Cycles Of Nivolumab Research Articles

PATH-43. MALIGNANT TRANSFORMATION OF MENINGEAL MELANOCYTOMA - GENETIC ALTERATIONS AND RESPONSE TO CHECKPOINT BLOCKADE IMMUNOTHERAPY

Abstract INTRODUCTION Meningeal melanocytomas are uncommon tumors that develop from leptomeningeal melanocytes. These tumors can exhibit aggressive behavior, leading to symptoms due to compression and potential invasion of nearby central nervous tissue. Case: In this report, we discuss the case of a 45-year-old man who was diagnosed 18 years ago with a meningeal melanocytoma in the right temporal region. He underwent complete resection with each recurrence and received focal intensity-modulated radiation therapy after a third recurrence in 2013. In May 2022, he developed progressive headaches and diplopia secondary to tumor recurrence on the right temporal region. Resection revealed that the tumor had progressed to malignant meningeal melanoma with 34 mitoses per 10 high-power fields. Next-generation sequencing (NGS) showed GNAQ mutation confirming tumor of central nervous system (CNS) origin, and also showed an SF3B1 mutation, indicating aggressive behavior. Several chromosomal abnormalities were also detected. Systemic workup revealed liver, lung, and bone metastasis. Liver biopsy confirmed meningeal melanoma of central origin. The patient received radiosurgery with a total of 30Gy over five fractions to intracranial surgical cavity, followed by three cycles of nivolumab and relatlimab. Unfortunately, the patient experienced severe intracranial and systemic progression, leading to his death six months after the malignant transformation. DISCUSSION Meningeal melanocytomas are rare however these tumors have a high recurrence rate with potential malignant transformation over time. NGS is a valuable tool for confirming the CNS origin of the tumor and predicting its aggressive behavior. Despite microscopic similarity with cutaneous melanomas, meningeal melanocytomas have different pathogenesis and do not seem to respond to immunotherapy, as observed in this case.

Prospective screening and proposed treatment algorithm for immune checkpoint inhibitor induced myositis in neoadjuvant-treated rectal cancer patients: data from the phase II CHINOREC trial

Abstract Background Myositis is an infrequent (<1%) but potentially life-threatening (case fatality rate 40-50%) immune-related adverse event (irAEs) of immune checkpoint inhibitors (ICI), such as ipilimumab (IPI) and nivolumab (NIVO). The true incidence is likely to be underestimated and may not be representative for curative neoadjuvant treatment approaches in gastrointestinal (GI) cancers, especially in combination with chemoradiotherapy (CRT). Currently, the summary of product characteristics (SmPC) does not suggest any pre-emptive screening or surveillance. Methods The CHINOREC study is an ongoing prospective, randomized, open-label, multicenter, phase II investigator-initiated trial (IIT). Patients with intermediate to locally advanced rectal cancer (LARC) receive either neoadjuvant CRT alone or in combination with a single dose of IPI and 3 cycles of NIVO, following surgical resection. Patients are monitored at baseline and throughout the whole study period for myotoxicity biomarkers, including cardiac troponin T (cTnT) and cardiac troponin I (cTnI). Findings From 06/2020 to 11/2023, 80 patients have been enrolled of whom 50 patients were randomized to the CRT+IPI/NIVO arm. Six patients (12%) developed biopsy-verified myositis. Myositis treatment was promptly implemented using a pragmatic step-up approach. Patients received glucocorticoids (GC) with concomitant intravenous immunoglobulin (IVIG). If myotoxicity biomarkers did not improve, patients received infliximab (INFLIXI) and/or plasma exchange (PLEX). Although all patients had strikingly elevated cTnT (median peak 284 ng/L, 95% CI 39-3097), cTnI levels remained largely normal, correlating with a negative cardiac magnetic resonance (CMR). All patients underwent successful tumor surgery without any major surgical complication. As of today, all patients' creatine kinase (CK) and myoglobin (MB) levels have normalized and they are tumor free without any major sequela. Interpretation Longitudinal biomarker screening (cTnT/cTnI) for ICI-induced myotoxicities is pivotal in curative neoadjuvant-treated cancer patients to initiate an early counter treatment in a holistic step-up approach, without compromising oncological principles.

Stereotactic Radiotherapy Plus Nivolumab in Patients with Locally Advanced Pancreatic Cancer: Results from Phase 1/2 Clinical CA209-9KH Trial.

The dismal prognosis of pancreatic ductal adenocarcinoma (PDAC) highlights the urgent need for novel therapeutic strategies. Immune checkpoint inhibitors (ICIs) seem to be ineffective in most PDAC studies. Therefore, we conducted an open-label, multicenter phase 1/2 study (CA209-9KH) to evaluate the safety of stereotactic radiotherapy (SRT) and sequential ICI therapy in PDAC, as well as to validate the efficacy of this regimen as a potential activator of antitumor immunity. Patients aged ≥ 18years with unresectable non-metastatic PDAC following four FOLFIRINOX induction cycles were included. Treatment comprised SRT (4 × 8Gy) and sequential nivolumab administration until disease progression or unacceptable toxicity. The primary endpoints were safety and toxicity assessment. Secondary endpoints included progression-free survival (PFS), overall survival (OS), biomarker evaluation, and quality of life (QoL) analysis. Twenty-two patients were screened, with 15 enrolled. Eleven (median) nivolumab cycles were administered. SRT demonstrated low and clinically nonsignificant toxicity, whereas nivolumab toxicity aligned with prior safety profiles, without grade 4-5 events observed. Three patients discontinued therapy owing to toxicity. Median PFS and OS were 8.1 and 13.0months, respectively, with 12-month PFS and OS rates of 0% and 66.7%, respectively, and a 24-month OS rate of 8.9%. Biomarker levels correlated with clinical or radiological disease control. Patient-reported QoL remained acceptable, deteriorating with disease progression. SRT and nivolumab therapy exhibited manageable toxicity profiles consistent with previous findings; however, long-term treatment responses were not achieved with this regimen in locally advanced PDAC. Another strategy to trigger antitumor immunity in PDAC needs to be sought. EudraCT: 2017-003404-52; ClinicalTrials.gov: NCT04098432.

Evaluating the Effectiveness of Nivolumab in Metastatic Lung Cancer Among Patients Aged 65 and Older.

Background: Lung cancer remains the leading cause of cancer-related mortality globally, predominantly affecting older individuals. Despite the increasing use of immune checkpoint inhibitors (ICIs) like nivolumab in non-small cell lung cancer (NSCLC), the efficacy and safety in elderly patients, particularly those aged 65 and above, remain underexplored due to their underrepresentation in clinical trials. Methods: This retrospective study analyzed data from 60 elderly patients (≥65 years) with metastatic NSCLC who received nivolumab as second-line or later therapy between January 2020 and May 2023. Results: The median age was 67 years, with a predominance of males (78%). Nivolumab was administered for a median of 8 cycles, with 33.3% of patients receiving 15 or more cycles. The median OS was 23 months, and the 1-, 3-, and 5-year survival rates were 93.3, 54.1, and 18.6%, respectively. Multivariate analysis identified adenocarcinoma histology, fewer than 15 cycles of nivolumab, and non-response to prior therapies as independent predictors of poor OS. Nivolumab treatment was generally well-tolerated, with 45% of patients experiencing at least grade 1 toxicity. Conclusions: Nivolumab is effective and well-tolerated in elderly patients with metastatic NSCLC, providing survival benefits comparable to those observed in younger populations. The number of treatment cycles and initial response to therapy are key determinants of survival, underscoring the importance of continued treatment in this age group.

Phase I/II study of BMS-986156 with ipilimumab or nivolumab with or without stereotactic ablative radiotherapy in patients with advanced solid malignancies

BackgroundBMS-986156 is an agonist of the glucocorticoid-induced tumor necrosis factor receptor (TNFR)-related protein (GITR) and promotes increased effector T-cell activation. Combined anti-GITR, anti-programmed death-1, anti-cytotoxic T-lymphocyte-associated protein 4 antibodies and...

Neoadjuvant nivolumab and relatlimab in locally advanced MMR-deficient colon cancer: a phase 2 trial.

Mismatch repair deficiency (dMMR) is found in approximately 15% of non-metastatic colon cancers (CCs) and is characterized by a defective DNA mismatch repair system, resulting in hypermutated and highly immunogenic tumors. Although patients with dMMR CC have limited benefit from chemotherapy, these tumors have been shown to respond exceptionally well to neoadjuvant anti-PD-1 plus anti-CTLA-4, with high rates of pathologic responses. Here, based on data from melanoma studies, we postulated a high efficacy and favorable toxicity profile of anti-PD-1 plus anti-LAG-3. In the NICHE-3 study, a total of 59 patients with locally advanced dMMR CC were treated with two 4-weekly cycles of nivolumab (480 mg) plus relatlimab (480 mg) before surgery. Pathologic response was observed in 57 of 59 (97%; 95% confidence interval (CI): 88-100%) patients, meeting the primary endpoint. Responses included 54 (92%; 95% CI: 81-97%) major pathologic responses (≤10% residual viable tumor) and 40 (68%; 95% CI: 54-79%) pathologic complete responses. With a median follow-up of 8 months (range, 2-19), one patient had recurrence of disease. The treatment displayed an acceptable safety profile, with all-grade and grade 3-4 immune-related adverse events (irAEs) occurring in 80% and 10% of patients, respectively. The most common irAEs were infusion-related reactions (29%), thyroid dysfunction (22%) and fatigue (20%). In conclusion, our results show that neoadjuvant nivolumab/relatlimab induces high rates of pathologic responses and that further investigation of this treatment in larger studies is warranted. These data add to the body of evidence in support of neoadjuvant immunotherapy regimens in dMMR CC. ClinicalTrials.gov identifier: NCT03026140 .

Diaphragmatic Myopathy Associated with Dual Immune Checkpoint Inhibitors in a Patient with Renal Cell Carcinoma

ABSTRACT Immune-related adverse events (irAEs) have become increasingly prevalent with immune checkpoint inhibitor (ICI) cancer treatment. We present a 79-year-old man with metastatic renal cell carcinoma who developed shortness of breath and hypercapnic respiratory insufficiency after his first cycle of nivolumab and ipilimumab. Laboratory data showed elevated creatinine kinase, troponins, and transaminases. Computed tomography of the chest demonstrated bilateral lower lobe atelectasis. Heart catheterization and endomyocardial biopsy were unremarkable. Electromyogram (EMG) and nerve conduction studies (NCS) of the limb muscles revealed mild diffuse myopathy, normal sensory nerve conductions, and low-amplitude motor responses. Subsequent diaphragmatic EMG and NCS demonstrated severe myopathy. ICI-mediated myopathy predominantly affecting diaphragmatic muscles was diagnosed. Treatment included intravenous methylprednisolone, infliximab, abatacept, rituximab, and plasmapheresis. He underwent tracheostomy placement on hospital day 11 due to minimal improvement. He was discharged to a long-term acute care hospital, but unfortunately, he died less than 1 month later due to recurrent infections. irAEs can affect any organ system, but diaphragmatic dysfunction is uncommon. Use of diaphragmatic EMG, NCS, ultrasound study, or biopsy can support the diagnosis. Treatment includes systemic steroids, plasmapheresis, immunosuppressive medications, respiratory support, and cessation of causative medications. ICI-related diaphragmatic dysfunction should be suspected in those patients at risk with hypoxia, hypercapnia, or prolonged invasive or noninvasive ventilation without a distinct etiology. This case report exemplifies the importance of multidisciplinary workup and management of respiratory symptoms and insufficiency to identify and ameliorate irAEs. Diaphragmatic involvement can be associated with significant morbidity and mortality despite early aggressive multimodal therapy.

Epithelioid pleural mesothelioma successfully treated with perioperative immunotherapy: a case report

BackgroundPleural mesothelioma, characterized by a dismal prognosis even with multimodal therapy, has seen emerging interest in immune checkpoint inhibitors (ICIs) due to their demonstrated efficacy. Here, we present a case of epithelioid-type pleural mesothelioma with chest wall invasion treated with definitive ICI therapy, resulting in a remarkable pretreatment effect.Case presentationA 46-year-old man was diagnosed with an abnormal chest shadow on a medical check, and a computed tomography scan showed pleural thickening at the dorsal right upper chest wall. One of the nodules was suspected to have invaded the chest wall. A needle biopsy revealed epithelioid-type pleural mesothelioma. After five cycles of nivolumab plus ipilimumab, he underwent right pleurectomy/decortication (P/D). Pathological examination revealed a significant treatment effect, showing numerous lymphocytes infiltrating the tumor nodule and viable tumor cells localized at approximately 6 mm.ConclusionAlthough further accumulation of cases is required to evaluate the effectiveness and case selection, P/D after immunotherapy is a useful curative treatment option for advanced pleural mesothelioma.

Preoperative nivolumab plus SOX in patients with locally advanced gastric or gastro-esophageal junction cancer: A phase 2, single-arm trial.

4074 Background: Preoperative chemotherapy has been widely recommended in patients with locally advanced gastric or gastro-esophageal junction cancer (GC/GEJC), and the addition of programmed cell death 1 (PD-1) inhibitor is under investigation. We conducted a single-arm phase II trial (Stimulate-01) to evaluate the efficacy and safe of the anti-PD-1 antibody nivolumab plus SOX regimen in patients with locally advanced GC/GEJC and to explore the biomarker associated with therapy response. Methods: Patients with locally advanced GC/GEJC (cT3-4N+M0) were enrolled and received either 3 preoperative and 3 postoperative cycles of nivolumab (360 mg, IV, d1, Q21d) plus SOX regimen (oxaliplatin 130 mg/m2, IV, d1 with oral S-1 40-60mg, bid, d1-d14, Q21d) therapy, followed by 11 cycles of nivolumab monotherapy. The primary endpoint was the pathological complete response (pCR) rate, while the major pathological response rate (mPR), 3-year-DFS and 3-year-OS as the second endpoint. This clinical trial was registered at Clinicaltrial.gov (NCT05739045). In addition, tissue sample before and after treatment from patients were performed scRNA-seq. Results: Forty-six patients were enrolled from November 2022 to March 2023, with a median age of 66 years (range, 34-74), and 38 were male. The pCR rate was 28.26% [95% confidence interval (CI), 15.2%-41.3%], and the major pathologic response (mPR) [tumor regression grade (TRG)0/1] rate was 41.3% (95% CI, 27.1%-55.5%). All the patients underwent R0 resection. The mPR rate in patients with PD-L1 CPS ≥5 and patients with PD-L1 CPS<5 was 42.86% vs 38.89% ( P= 0.790). In addition, This clinical study period spans from epidemic control to full liberalization in China. The mPR rate in patients infected with COVID-19 was 44.44% (12/27), while the mPR rate in patients who have not been infected with COVID-19 was 36.84% (7/19) ( P=0.146). There were no severe complications or death related to the surgery. The scRNA-seq data revealed that the composition of MHC-II (HLA-DRA, HLA-DPA1, HLA-DRB1, HLA-DPB1 and HLA-DQB1) were significantly over-expressed in cancer cell of treatment-sensitive patients (TRG0/1) compared to that of treatment-insensitive patients (TRG2/3). Then the MHC-II expression in pre-treatment biopsy samples from 240 GC patients who received preoperative immunotherapy plus chemotherapy were performed by immunohistochemistry. The results showed that the mPR rate in patients with MHC-II IHC ≥2 and patients with MHC-II IHC<2 was 58.87% (83/141) vs 21.21% (21/99) ( P<0.001). Conclusions: Nivolumab plus SOX as neoadjuvant therapy showed an encouraging pCR rate, mPR rate, and manageable safety. The long-term efficacy of this combination of regimens will be continued to follow up. In addition, the MHC-II expression may be a potential biomarker for predicting the effectiveness of immunotherapy combined with chemotherapy for GC/GEJC. Clinical trial information: NCT05739045 .

BIOLUMA: A phase II trial of nivolumab and ipilimumab in lung cancer—Results from the SCLC TMBhigh cohort.

8099 Background: Therapeutic options and prognosis for patients with small-cell lung cancer (SCLC) remain poor. Treatment with checkpoint inhibition can achieve remarkable responses, but this holds true for a small percentage of SCLC patients only. While tumor mutation burden (TMB) emerged as possible predictive biomarker for nivolumab and ipilimumab combination therapy in SCLC patients, to our knowledge, tissue-based TMB has never been evaluated prospectively in SCLC patients. Here, we present the results of the cohort 2b of the BIOLUMA trial, which evaluates efficacy and safety of nivolumab in combination with ipilimumab in SCLC patients with high tumor mutation burden. Methods: BIOLUMA is an investigator initiated multicentre non-randomised phase II trial in 2nd line patients with SCLC. The initial all-comer SCLC cohort was amended for inclusion of patients with high TMB only. FFPE tumor tissue was used for TMB pre-screening by whole exome sequencing (WES) at time of first diagnosis. TMBhigh was defined as the upper tertile of total missense mutations. After progression on platinum-based therapy, patients received 4 cycles of nivolumab 1 mg/kg q3w in combination with ipilimumab 3 mg/kg q3w and subsequently nivolumab 240 mg flat dose as monotherapy. Primary endpoint was overall response rate (ORR) of the combination therapy. Additionally, exploratory analyses of sequential tumor biopsies and blood samples were performed at different time points. Results: TMB analysis was feasible for most patients without necessity of performing additional tumor biopsy. Evaluation of TMB on FFPE tumor tissue obtained at first diagnosis was sufficient for TMB analysis in 92.5% of cases. TMB status was determined for 297 patients: 45.8% belonged to the TMB high group, while 54.2% had low or medium TMB. In total, 45 TMBhigh patients were enrolled in the study with 44 subjects evaluable for primary endpoint analysis. Six patients (13.6%) showed response to therapy, of whom in 4 patients (9%) response could be confirmed according to RECIST 1.1 criteria. One patient, who is not evaluable for endpoint analysis experienced a remarkably long lasting PR, which is still ongoing for more than three years. This patient received concomitant palliative radiation during induction with nivolumab and ipilimumab. Disease control rate (DCR) was 20.4% (n=9), three more patients showed unconfirmed SD. Three patients with confirmed PR or SD experienced long lasting treatment benefit, which is still ongoing at data cut-off. Conclusions: This represents the first trial to prospectively evaluate the combination therapy of nivolumab and ipilimumab in TMBhigh SCLC patients. The primary endpoint ORR was not reached. However, we observed an impressive clinical benefit in single patients, which warrants further investigation in order to get more insight into the mechanisms leading to these long-lasting tumor responses. Clinical trial information: NCT03083691 .

A phase II trial of neoadjuvant nivolumab, docetaxel, and cisplatin followed by surgery and radiation therapy for resectable high-grade salivary gland carcinoma.

e18061 Background: High-grade resectable salivary gland carcinomas, typically treated with surgery and adjuvant therapies, often recur. This study explores combining an immune checkpoint inhibitor (ICI) with chemotherapy as neoadjuvant therapy to improve outcomes in high-risk, operable cases. Methods: This trial enrolled high-grade SGC patients with clinically positive lymph nodes. Participants received three cycles of nivolumab in conjunction with docetaxel and cisplatin every three weeks. The primary response was assessed three weeks post-treatment, and surgery followed at seven weeks in cases deemed operable. The pathologic outcomes determined the need for adjuvant radiotherapy, administered at 59.4Gy (R0) or 66.0Gy (R1 or R2). The study's primary endpoint was the major pathologic response rate (MPR). We aimed to recruit 50 patients. Herein, we present an interim analysis (NCT05727410). Results: Since November 2022, 19 patients have enrolled; predominantly male (89.5%) with a median age of 62 (range 42-75). Histologic analysis identified various subtypes, primarily salivary duct carcinoma (68.4%). Other histologies included high-grade adenocarcinoma (10.5%), mucoepidermoid carcinoma (10.5%), basaloid squamous cell carcinoma (5.3%), and secretary carcinoma (5.3%). At the time point of analysis, surgery was performed on 16 patients, and 3 patients are still under neoadjuvant therapy. Complete resection (R0) was achieved in 87.5% (n=14) of the cases, with one patient having R1 and another R2 resection. Pathologic analysis showed 12.5% (n=2) achieving pathological complete response and 18.8% (n=3) achieving MPR. Tumor viability varied, with 37.5% (n=6) presenting with 10% to 50% viability and 31.3% (n=5) presenting with 50% or higher viability. A patient with salivary duct carcinoma histology with tumor viability of 20% after neoadjuvant treatment experienced recurrence after 4.1 months from surgery. Notably, throughout the neoadjuvant treatment phase, no patients discontinued due to toxicity or intolerance, indicating a favorable tolerance profile for the combination therapy. An ongoing exploratory biomarker study includes PD-L1 expression and genomic profiling. Conclusions: The preliminary findings of this study demonstrate that the neoadjuvant combination of immune checkpoint inhibitor with chemotherapy significantly reduces tumor burden in salivary gland carcinoma, as evidenced by the high rate of complete resections (R0) and favorable pathologic responses. This treatment strategy not only facilitates surgical outcomes but also exhibits an acceptable safety profile, with no instances of treatment discontinuation due to toxicity or intolerance. These promising results underscore the potential of ICI combination therapy in the management of SGC and warrant further detailed investigations. Clinical trial information: NCT05727410 .

Checkpoint inhibitor immunotherapy induced inflammatory arthritis secondary to Nivolumab and Ipilimumab: a pediatric first

BackgroundImmune checkpoint inhibitors (ICIs) have expanded the arsenal of cancer therapeutics over the last decade but are associated with a spectrum of immune-related adverse events (irAEs), including inflammatory arthritis. While these complications are increasingly recognized in the adult population, no cases of inflammatory arthritis irAEs have been reported in the pediatric literature.Case PresentationA 14-year-old female with metastatic epithelioid mesothelioma was referred to the pediatric rheumatology clinic after developing progressive inflammatory joint pain in her bilateral shoulders, hips, and small joints of hands following the second cycle of Nivolumab and Ipilimumab. Initial examinations showed bilateral shoulder joint line tenderness, positive FABERs test bilaterally, tenderness over bilateral greater trochanters, and bilateral second PIP effusions. Her serological profile was notable for positive HLA-B27, positive anti-CCP, negative Rheumatoid Factor, and negative ANA. PET-CT scan performed for disease response following immunotherapy showed symmetric increased metabolic activity primarily involving the supraspinatus, gluteus medius and minimus, and semimembranosus tendon insertions. Her presentation was consistent with a grade 1 irAE that worsened to a grade 2 irAE despite NSAID therapy, prompting a short course of oral prednisolone. She achieved clinical remission of her mesothelioma following six cycles of Nivolumab and Ipilimumab and her inflammatory arthritis was controlled on Celebrex monotherapy.ConclusionsTo our knowledge, this is the first pediatric case of ICI-induced inflammatory arthritis and enthesitis. This case highlights the importance of increasing awareness of diagnosis and management of irAEs in children.

Enrichment of circulating helper-T (Th) and unswitched memory-B (NSwM-B) cell populations and responsiveness to immune checkpoint blockade (ICB) in microsatellite-stable (MSS)/mismatch repair-proficient (pMMR) colorectal cancer (CRC).

150 Background: The anti-tumor activity of ICB in MSS/pMMR-CRC is limited. However, recent studies have highlighted the possibility of inducing ICB responsiveness by oxaliplatin-based chemotherapy. The understanding of underlying mechanisms and identification of rational biomarkers are major focus areas in immuno-oncology. Methods: Patients with previously untreated, unresectable abdominal metastases from MSS/pMMR-CRC were randomly assigned to the oxaliplatin-based standard Nordic FLOX regimen (control arm) or 2 FLOX cycles followed by 2 ICB (nivolumab) cycles in a repeat sequential schedule (experimental arm). Radiologic response assessment was done every 8 weeks, and the study arms reached identical primary endpoint – median progression-free survival (PFS) 9.3 months. Experimental-arm patients at one study center had peripheral blood mononuclear cells (PBMC) prepared at study entry (V1), after the initial 2 FLOX cycles (V3), and after the succeeding 2 nivolumab cycles (V5). The PBMC were incubated with 19 cell-surface antibodies and analyzed by mass cytometry. Patients were categorized in PFS >9.3 months (improved; n = 7) or PFS <9.3 months (shortened; n = 6). Live cell clusters were identified by hierarchically applying automated 1D gates to the available lineage markers. After gating, all cells were assigned to soft clusters according to phenotypes. The cluster sizes were used to compute the differential abundance of immune-cell populations and a Peacock test assessed multivariate changes between the improved and shortened PFS groups. Results: Circulating CD4+ (Th) cells and CD27+IgD+ (NSwM-B) cells were concurrently enriched in the improved PFS group. After the initial 2 FLOX cycles (V3), median increase (from V1) was 2.89% (of lymphocyte count) for Th cells and 0.54% (of leukocyte count) for NSwM-B cells (p < 0.001). Continued responses occurred over the succeeding 2 nivolumab cycles (until V5) with median increase of 1.19% for Th cells and 0.19% for NSwM-B cells (p < 0.001). The association between the immune-cell alterations and PFS was validated by categorizing the cases in above or below the median increase in Th and NSwM-B cell populations from V1 to V5. The high-increase group achieved median PFS 15.0 months (95% CI, 10.8-19.2) compared to 4.0 months (95% CI, 1.9-22.1) for the low-increase group (log-rank; p = 0.002). Conclusions: This unsupervised analysis of high-dimensional PBMC data from a limited case number revealed that circulating Th and NSwM-B cell populations may mediate ICB responsiveness invoked by short-course oxaliplatin-based chemotherapy in patients with abdominal metastases from MSS/pMMR-CRC. Owing to weaknesses of such a post-hoc analysis, further studies are needed to confirm the generalizability of these findings. Clinical trial information: NCT003388190 .

Short course immunotherapy as curative-intent treatment in stage I-III dMMR rectal cancer.

121 Background: Neoadjuvant chemo-radiation followed by resection is standard treatment for patients with locally advanced rectal cancer (RC). A subset of RC are mismatch repair deficient (dMMR). Check-point inhibitors (CPI) are the standard of care in dMMR colorectal cancer (CRC) in the metastatic setting, and recent trials have demonstrated impressive efficacy in early CRC, even with a limited number of cycles. In the NICHE-II trial (Chalabi et al, ESMO 2022) 72 of 107 patients (67%) with colon cancer obtained pathological complete response (pCR) after short course CPI. In patients with RC, Cercek et al (NEJM 2022) showed that 12 patients (100%) obtained pCR after 6 months of dostarlimab. The efficacy of CPI in dMMR RC has only been evaluated in few studies. Here we report data from a Danish trial with early dMMR RC. EU CT number 2022-500646-14-00. Methods: The purpose was to evaluate the efficacy and tolerability of 1 cycle of nivolumab (3 mg/kg days 1 and 15 - nivo) and ipilimumab (1 mg/kg day 1 - ipi) in patients with early stage dMMR RC. The primary endpoint was number of patients with clinical complete response (cCR - no visible or palpable tumor) evaluated 4 weeks after nivo-ipi. Patients achieving a clinical, radiological, pathological (representative biopsy without viable tumor cells), and molecular complete response was offered a thorough watchful waiting strategy without surgery. Results: 5 patients were treated, 4 patients received a single cycle of nivo-ipi and 1 patient received 2 cycles of nivo-ipi, as the tumor was still visible at the first endoscopy (Table). All 5 patients were evaluated 4 weeks after completing nivo-ipi and all 5 patients (100%) achieved cCR. All 5 patients were ctDNA positive (Jensen et al, Clin Chem 2020) at diagnosis, 4 patients turned negative after therapy (1 pending). No patient needed radiotherapy and all patients agreed to non-surgical watchful waiting. No patient has had progression or recurrence (1-42 months follow-up). Conclusions: Short-course nivo-ipi is very effective in locally advanced dMMR rectal cancer and may become an alternative to resection. Clinical trial information: 2022-500646-14-00 . [Table: see text]

Neoadjuvant anti-programmed death 1 (PD-1) therapy in patients (pts) with resectable mismatch repair–deficient (dMMR) locally advanced rectal cancer (LARC): EPOC2201.

TPS226 Background: Neoadjuvant radiotherapy and chemotherapy followed by surgical resection is a standard treatment for LARC. As anti-PD-1 therapy for patients with dMMR colorectal cancer is responsive in the context of metastatic disease, several clinical trials which evaluate the efficacies of anti-PD-1 therapy in patients with dMMR LARC are on-going and suggested the outstanding responses (Cercek A. et al., N Engl J Med 2022). Methods: We initiated the EPOC 2201 VOLTAGE-2 study, which is an ongoing, non-randomized, single-arm phase II trial. The major eligibility criteria were as follows: treatment-naïve with rectal cancer located 12 cm from the anal verge; confirmed dMMR; clinical stage II/III in primary cohort (N=35) and stage I in exploratory cohort (N=20); age ≥ 18; Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1; and presence of sufficient organ function. The study treatments include 12 cycles of nivolumab (NIVO) monotherapy (240 mg every 2 weeks) followed by assessment using Memorial Sloan Kettering (MSKCC) Regression Schema (Smith J.J. et al., BMC Cancer 2015). If clinical complete response (cCR) or near complete response (nCR) are observed, non-operative management with additional 12 cycles of NIVO will be performed. If incomplete response (IR) is observed, standard chemoradiotherapy with 50.4Gy of radiation plus capecitabine followed by surgery will be performed. The primary endpoint is the 2-year cCR rate in primary cohort. Various survival endpoints including progression-free survival (PFS) and overall survival (OS) are assessed as secondary endpoints. Safety analyses are performed using the Common Terminology Criteria for Adverse Events (CTCAE) ver. 5.0, and the Clavien‒Dindo classification (ver. 2.0) is added for postoperative complications. Assuming null and alternative hypotheses, cCR rates of 23% and 45%, the planned sample size for primary cohort was set at 35, with a one-sided alpha of 5% and power of 80%. An exploratory biomarker study was also conducted using serially collected tumor and blood samples. Whole genome-based minimal residual disease (MRD) assay and whole exome/whole transcriptome-based tumor and immune microenvironment analyses are performed. As of August 2023, patient’s enrollment is ongoing. Clinical trial information: jRCT2031220484 .

A phase II trial of CapeOX plus nivolumab for early relapsed HER2-negative gastric cancer (JACCRO GC-11: FirSTAR trial).

TPS423 Background: Fluoropyrimidine-based post-operative chemotherapy is one of the standard adjuvant therapies for curatively resected gastric cancer (GC).1,2 The current standard first-line chemotherapy consists of fluoropyrimidine and oxaliplatin combined with nivolumab in advanced HER2-negative GC patients including cases with a recurrence > 6 months after completion of post-operative chemotherapy, based on the CheckMate 649 and ATTRACTION-4 trials. However, in GC patients with early recurrence during or ≤ 6 months after completion of post-operative 5-FU based chemotherapy, optimal treatments remain to be established. A previous phase II study showed that capecitabine plus cisplatin is an active regimen for early relapsed GC after post-operative S-1 monotherapy.3 This trial aims to investigate the efficacy of capecitabine plus oxaliplatin (CapeOX) plus nivolumab for patients with early relapsed HER2-negative GC. Methods: This is a multicenter single-arm phase II trial. The main eligibility criteria include: histologically confirmed HER2-negative adenocarcinoma of stomach or esophagogastric junction; radiologically diagnosed recurrence during or ≤ 6 months after post-operative chemotherapy with S-1 or S-1 plus docetaxel conducted for stage II/III GC after curative resection; age ≥ 18 years; ECOG performance status 0-1; having measurable lesions according to RECIST ver. 1.1; and adequate oral intake and organ functions. Enrolled patients will receive 21-day cycles of nivolumab with CapeOX at the following dose until disease progression or unacceptable toxicities: capecitabine, 1000 mg/m2 twice per day on day 1-14; oxaliplatin, 130 mg/m2 on day 1; and nivolumab, 360 mg on day 1. The primary endpoint is objective response rate (ORR), and the secondary endpoints include overall survival, progression-free survival, disease control rate, duration of response, and safety. PD-L1 combined positive score will be tested for the association with efficacy. We assume null ORR of 20% and alternative ORR of 32%. With two-sided alpha level of 10% and 80% power, sample size would be calculated as 85. Thus, a total of 92 patients are planned for enrollment within a 2.5-year accrual period. Enrollment opened in March 2023. Clinical trial information: jRCTs031220572. 1. N Engl J Med. 2007;357:1810-20. 2. J Clin Oncol. 2019;37:1296-1304. 3. Gastric Cancer. 2018;21:811-8. Clinical trial information: jRCTs031220572 .

R-GemOx Plus Nivolumab Vs R-GemOx As Second-Line Therapy for Large B-Cell Lymphoma in Transplant-Ineligible Patients: Interim Analysis of the Niveau Trial, an International, Randomized Phase 3 Study of the AGMT, GLA, HOVON, Lysa and PLRG

Introduction: Patients (pts) with relapsed or refractory ( R/ R) large B-cell lymphoma (LBCL) after first-line treatment who are unable to undergo consolidative high-dose chemotherapy (HDCT) and hematopoietic stem cell transplantation (HSCT) have poor outcomes and limited treatment options. Rituximab, gemcitabine and oxaliplatin (R-GemOx) is a common immuno-chemotherapy regimen used in this setting. The objective of the open-label, phase 3, NIVEAU study (NCT03366272) was to evaluate the efficacy and safety of Nivolumab added to R-GemOx in pts with R/ R LBCL after 1 prior line of therapy not eligible for HDCT/HSCT owing to age and/or comorbidities. Patients and Methods: Eligible pts were adults with R/R LBCL that were refractory to or had relapsed after first-line immuno-chemotherapy and who were not deemed candidates for HDCT/HSCT based on physician's assessment and at least one of the following criteria: age ≥65 years; age ≥18 years and Hematopoietic Cell Transplantation-specific Comorbidity Index (HCT-CI) score ≥3; or age ≥18 years and prior ASCT (as 1st line consolidation). Therapy consisted of 8 cycles R-GemOx (arm A) or 8 cycles of nivolumab plus R-GemOx followed by nivolumab as maintenance for up to 1 year in total or until progression or unacceptable toxicity (arm B). The primary endpoint was progression-free survival (PFS) after 1 year. Major secondary endpoints were response rates, event-free- (EFS) (time to progression, relapse, death or unplanned anti-lymphoma treatment), overall survival (OS) and toxicity. The protocol specified a pre-planned interim analysis after the first 180 pts completed up to at least 1 follow-up investigation. Results: Between Jan 2018 and May 2021, 180 pts were randomized. Two pts did not receive any treatment (one withdrawn informed consent, one death) resulting in a full analysis set of n=90 (arm A) and n=88 (arm B). Median age was 76 years (range 44-87), 52% of pts were >75 years of age, 37% were primary progressive after first-line therapy, 62% had IPI 3-5. Overall response (OR) and complete response (CR) rates were similar with 34% and 20% (arm A) vs. 34% and 22% (arm B), respectively. Rates of progressive disease (PD) were 53% (arm A) vs. 50% (arm B). After a median follow-up of 21 months, 1-year PFS was 28% (95%-CI: 18%-37%) in arm A vs. 20% (95%-CI: 11%-28%), (p=0.827) in arm B (Figure A). 1-year EFS was 22% (95%-CI: 13%-31%) in arm A vs. 20% (95%-CI: 11%-28%), (p=0.654) in arm B. One-year OS was 48% (95%-CI: 38%-59%) in arm A vs. 58% (95%-CI: 47%-68%), (p=0.126) in arm B. At 2 years, PFS, EFS and OS were 15% (95%-CI: 6%-24%), 13% (95%.CI: 5%-21%) and 34% (95%-CI: 22%-46%) in arm A vs. 15% (95%-CI: 7%-23%), 15% (95%-CI: 7%-23%) an 43% (95%-CI: 32%-55%) in arm B. Because of an identical PFS but a trend toward better OS for arm B, we performed an event-driven OS analysis of pts after second progression or relapse (n=70 in arm A, n= 73 in arm B). OS survival was superior in arm B vs. arm A after second progression or relapse (Log Rank p= 0.010) (Figure B). There was a small increase in number of pts with grade 3-5 AEs in arm B (arm A/arm B: thrombocytopenia 37%/39%; anemia 19%/26%; leukopenia 19%/24%; infection 15%/22%). No increase in number of pts with immune-related grade 3-5 AEs was observed except asymptomatic increase of lipase (arm A/arm B: 23%/27%), (p=0.625) and amylase (arm A/arm B: 5%/11%), (p=0.192). Most common grade 3-5 AEs during nivolumab consolidation in arm B were leukopenia 13%, peripheral neuropathy 10%, increase of lipase 8%, anemia 5% and infection 5% of pts). In total, 7 treatment-related deaths occurred (arm A/arm B: 3 (3%)/4 (5%). After this interim analysis revealed futility to demonstrate superiority for the primary endpoint, recruitment was stopped in March 2023. At that point, 270 of 310 initially intended pts had been recruited. Conclusions: In pts with R/R LBCL, the addition of nivolumab to R-GemOx followed by nivolumab maintenance is feasible without relevant additive toxicity. The addition of Nivolumab did not improve PFS of the R-GemOx regimen alone. These results demonstrate the poor prognosis of R/R transplant-ineligible pts treated with immuno-chemotherapy. However, a trend towards a better OS was observed, which allows for the hypothesis that nivolumab might enhance the efficacy of subsequent therapies. The final analysis of the study is scheduled after completion of follow-up of the last patient included as defined by the study protocol.

Efficacy of Low-Dose Nivolumab in Multiple Cancer Types

Introduction: Cancer is the uncontrolled growth and development of cells in the body, and is one of the foremost reasons of deaths throughout the world. Immunotherapy is a broad category of cancer therapies that triggers the body's immune system to fight cancer cells. Nivolumab, a monoclonal antibody, is used an immunotherapy drug that binds to the Programmed Cell Death protein (PD-1) to help immune cells kill cancer cells better and is used to treat many different types of cancer. This study is about two cancer patients, one being a case of Squamous Cell Carcinoma of the Right Lung, another being a case of metastatic Stage IV Renal Cell Carcinoma. They were treated with low-dose Nivolumab and resulted in remission of the malignancy without any significant complications. Case Presentation: The current study was conducted with 2 Bangladeshi male patients. The first patient, case of Carcinoma Lung, 55 years old, and the second patient, Renal Cell Carcinoma, 57 years old. They were treated with 6 cycles of Nivolumab at 40 mg dose for immunotherapy regimen. Both of them are clinically stable and no complications have been detected. Conclusion: Treatment with Nivolumab in such fatal cancers has demonstrated remarkable clinical response with significant remission of the disease. In addition, adverse effects are minimal compared to previous drug regimens.

FRI331 Autoimmune Hypophysitis Secondary To Ipilimumab And Nivolumab Combination Therapy In A Patient With Advanced Renal Cell Carcinoma

Abstract Disclosure: E.Y. Ibrahim: None. I. Hulinsky: None. D. Regelmann: None. Introduction: Ipilimumab and nivolumab combination therapy is an effective immune checkpoint inhibitor regimen indicated for advanced stages of renal cell carcinoma. Autoimmune hypophysitis is a rare adverse event from this therapy that occurs in only 3-6% of patients. The mechanism underlying immune checkpoint inhibitor-induced hypophysitis is not fully understood but involves immune, inflammatory, and genetic factors. Clinical Case: A 65-year-old male with a history of hypertension and type 2 diabetes mellitus, recently diagnosed with renal cell carcinoma with metastasis to the lungs presents to the emergency department with three days of generalized weakness and worsening confusion, accompanied by 2 weeks of headache. Two months prior to presentation, the patient began chemotherapy with four cycles of nivolumab and ipilimumab. The emergency department team initiated a stroke code for right facial droop and right-sided weakness seen on his physical exam. The CT of the patient’s head was unremarkable. The patient was also hypotensive (BP 90/40 mmHg) and tachycardic (140 bpm). He received 3 liters of crystalloid as well as diltiazem injection without improvement. Random cortisol on admission at 11:00 am was 1 ug/dl (3.4-22), ACTH was 7 pg/mL (6-50), Na was 135 mEq/L (137 - 145) and K was 5.1 mEq/L (3.5 - 5.0). Furthermore, TSH 0.02 μIU/ml (0.47-4.70), ILGF 39 ng/mL (41-279), and total testosterone levels <3 ng/dL (139-740) were low. The free thyroxine level was measured at 1.00 ng/dL (0.8-1.9), and MRI revealed a normal sella tursica. Based on these findings, we diagnosed the patient with hypopituitarism, likely due to hypophysitis as an immune-related adverse event of immune checkpoint inhibitor therapy. Consequently, we discontinued the administration of Ipilimumab-Nivolumab combination therapy and started oral dexamethasone 8 mg and fludrocortisone 0.1 mg for mineralocorticoid supplementation. The patient’s symptoms resolved, and laboratory data showed improvements in hyponatremia, hyperkalemia, and hypoglycemia. The care team transitioned the patient’s steroid regimen to prednisone 25 mg daily maintenance dose, and the patient was discharged with stress dosing instructions. Conclusion: Diagnosis of hypophysitis as an immune-related adverse event is challenging due to its vague presentation. However, a delayed diagnosis can be life-threatening. As a result, clinicians must maintain a high index of suspicion for presentations of weakness and headache in consistent clinical contexts, in order to provide optimal management and minimize morbidity. Additionally, early management of hypophysitis can reduce the interval of immune checkpoint inhibitor therapy, which in turn affects the course of cancer. Presentation: Friday, June 16, 2023

Unique T-cell Sub-Population Shifts after SBPT and Nivolumab in Platinum Refractory HNC: Biomarker Correlates from ROR1771

ROR1771 was a clinical trial investigating the use of stereotactic body proton radiotherapy (SBPT) and nivolumab in recurrent platinum refractory head and neck squamous cell carcinoma (HNSCC). The planned analysis of T-cell subpopulation and biomarker response is herein presented. Patients with metastatic histologically confirmed HNSCC from any primary site received 2 cycles of nivolumab followed by SBPT to 1-2 selected target lesion(s) (hilar/lung: 8 of 12 patients), followed by maintenance nivolumab. Peripheral blood mononuclear cells were isolated pre-/post-treatment. Flow cytometry identified T-cell subpopulations. Single Cell 5' Gene Expression (GEX) and V(D)J T Cell Receptor libraries were prepared using Single Cell Immune Profiling. Seurat (v4.1.1) was used to identify cell type clusters, and differential expression post-filtration was evaluated using the Wilcoxon Rank Sum test. A total of 12 patients were eligible for analysis, with one alive at time of analysis, 52 months from start of treatment. Median overall survival here was 12.5 months vs. 7.5-months on CheckMate 141. SBPT ranged from 35-50 Gy. Sequential changes in T-cell populations from baseline were noted with initiation of nivolumab, driving decrease in tumor-reactive (TTR; CD11ahighPD1+CD8+), central memory (TCM; CCR7+CD45RA-), and effector T-cells (TEF; CCR7-CD45RA-). TTR and TCM increased following SBPT, with greatest increase (3.5x TTR and 5.2x TCM) in the surviving patient. An average of 68 genes with significant differential expression between timepoints (p<0.0001) demonstrated RNA gene expression changes across all cell subtypes, including ribosomal (RPL and RPS) genes, ACTB, FTL, MALAT1, and others. This averaged 113 genes across all timepoints in the surviving patient, with peak following nivolumab induction. On T-cell receptor (TCR) analysis of this patient, the predominant clonotype diversity changed substantially following nivolumab. Following SBPT, clonotype diversity again changed to include a milieu seen neither at baseline nor with nivolumab alone. These TCRs persisted for approximately 2 weeks following SBPT before returning to resemble the nivolumab-induced TCR diversity alone, coinciding with disease recurrence. ROR1771 demonstrated overall survival favorably comparable to CheckMate 141. Biomarker analysis of peripheral blood samples demonstrated significant shifts in T-cell subpopulations and underlying gene expression to nivolumab and then to SBPT administration. SBPT to a target lesion changed TCR clonotypes within the peripheral blood beyond those seen with nivolumab administration, with fading of these TCR clonotypes coinciding with recurrence. SBPT in combination with nivolumab may drive systemic immunologic change above that induced by nivolumab alone and warrants further investigation.