkmate 743 demonstrated that ipilimumab and nivolumab is a new standard of care for non-epithelioid mesothelioma. Surgery typically has not been offered to this group of patients given their historically poor outcomes. With the significant survival gains seen patients with sarcomatoid mesothelioma treated with immunotherapy, we hypothesized that surgery may extend the benefits seen with immunotherapy. Methods: Alliance for Clinical Trials in Oncology A082101 is a prospective, phase 2 nonrandomized clinical trial for patients with sarcomatoid mesothelioma. The co-primary objectives are to determine the percentage of patients with potentially resectable sarcomatoid mesothelioma able to proceed with surgery after neoadjuvant ipilimumab and nivolumab, and the progression-free survival (PFS) at 12 months (12-month PFS) after the initiation of ipilimumab and nivolumab. For sample size determination, we assumed that if the true rate of surgery is 75% or greater, it would indicate that neoadjuvant immunotherapy is feasible to be given prior to surgery. On the other hand, if the true rate of surgery is 50% or less it would indicate that neoadjuvant immunotherapy is not worthy of further investigation. Twenty-six (26) eligible patients will be needed to receive neoadjuvant immunotherapy. If 16 or fewer of the 26 eligible patients proceed to surgery, it will be concluded that the experimental therapy is not worthy of further investigation. Otherwise, it will be concluded that the experimental therapy is worthy of further investigation. Safety monitoring will be done through a 6-week run-in for the first 10 patients to assess for pre-operative and post-operative toxicities and complications. Sequential boundaries will be used to monitor severe toxicity and complication rates. Accrual will be halted if excessive numbers of severe toxicity and complications in pre-operative and post-operative phases are seen. The accrual and safety data will be summarized in reports for semiannual reviews by Alliance Data and Safety Monitoring Board. Tumor and blood-based biomarkers will be included as exploratory biomarkers. Support: U10CA180821, U10CA180882, U24 CA196171; https://acknowledgments.alliancefound.org . Clinical trial information: NCT05647265 .

Phase II study of neoadjuvant ipilimumab and nivolumab in combination with paclitaxel following anthracycline-based chemotherapy in patients with treatment resistant stage III triple negative breast cancer (TNBC): BCT1702—Survival results.

608 Background: We examined the efficacy and safety of neoadjuvant ipilimumab and nivolumab combined with paclitaxel following suboptimal response to anthracycline-based chemotherapy in patients with early-stage TNBC. Methods: This single arm phase 2 study enrolled 34 patients at 8 sites. Patients had stage 3 TNBC, after 4 cycles of anthracycline-based therapy, with ≥15mm of tumor remaining or ≥10mm of tumor with ≥1 positive lymph node. A suboptimal response at baseline was defined as &lt;50% reduction in tumor volume after anthracycline-based therapy. Patients received neoadjuvant ipilimumab 1mg/kg IV 6 weekly for 2 doses and nivolumab 240mg every 2 weeks for 6 doses, with weekly paclitaxel at 80mg/m2 for 12 weeks, followed by surgery. Nivolumab (480mg 4-weekly) continued post operatively for a further 9 months. Primary endpoint was pathological complete response (pCR: ypT0/is, ypN0) in breast and axilla, with secondary endpoints pCR in the suboptimal responders, pCR in PD-L1 positive (≥1% by SP142) or TIL% high (≥30%), event-free (EFS) and overall survival (OS). Results: Between December 2018 and April 2020, 34 patients were enrolled, 33 were evaluable for the primary endpoint. Median age was 46.6yrs. At diagnosis, 97% patients were clinical stage III, 24/34 (70.5%) were clinically node positive, 9/31 (27%) were PD-L1 positive and 6/30 (20%) were TILs% high. At study entry (after anthracycline-based chemo), the median tumor size by ultrasound was 28mm (12-62). The pCR rate was 24.2% (95% CI, 11.09-42.26) in all evaluable, 44.4% [4/9] in PD-L1+ and 9.5% [2/21] in PD-L1- patients. In suboptimal responders, the pCR rate was 25% (95% CI,8.6-49.1) (3/16). At a median follow up of 36.6 months, 9 patients have died. The KM estimates for EFS and OS at 12 months were 96.8% and 93.7%, at 24 months were 84.4% and 84.4% and at 36 months 61.2% and 71.9%, respectively. Patients who achieved a pCR had numerically better EFS (HR 3.61 (0.47-28.2, p=0.2) and OS (HR 2.6 (0.33-21.08); p=0.34). Patients with PD-L1+ tumors vs PD-L1- had a 3-year EFS of 100% vs 52% (p=0.01) and 100% vs 67% OS (p=0.05). Results were similarly favorable for TIL high vs low. Conclusions: The addition of ipilimumab and nivolumab to neoadjuvant chemotherapy resulted in 100% survival for high-risk patients with PD-L1+ and/or TIL% high tumors. Combination CTLA4 and PD-1 targeting agents should be further investigated in Stage 3 TNBC patients. Translational research is ongoing. Clinical trial information: ACTRN12617000651381. [Table: see text]

NeoRad(Low): A phase 2 trial of neoadjuvant (NA) ipilimumab + nivolumab (ipi+nivo) with low dose stereotactic body radiation therapy (SBRT) as an immune stimulant in patients with resectable stage IB-III non-small cell lung cancer (NSCLC).

e20081 Background: Standard NA immune checkpoint blockade for patients with resectable NSCLC targets PD1 only and must be combined with platinum-based chemotherapy. In a randomized phase 2 NA study, ipi + nivo demonstrated greater immune-mediated efficacy compared to nivo alone with major pathologic response (MPR) 50% vs. 24%, Cascone T, et al. Nat Med. 2021;27(3):504-14). Preclinical and clinical studies have demonstrated that low doses of radiation enhance immune response by multiple mechanisms (dsDNA breaks, induction of STING, transcription of pro-inflammatory proteins, increased expression of neoantigens while sparing effector T cells). An approach incorporating low dose radiation as an immune stimulant potentially may improve immune-mediated efficacy and shorten the duration of NA treatment compared to approaches that use combined cytotoxic chemotherapy. Methods: This single-arm trial tested NA ipi (1 mg/kg d1) + nivo (3mg/kg d1, 15, 29) plus low-dose SBRT delivered as 2 fractions (4Gy x 2) to the gross primary tumor and nodal disease immediately following day 1 infusion and completed by day 3 in patients with medically operable stage IB-III NSCLC Patients went on to surgical resection between days 49 -63. The primary efficacy outcome measure was pathologic response (including MPR, and complete PR (CPR)). Secondary outcome measures included safety, and exploratory biomarkers of immune response in pre- and post-operative blood and tissue. A two-stage design was employed to stop the study for lack of efficacy if fewer than 3 of the first 9 evaluable patients achieved MPR or experienced undue toxicity. Results: Patients were treated on study: 4 men, 5 women, aged 40-71, stage IB (2), IIB (5), IIIA (1), IIIB (1); adenocarcinoma 7 (all EGFR,ALK -), squamous 2; ECOG PS 0-1 (9); all were former smokers. There were no dose limiting toxicities. Study-related toxicities were ≤ grade 2 including rash (2) and abdominal pain (1). There were no study-related surgical complications. One patient (IIIA, T1N2) experienced clinical and radiologic progression during study treatment and was confirmed to have pleural metastases at surgery. Of 7 patients resected to date, there was 1 CPR, 0 further MPR and 1 patient with surgery pending. All resected patients had some treatment effect, 3 were down staged and these elected not to receive adjuvant cytotoxic chemotherapy. The only patient to progress in 8 months med f/u was the patient progressing during NA therapy. Conclusions: Low-dose radiation with concurrent NA ipi + nivo was safe and well tolerated in this small cohort but did not improve MPR compared to historical phase 2 data of ipi + nivo alone. Standard and exploratory biomarkers of immune response will be presented to determine if patient selection played a role in these results. Clinical trial information: NCT04933903 .

Combined EORTC FDG-PET/CT and RECIST 1.1 response criteria and prediction of pathological response to neoadjuvant nivolumab and ipilimumab for clinical stage III melanoma.

9590 Background: Accurate identification of pathological response to neoadjuvant therapy for clinical stage III melanoma before surgery may allow us to better tailor the treatment. RECIST 1.1 has shown poor concordance rates with pathological responses and EORTC FDG-PET/CT response criteria using SUV max is susceptible to internal and external variables leading to difficulty in determining accuracy appropriately. Methods: We conducted a multicenter retrospective analysis of patients with clinical stage III melanoma treated with neoadjuvant nivolumab 3mg/kg + ipilimumab 1mg/kg(N3+I1) for two cycles who did baseline and pre-operative 18F-FDG-PET/CT. RECIST 1.1 and EORTC PETCT criteria were used to classify patients in terms of response. The pathological results were correlated to the image findings. Results: Between Jan 2019 and Jan 2024, 37 patients with clinical stage III melanoma treated with neoadjuvant N3+I1 were identified. Gender: 25 males (67%), median age (years): 58 (range: 31-78), BRAFV600 mut: 25(67%), positive nodes on baseline exam:1=30 (81%), 2=4(11%), and 3 or more =3(8%). Stage AJCC 8th edition: IIIB=23 (62%), IIIC=12 (32%), IIID=2(6%). Among them, 34 had baseline and post-neoadjuvant therapy PET-CT. Twenty-one (62%) had major pathological response (MPR) and 13(38%) had non-MPR. Using objective response and non-objective criteria to capture MPR and non-MPR, respectively, we found the following results: RECIST 1.1 (sensitivity= 48%, specificity=100%, accuracy=68%), EORTC-PET (sensitivity=90%, specificity=69%, accuracy=82%). Combining RECIST 1.1 and EORTC-PET/CT analysis, we found that: double objective responders (CR/PR and CMR/PMR, n=10) had 100% specificity to MPR and double progressors (PD/PMD, n=9) had 95% specificity to non-MPR. The only patient classified as double progressor that did not have non-MPR presented an intense inflammatory response with fever, pain and erythema leading to an increase in the size and number of lymph-nodes. No viable cells were found in the pathological report. Conclusions: Using combined RECIST 1.1 and EORTC-PET/CT response criteria may help to predict pathological response in patients with clinical stage III melanoma who undergo to neoadjuvant nivolumab and ipilimumab.

Serologic, radiographic, and tissue-based markers associated with major pathologic response after treatment with neoadjuvant immunotherapy in patients with resectable hepatocellular carcinoma.

561 Background: Neoadjuvant immunotherapy can induce a major pathologic response (MPR) in patients with resectable hepatocellular carcinoma (HCC), which may be associated with prolonged recurrence-free survival. This study aimed to understand which variables correlate with achieving an MPR. Methods: Patients with resectable HCC who received either neoadjuvant nivolumab plus ipilimumab or nivolumab alone and underwent surgery were included. 18 patients had baseline and post-treatment computed tomography, alpha-fetoprotein (AFP), and elastography. 17 of these patients had baseline and post-treatment tissue available for immunohistochemistry. Patients were classified into two groups: MPR, defined as necrosis of &gt;70%, and no MPR. Data was summarized using descriptive statistics and compared using Wilcoxon rank sum test. P value &lt;0.05 was considered statistically significant. Results: Statistically significant differences in objective response (OR) and changes in CD8, Granzyme B, and PD-1 expression were identified upon comparison of patients with an MPR to those without an MPR (Table 1). Additionally, numerical differences in baseline tumor size, change in AFP, and both non-tumor and tumor liver fibrosis (at baseline, after treatment, and interim change) were identified upon comparison of patients with an MPR to those without an MPR. Conclusions: Our data show that large baseline tumor size, greater OR, reduction in AFP, increase in liver and tumor fibrosis, and increase in CD8, Granzyme B, and PD-1 expression after receipt of neoadjuvant immunotherapy are associated with achieving an MPR in patients with resectable HCC. [Table: see text]

1096P Prolonged follow-up confirms durability of favorable outcomes after neoadjuvant ipilimumab plus nivolumab in melanoma

1096P Prolonged follow-up confirms durability of favorable outcomes after neoadjuvant ipilimumab plus nivolumab in melanoma

1095P Associations between baseline biomarkers and 3-year survival in the PRADO trial testing neoadjuvant ipilimumab and nivolumab in stage III melanoma

1095P Associations between baseline biomarkers and 3-year survival in the PRADO trial testing neoadjuvant ipilimumab and nivolumab in stage III melanoma

Overview, Diagnosis, and Perioperative Systemic Therapy of Upper Tract Urothelial Carcinoma.

Upper tract urothelial carcinoma comprises 5-10% of all urothelial carcinoma cases. This disease tends to have a more aggressive course than its lower urinary tract counterpart, with 60% of patients presenting with invasive disease and 30% of patients presenting with metastatic disease at diagnosis. The diagnostic workup of UTUC involves imaging with CT urogram, urine cytology, and direct visualization and biopsy of suspected lesions via ureteroscopy. Standard treatment of high-grade UTUC involves radical nephroureterectomy (RNU) and excision of the ipsilateral bladder cuff. Both the NCCN and EAU Guidelines include neoadjuvant chemotherapy as a treatment option for select patients with UTUC; however, there are no strict guidelines. Much of the rationale for neoadjuvant chemotherapy is based on extrapolation from data from muscle-invasive bladder cancer, which has demonstrated a 5-year OS benefit of 5-8%. Retrospective studies evaluating the use of NACT in urothelial carcinoma have yielded pathologic objective response rates of 48% in UTUC cohorts. The randomized Phase III POUT study noted a DFS advantage with adjuvant platinum-based chemotherapy, compared with surveillance in UTUC, of 70% vs. 51% at 2 years. Though not the standard of care, multiple studies have explored the use of perioperative immunotherapy or chemoimmunotherapy in the management of invasive urothelial carcinoma. The PURE-02 study explored the use of neoadjuvant pembrolizumab in patients with high-risk UTUC. A small study of 10 patients, it showed no significant signals of activity with neoadjuvant pembrolizumab. Another Phase II study of neoadjuvant ipilimumab and nivolumab in cisplatin-ineligible UTUC yielded more promising findings, with 3/9 patients attaining a pathologic CR and the remaining six pathologically downstaged. The ABACUS trial found a 31% pathologic complete response rate amongst cisplatin-ineligible MIBC patients treated with neoadjuvant atezolizumab. The use of adjuvant immunotherapy has been explored over three phase III trials. The CheckMate-274 trial found a DFS benefit with the addition of one year of adjuvant nivolumab in patients with high-risk urothelial carcinoma. The IMvigor-010 study of adjuvant atezolizumab was a negative study. The AMBASSADOR trial of adjuvant pembrolizumab is pending results. With the FDA approval of erdafitinib in metastatic urothelial carcinoma, similar targets have been explored for use in perioperative use in invasive urothelial carcinoma, as with adjuvant infigratinib in the PROOF-302 trial. As the treatment paradigm for urothelial carcinoma evolves, further prospective studies are needed to expand the perioperative treatment landscape of UTUC.

Sarcomatoid renal cell carcinoma with an inferior vena cava tumor thrombus that was completely resected by robot-assisted laparoscopic radical nephrectomy after neoadjuvant therapy nivolumab plus ipilimumab: a case report.

We here present a patient with a sarcomatoid renal cell carcinoma complicated by inferior vena cava tumor thrombus that we treated with nivolumab plus ipilimumab. This resulted in shrinkage of the tumor, enabling complete resection by robot-assisted laparoscopic radical nephrectomy. The patient is still alive with no evidence of recurrence.

The impact of response-directed surgery and adjuvant therapy on long-term survival after neoadjuvant ipilimumab plus nivolumab in stage III melanoma: Three-year data of PRADO and OpACIN-neo.

101 Background: Neoadjuvant ipilimumab (IPI) + nivolumab (NIVO) has been shown to induce high pathologic response rates associated with an excellent relapse-free survival (RFS) in high-risk stage III melanoma. While OpACIN-neo tested different neoadjuvant IPI + NIVO regimens followed by therapeutic lymph node dissection (TLND) without adjuvant systemic therapy (ST), PRADO tested a personalized approach. In patients (pts) achieving a major pathologic response (MPR; ≤10% viable tumor), TLND and adjuvant ST were omitted, and pts with pathologic non-response (pNR; &gt;50% viable tumor) were treated with adjuvant ST (BRAFi/MEKi or anti-PD1) ± radiotherapy after TLND. Here, we address 1) whether omitting TLND in MPR pts had an adverse effect on long-term survival and 2) whether adding adjuvant ST in pNR pts had a favorable effect on survival. Methods: The 3-year (3y) RFS and distant metastasis-free survival (DMFS) of pts with MPR and pNR from PRADO and OpACIN-neo were analyzed, comparing MPR pts with TLND versus without TLND and pNR pts with adjuvant ST versus without adjuvant ST. Survival rates were calculated and compared with Kaplan-Meier and log-rank methods. Associations between baseline characteristics and RFS or DMFS were examined by Cox regression analysis. Results: Median follow-up was 37.9 months in PRADO (cutoff Jan 8, 2023) and 46.8 months in OpACIN-neo (cutoff Feb 14, 2022). For MPR pts, TLND omission did not affect survival, with a 3y RFS of 93% versus 96% (p=0.47) and 3y DMFS 98% versus 98% (p=0.92) for pts without TLND (n=59) versus with TLND (n=53), respectively. In pNR pts, an indication for a RFS and DMFS benefit was seen favoring pts with adjuvant ST (n=17: n=10 BRAFi/MEKi and n=7 anti-PD1) over pts without adjuvant ST (n=23), with 3y RFS rates being 64% versus 35% (p=0.10) and 3y DMFS rates 70% versus 52% (p=0.24). Baseline clinical characteristics did not differ between PRADO and OpACIN-neo pts or were not associated with RFS and DMFS. Conclusions: Omitting TLND in MPR pts after neoadjuvant IPI + NIVO seems not to affect RFS/DMFS. Given the high survival rates, adjuvant ST is unlikely to give further benefit in these pts. In pts with pNR, addition of adjuvant ST with ongoing anti-PD1 or switch to BRAFi/MEKi appears to improve RFS and DMFS. Clinical trial information: NCT02977052 . [Table: see text]

Neoadjuvant immunotherapy in sarcomatoid mesothelioma (Alliance A082101).

TPS8602 Background: Sarcomatoid mesothelioma is the most aggressive form of pleural mesothelioma and is associated with the worst prognosis of the histologic variants of this disease. In the Checkmate 743 clinical trial the patients with sarcomatoid mesothelioma who received ipilimumab and nivolumab had survival outcomes that were similar to those of patients with epithelioid mesothelioma. In comparison, the patients with sarcomatoid mesothelioma who received chemotherapy had the worst outcomes in this trial, highlighting the known limited efficacy of chemotherapy against this histologic variant. Checkmate 743 demonstrated that ipilimumab and nivolumab is a new standard of care for non-epithelioid mesothelioma. Surgery typically has not been offered to this group of patients given their historically poor outcomes. With the significant survival gains seen patients with sarcomatoid mesothelioma treated with immunotherapy, we hypothesized that surgery may extend the benefits seen with immunotherapy. Methods: Alliance for Clinical Trials in Oncology A082101 is a prospective, phase 2 nonrandomized clinical trial for patients with sarcomatoid mesothelioma. The co-primary objectives are to determine the percentage of patients with potentially resectable sarcomatoid mesothelioma able to proceed with surgery after neoadjuvant ipilimumab and nivolumab, and the progression-free survival (PFS) at 12 months (12-month PFS). For sample size determination, we assumed that if the true rate of surgery is 75% or greater, it would indicate that neoadjuvant immunotherapy is feasible to be given prior to surgery. On the other hand, if the true rate of surgery is 50% or less it would indicate that neoadjuvant immunotherapy is not worthy of further investigation. Twenty-six (26) eligible patients will be needed to receive neoadjuvant immunotherapy. If 16 or fewer of the 26 eligible patients proceed to surgery, it will be concluded that the experimental therapy is not worthy of further investigation. Otherwise, it will be concluded that the experimental therapy is worthy of further investigation. Safety monitoring will be done through a 6-week run-in for the first 10 patients to assess for pre-operative and post-operative toxicities and complications. Sequential boundaries will be used to monitor severe toxicity and complication rates. Accrual will be halted if excessive numbers of severe toxicity and complications in pre-operative and post-operative phases are seen. Tumor and blood-based biomarkers will be included as exploratory biomarkers. Clinical trial information: NCT05647265 .

FDG-PET/CT response and prediction of pathological response to neoadjuvant nivolumab and ipilimumab for clinical stage III melanoma.

9585 Background: Neoadjuvant immunotherapy with nivolumab 3mg/kg and ipilimumab 1 mg/kg (N3+I1) for two cycles for clinical stage III melanoma have shown rates of major pathological response (MPR) of approximately 60%.The prognosis of this group seems to be excellent so far. On the other hand, patients classified as pathological non-responders have a worse outcome and early identification of this group may allow us to tailor the treatment before surgery. Methods: We conducted a multicenter retrospective analysis of patients with clinical stage III melanoma treated with neoadjuvant N3+I1 for two cycles who did baseline and pre-operative 18F-FDG-PET/CT. The total number of FGD avid lesions and the percentual difference between the maximum SUV per lesion was calculated. The pathological results were correlated to FGD-PET/CT findings. Results: Between January 2019 and January 2023, 28 patients with clinical stage III melanoma treated with N3+I1 who had baseline and preoperative 18F-FDG PET were identified. Gender: 20 (71%) males, median age (range):55 (34-78), BRAFV600E/K mut: 15(53%), positive nodes on baseline PET/CT:1 = 26 (92%), 2 = 1(4%), and 3 = 1(4%). All known lesions identified by CT scan were also captured by FGD-PET/CT. Site of node(s): axilla = 12 (43%), cervical = 10 (36%), and inguinal = 6(21%). All but one patient received 2 cycles of N3+IP1(1 patient had grade 3 toxicity and received only one cycle). Pathological response: MPR = 19(68%), non-MPR: 8 (28%), and 1(4%) did not undergo surgery due to widespread progression. An increase in maximum SUV and/or appearance of new lesion(s), n = 8(28%), was correlated to non-MPR or metastatic disease in all cases, including a patient who developed sarcoidosis-like reaction with increase of SUV in the index lesion (+68%) and appearance of inflammatory mediastinal lymph-nodes. The median increase was (range): +73% (+11% to 483%). Reduction or stable maximum SUV with no appearance of new lesion, n = 20 (72%), was associated with MPR in 19 patients (95%). One patient,who had G3 colitis (with the need of infliximab), had 32% of reduction in maximum SUV but 100% of viable tumor cells on pathological report. The median decrease (range) was -76% (-1.2% to -100%). Conclusions: FGD-PET/CT may help to predict pathological response in patients with clinical stage III melanoma who undergo to neoadjuvant nivolumab and ipilimumab.