Concurrent Nivolumab Research Articles

Feasibility Study of Nivolumab in Combination with Carboplatin Plus Paclitaxel and Concurrent Thoracic Radiation in Patients with Untreated Unresectable Locally Advanced Non-Small Cell Lung Cancer.

Despite advancements in diagnosing and treating non-small cell lung cancer (NSCLC), the prognosis remains poor. Immune checkpoint inhibitors have shown promise in enhancing survival rates. Therefore, this study aimed to investigate the safety of nivolumab administration with concurrent chemoradiation therapy (CCRT) in patients with unresectable locally advanced NSCLC. Twelve patients with unresectable locally advanced NSCLC at Kansai Medical University Hospital and Izumi City General Medical Center were enrolled from May 2018 to September 2020. They received nivolumab (360 mg) tri-weekly twice, weekly carboplatin (AUC 2 min × mg/mL) and paclitaxel (40 mg/m2) for 6 weeks, and thoracic radiotherapy (60 Gy/30 fractions), followed by maintenance nivolumab therapy (360 mg, tri-weekly) for 6 months. The primary endpoint was incidence of dose-limiting toxicities (DLTs), and the secondary endpoints included safety, response rate, progression-free survival (PFS), overall survival (OS), 2-year survival rate, and treatment completion rate. Three patients completed the protocol. Nine discontinued due directly to interstitial pneumonia (three) and pneumonia (one). Ten patients (83.3%) experienced a grade 3 or higher event, of which three (25%) experienced a grade 4 or higher event, and of these, one (8.3%) experienced a grade 5 event. Three patients experienced DLTs. Concurrent nivolumab with CCRT was tolerated in unresectable locally advanced NSCLC, which offers potential treatment benefits.

Esophageal chemoradiotherapy with concurrent nivolumab: Pilot results in the palliative treatment of oligometastatic disease.

Many patients diagnosed with esophageal cancer have dysphagia from their primary tumor and de novo metastatic disease. The purpose of this study was to test the safety and efficacy of nivolumab given concurrently with hypofractionated chemoradiotherapy to patients with oligometastatic and obstructing esophageal tumors. Patients were enrolled in a planned single-arm, phase 2 clinical trial. Eligible participants had previously untreated oligometastatic (≤5 metastases on fludeoxyglucose-18 positron emission tomography scan outside the primary tumor radiotherapy field) esophageal or gastroesophageal carcinoma, dysphagia, and Eastern Cooperative Oncology Group performance status 0-1. Treatment was with 2weeks of concurrent hypofractionated radiotherapy (30Gy/10#) to the primary tumor, weekly carboplatin AUC2, weekly paclitaxel 50mg/m2, and q2weekly nivolumab 240mg, followed by nivolumab 480mg continuing q4weekly until disease progression or 24 months total. A single metastasis was treated with stereotactic radiotherapy (SBRT) (24Gy/3#) in week 7. Five patients were recruited before trial closure to new participants for logistical reasons. Existing participants continued treatment per protocol as a pilot study at one center. All five patients completed chemoradioimmunotherapy and SBRT. All patients derived an improvement in their dysphagia. Two patients completed 24 months of nivolumab without disease progression. Grade 3 adverse events (AEs) occurred in 3 patients, however, there were no grade 4 AEs, AEs due to SBRT, or AEs of special interest as defined by the protocol. Pilot results from five patients at one center found that treatment was well tolerated and effective for dysphagia relief. The efficacy of hypofractionated chemoradiotherapy with concurrent checkpoint inhibition should be tested in a multicentre study.

Proton Craniospinal Irradiation with Immunotherapy in Two Patients with Leptomeningeal Disease from Melanoma.

Proton craniospinal irradiation (pCSI) is a treatment option for leptomeningeal disease (LMD), which permits whole neuroaxis treatment while minimizing toxicity. Despite this, patients inevitably experience progression. Adding systemic therapy to pCSI may improve outcomes. In this single-institution retrospective case series, we present the feasibility of treatment with pCSI (30Gy, 10 fractions) and an immune checkpoint inhibitor (ICI) in two sequential patients with LMD from melanoma. The first patient developed LMD related to BRAF V600E-mutant melanoma after prior ICI and BRAF-targeted therapy. After pCSI with concurrent nivolumab, the addition of relatlimab, and BRAF-targeted therapy, he remained alive 7 months after LMD diagnosis despite central nervous system progression. The second patient developed LMD related to BRAF-wildtype melanoma after up-front ICI. He received pCSI with concurrent ipilimumab and nivolumab, then nivolumab maintenance. Though therapy was held for ICI hepatitis, the patient remained progression-free 5 months after LMD diagnosis. Adding an ICI to pCSI is feasible for patients with LMD and demonstrates a tolerable toxicity profile. While prospective evaluation is ultimately warranted, pCSI with ICI may confer survival benefits, even after prior ICI.

Concurrent nivolumab and external beam radiation therapy for hepatocellular carcinoma with macrovascular invasion: A phase II study

Nivolumab was the first immune checkpoint inhibitor approved for hepatocellular carcinoma (HCC). External beam radiation therapy (EBRT) is locally effective and may enhance the effectiveness of immunotherapy. This study investigated the efficacy and safety of concurrent nivolumab and EBRT in HCC with macrovascular invasion. In this phase II multicenter trial, patients with HCC and macrovascular invasion were concurrently treated with intravenous nivolumab (3mg/kg every 2 weeks) and EBRT, followed by maintenance nivolumab until progression or unacceptable toxicity. Primary endpoints were progression-free survival (PFS) and safety, and secondary endpoints were overall survival, time-to-progression, objective response rate, and disease control rate. Between January 2020 and June 2021, 50 patients (male 84%, median age 62.5) were enrolled; 47 (94.0%) and 13 (26.0%) with portal (Vp1/2, n= 21; Vp3, n= 23; Vp4, n= 3) and hepatic vein invasion, respectively. Patients received EBRT (median dose: 50 [IQR 43-50] Gy) after the first nivolumab dose. The median number of nivolumab doses was 8.5. Median PFS was 5.6 (90% CI 3.6-9.9) months. Median overall survival and time-to-progression were 15.2 (90% CI 10.8-19.6) and 5.6 (90% CI 3.6-9.9) months, respectively. The objective response rate and disease control rate were 36.0% and 74.0%, respectively. The median duration of response was 9.9 months. Of 35 patients with follow-up data, 23 received subsequent systemic treatment, including atezolizumab-bevacizumab, sorafenib, lenvatinib, and regorafenib. Treatment-related any grade adverse events (AEs) and grade 3/4 AEs occurred in 40 (80.0%) and 6 (12.0%) patients, respectively. Common treatment-related AEs included pruritus (38.0%) and rash (16.0%), with no treatment-related deaths. Concurrent nivolumab therapy and EBRT showed encouraging PFS with acceptable safety in patients with advanced HCC and macrovascular invasion. Immune checkpoint inhibitors, the standard care for advanced hepatocellular carcinoma (HCC), show relatively poor therapeutic effects in patients with advanced HCC and macrovascular invasion. In this investigator-initiated phase II study, we, for the first time, show that concurrent external beam radiation therapy with nivolumab, an immune checkpoint inhibitor, led to encouraging progression-free survival in patients with HCC and macrovascular invasion. The concurrent treatment was tolerable without significant safety concerns. Further randomized studies investigating the combination of immunotherapy and external beam radiation therapy are required. NCT04611165.

Phase II Trial of Concurrent Nivolumab and Radiation Therapy for Muscle-Invasive Bladder Cancer of Older or Chemotherapy-Ineligible Patients

Bladder cancer is predominantly a disease of older individuals. Concurrent chemotherapy and radiation is a bladder-sparing strategy for management of muscle-invasive bladder cancer; however, many patients are not candidates for chemotherapy due to comorbidities or impaired performance status. We conducted a study in a chemotherapy-ineligible patient population with the objectives of evaluating the safety, efficacy, and quality-of-life effect of the combination of nivolumab and radiation therapy in patients with localized/locally advanced urothelial cancer. Eligible patients had muscle-invasive bladder cancer and were not candidates for standard chemoradiation strategy due to at least one of the following: performance status of 2, creatinine clearance ≤60 mL/min, cardiac disease, neuropathy, and intolerance to previous treatment. Creatinine clearance ≥40 mL/min, normal marrow, and liver function were required. The primary endpoint was progression-free survival at 12 months. Nivolumab was started within 3 days of radiation therapy and administered at a dose of 240 mg intravenously every 2 weeks for a maximum of 6 months. Radiation therapy was per standard of care for bladder cancer. Imaging and cystoscopy and biopsy evaluation were required at months 3, 6, and 12 and then annually until progression. Twenty patients were enrolled, with a median age of 78.5 years (range, 58-95 years); 80% of patients were >70 years of age, and 8 (40%) were >80 years of age. Median creatinine clearance was 52 mL/min. Nine patients (48%) were progression free at 12 months. Median progression-free survival was 11.4 months (90% CI, 7.5-23.7 months), and median overall survival was 15.6 months (90% CI, 9.1-26.1 months). Concurrent nivolumab and radiation therapy is tolerable but demonstrated limited efficacy in an older population with multiple comorbidities. Immune correlates demonstrated that patients with baseline programmed cell death ligand 1 combined prognostic score ≥5% had numerically longer progression-free survival.

LBP-25 - Concurrent nivolumab and external beam radiation therapy for patients with advanced hepatocellular carcinoma with vascular invasion: a phase 2, single-arm NEXTRAH trial

LBP-25 - Concurrent nivolumab and external beam radiation therapy for patients with advanced hepatocellular carcinoma with vascular invasion: a phase 2, single-arm NEXTRAH trial

Pneumonitis with combined immune checkpoint inhibitors and chemoradiotherapy in locally advanced non-small-cell lung cancer: a systematic review and meta-analysis.

Aims: This study systematically evaluated cases of pneumonitis following combined immune checkpoint inhibitors (ICI) and chemoradiotherapy (CRT) for locally advanced non-small-cell lung cancer (LA-NSCLC). Methods: Studies from Embase, PubMed and the Cochrane Library on patients with LA-NSCLC who received CRT and ICIs were reviewed. The primary outcomes were rates of all-grade, grade 3-5 and grade 5 pneumonitis. Results: Overall, 35 studies involving 5000 patients were enrolled. The pooled rates of all-grade, grade 3-5 and grade 5 pneumonitis were 33.0% (95% CI: 23.5-42.6), 6.1% (95% CI: 4.7-7.4) and 0.8% (95% CI: 0.3-1.2), respectively, with 7.6% of patients discontinuing ICIs because of pneumonitis. Conclusion: The incidence rates of pneumonitis following combined CRT and ICIs for LA-NSCLC were acceptable. However, the pulmonary toxicity of concurrent CRT and nivolumab plus ipilimumab should be noted.

Combination high-dose interleukin-2 and nivolumab for programmed cell death-1 refractory metastatic melanoma: a case series

BackgroundTherapeutic options are needed for metastatic melanoma refractory to therapies directed against programmed cell death-1. High-dose interleukin-2 has the potential to overcome programmed cell death-1 resistance.Case presentationWe report three consecutive Caucasian patients, two female (60 and 55 years old) and one male (56 years old), refractory to anti-programmed cell death-1 therapy who were treated with concurrent nivolumab and standard-dosing bolus high-dose interleukin-2. We did not see any unexpected toxicities with overlapping treatments as compared with either high-dose interleukin-2 or nivolumab alone.ConclusionsThe tolerance and disease control observed among the three patients in this limited series support formal exploration of this combination.

Combination of nivolumab with chemoradiotherapy for locally advanced cervical cancer: NiCOL phase I trial.

5534 Background: Current management of locally-advanced cervical cancers (LACC) relies on chemoradiotherapy (CRT) and brachytherapy. The causal relation between cervical cancer and human papillomavirus infection, which engenders tumor expression of immunoreactive neo-antigens, together with high PD-L1 expression, warrants consideration of immune checkpoint inhibitors (ICI) in the definitive treatment of this disease. We assessed the safety of concurrent and maintenance nivolumab in addition to CRT in patients with LACC. Methods: This prospective, multi-center, dose-confirmation, phase I clinical trial (NiCOL trial; NCT03298893) evaluated the tolerance profile of concurrent and maintenance nivolumab in addition to CRT (45 Gy in 25 fractions with cisplatin 40mg/m² q1w, followed by a brachytherapy boost to 85 Gy) for stage IB3-IVA cervical cancers. Nivolumab was administered at 240 mg q2w starting on day 1 of CRT and in maintenance after CRT completion for up to 6 months (13 cycles). The primary endpoint was the incidence of dose-limiting toxicities (DLT) within 11 weeks after the initiation of treatment (defining the DLT assessment period), corresponding to the first 6 cycles of nivolumab. DLT were defined as grade ≥3 non-hematological toxicities, grade ≥3 immune-related adverse event (irAE), persistent grade ≥2 irAE for ≥1 week despite optimal supportive care, or ≥1-week radiotherapy delay related to treatment toxicity. Secondary endpoints included overall response rate (ORR), progression-free survival (PFS) and treatment tolerance profile. Results: 16 patients (pts) were recruited between 11/2017 and 07/2020. Median age was 46 years [range: 27-77]. Histological types were squamous cell carcinomas (n = 14) and adenocarcinomas (n = 2). Tumors were staged as FIGO IB3 (n = 2), IIB (n = 8), IIIB (n = 1), IIIC1 (n = 4) and IVA (n = 1); 13 tumors were HPV-positive. Three patients experienced DLT, corresponding to grade 3 hypotension (n = 2) and grade 3 acute kidney injury (n = 1). Following the DLT assessment period, while receiving maintenance nivolumab, one patient developed a grade ≥3 irAE corresponding to a grade 3 diarrhea. Two months after brachytherapy completion, ORR was 93.8% [95%CI: 69.8%-99.8%]. With a median follow-up of 16.6 months, three patients experienced disease control failure (at 3,4 and 5 months); site of disease progression was local for two patients, and simultaneously local and distant for one patient. One-year PFS was 81.2% [95% CI: 64.2%-100%]. Conclusions: Concomitant nivolumab with definitive CRT, followed by maintenance nivolumab, appears to be a safe and feasible therapeutic option for LACC, associated with encouraging PFS rates. Further trials evaluating ICI combined with CRT for LACC are warranted in light of these promising results and of those from recent studies evaluating ICI in the metastatic setting. Clinical trial information: NCT03298893.

T cell repertoire in peripheral blood as a potential biomarker for predicting response to concurrent cetuximab and nivolumab in head and neck squamous cell carcinoma

BackgroundT cell receptor (TCR) signaling profile is a fundamental property that underpins both adaptive and innate immunity in the host. Despite its potential clinical relevance, the TCR repertoire in peripheral...

Concurrent Nivolumab and Metformin in Diabetic Cancer Patients: Is It Safe and More Active?

Recent evidence suggests potential synergistic antitumor effects of the combination of programmed death-1 (PD-1)/programmed death-ligand 1 (PD-L1) immune checkpoint inhibitors with the oral hypoglycemic agent metformin. The aim of this study was to investigate the safety and activity of metformin combined with nivolumab in diabetic cancer patients. Patients with advanced melanoma, renal cell carcinoma or lung cancer receiving nivolumab with concurrent diabetes treated with metformin were retrospectively collected. The primary endpoint was the safety of nivolumab plus metformin combination. We collected 40 patients with solid tumors who received metformin for concomitant diabetes and nivolumab as anticancer therapy in four Italian Hospitals. The concomitant use of nivolumab and metformin was well tolerated; adverse events (AEs) of any grade occurred in 75% of patients (mainly fatigue, pruritus, rash, and asthenia). Grade 3 AEs occurred only in 20% of cases; no grade 4 AEs were observed. A statistically significant correlation was found between higher doses of metformin (>1,000 mg daily) and longer progression-free survival (p=0.021), overall survival (p=0.037) and higher overall response rate. The combination of nivolumab and metformin was safe and might have an antitumor activity, supporting further investigations on the synergistic antitumor effect of this combination.

Prospective Neurocognitive Functions of Patients Treated With Concurrent Nivolumab and Stereotactic Brain Radiosurgery for NSCLC and RCC Brain Metastases

Previous studies have suggested activity of anti-PD1 antibodies against brain metastases from non-small cell lung cancer (NSCLC) and renal cell cancer (RCC). Our investigator-initiated phase 2 trial examined the neuropsychological effect of combining nivolumab with radiosurgery (SRS) in the treatment of patients with brain metastases from NSCLC and RCC.This is a multicenter open-label trial (NCT02978404) in which patients diagnosed with NSCLC or RCC, having ≤ 10 cc of un-irradiated brain metastases, no prior whole brain radiotherapy and no prior immunotherapy were eligible. Study treatment commenced with a dose of nivolumab (240mg or 480mg IV), which was continued until progression for up to 2 years at bi-weekly or monthly intervals. SRS (15-21 Gy) to all visible un-irradiated brain lesions was administered within 14 days of the first dose of nivolumab (cycle 1). Patients were followed by brain MRI and CT scans of the chest, abdomen and pelvis. Neurocognitive assessment was performed using the Hopkins verbal learning test-revised (HVLT-R), the Trail Making Test (TMT) and the Controlled Oral Word Association Test (COWA) RESULTS: 26 study patients (22 NSCLC and 4 RCC) were enrolled between Aug 2017 and January 2020. Patients had a median of 2 (1-9) brain metastases treated with SRS. The median diagnosis-specific graded prognostic assessment (GPA) score was 2 (1-3). Forty-two percent of the patients had received prior cytotoxic chemotherapy, and 1 patient had received prior brain SRS. PD-L1 status was known for 21 of the 22 NSCLC patients (12 with ≥50% PD-L1 expression (DAKO 22C3)). Median icPFS was 5.0 months (6 intracranial progressions and 9 deaths without progression in the brain). Accounting for death as a competing risk, the 1-year cumulative incidence of intracranial relapse was 20%, whereas the rate of extracranial relapse was 48.3% at 1-year. Median overall survival was 14 months. Neuropsychological evaluation was completed in 16 and 9 patients at 3 and 6-month follow-up, respectively. Median age of the 16 patients was 63 (46-77). At 3 months follow up, there was no significant difference on the patient's mean performance in any of the neurocognitive assessments; a deterioration of ≥1 standard deviation in at least 1 assessment from baseline was observed in 8 (50%) patients. At 6 months, participants significantly improved on the TMT- Parts A (P = 0.04) and Parts B (P = 0.03).Neurocognitive assessments suggest that upfront SRS concurrent with nivolumab PD1 inhibition is safe. Patient neurocognitive function showed potential improvements in patients able to complete 6-month assessments. A potential synergy between nivolumab and SRS loco-regionally within the brain may be present, leading to high intracranial control. However, the high rate of extracranial progression does not suggest an abscopal effect triggered by SRS during nivolumab.G.L. Masucci: Research Grant; BMS.O. Boucher: None. F. Marie: None. M. Plourde: None. V. Panet-Raymond: None. M. Pavic: None. S. Owen: None. L. Masson-Cote: None. C. Menard: Research Grant; Siemens Healthcare, Philips, Progenics, Varian. B. Routy: None. M. Tehfe: None. N. Blais: consultant; BMS.D. Roberge: Independent Contractor; CHUM, CDL Proton Therapy. Research Grant; Elekta. Honoraria; BrainLab, Varian Medical Systems, Siemens Medical Systems, EMD Serono, recordati. In-kind Donation; Accuray. ownership stake; afx, croton healthcare. P. Wong: Research Grant; BMS, AstraZeneca, NexPlasmaGen. Advisory Board; BMS, AstraZeneca. Travel Expenses; BMS, AstraZeneca.

Quantitate Image Responses in High Risk p16+ Oropharyngeal Cancer Patients Treated With Definitive ChemoRT and Concurrent Nivolumab Compared to ChemoRT Alone

Biomarkers of immunotherapy response are increasingly important in oropharyngeal cancer with the rapid expansion of treatment in the R/M population and many ongoing upfront trials. CPS score is the most commonly used method to quantify immune infiltration and predict response to immunotherapy, although limited by its static nature and sampling error. Previous studies show that pre-RT to mid-treatment changes in MRI-derived blood volume (BV) and apparent diffusion coefficient (ADC) as well as FDG-PET derived metabolic tumor volume (MTV) and total lesion glycolysis (TLG) serve as imaging markers for pattern failure of HNC treated by CRT. The goal of this study is to evaluate changes in image metrics during concurrent immunotherapy and CRT compared to those from CRT.MRI and FDG-PET scans were acquired pre- and mid-treatment (fx 10) from 75 patients with high risk p16+ OPSCC (AJCC stage 3 or "matted nodes") who were treated with definitive concurrent CRT on 2 prospective institutional trials. The patients included: 1) the first 15 patients treated with definitive CRT 70Gy/concurrent carboplatin/taxol and concurrent nivolumab (iCRT) and 2) 60 patients treated with 70-80Gy/concurrent weekly cisplatin/carboplatin (CRT). Changes in quantitative image metrics from pre- to mid-treatment of primary tumors and individual lymph nodes were evaluated: gross tumor volume (GTV), MTV at 50% max SUV, TLG, mean SUV, mean BV and ADC between the two treatment groups using unpaired t test.Clinical characteristics and baseline quantitative image metrics were similar between CRT and iCRT groups, except the iCRT group had a lower BV value of primary tumors and a greater MTV of nodal tumors than CRT group (P = 0.05). However, at mid-treatment, iCRT patients had: 1) significantly greater increases in mean BV and ADC of primary tumors than CRT patients (49% vs. 23% and 21% vs. 12%, P < 0.007 and 0.03, respectively); but 2) less decreases in MTV, TLG and mean SUV of primary tumors than CRT patients, for which 11% of the TLG decrease was significantly different from 43% decrease of CRT group (P < 0.05); and 3) 12% decrease in mean SUV of nodal tumors that was significantly less than 25% in CRT group (P < 0.0001). With a mean follow-up of 11 months in the iCRT group, there has been only 1 DM in a patient with persistent low BV in the primary tumor, consistent with our previous findings in CRT patients.This analysis suggests that high risk p16+ OPSCC patients treated with iCRT had larger increases in BV and ADC and a smaller decrease in TLG in primary tumors mid-treatment compared to CRT group. Increases in BV and ADC have been identified to be associated with improved tumor control by previous studies of CRT. The minimal reduction of FDG metrics of iCRT group may be due to inflammatory response to anti-PD1. These findings warrant further investigation as predictive biomarkers for iCRT response to treatment.

50: Prospective Neurocognitive Functions of Patients Treated with Concurrent Nivolumab and Stereotactic Brain Radiosurgery for NSCLC and RCC Brain Metastases

50: Prospective Neurocognitive Functions of Patients Treated with Concurrent Nivolumab and Stereotactic Brain Radiosurgery for NSCLC and RCC Brain Metastases

PO-1026 Re-irradiation with concurrent Nivolumab in locally recurrent Head and Neck Cancer

PO-1026 Re-irradiation with concurrent Nivolumab in locally recurrent Head and Neck Cancer

Abstract 538: Liquid biopsy approaches for determining pathologic response to neoadjuvant immunotherapy in esophageal cancer

Abstract We examined the utility of serial liquid biopsies to monitor clonal dynamics and predict pathologic response in patients with esophageal/gastroesophageal junction (E/GEJ) cancer undergoing treatment with neoadjuvant immunotherapy and concurrent chemoradiation (CA209-906; NCT03044613). Methods: Using Targeted Error Correction sequencing (TEC-Seq), we performed high-depth next generation sequencing on 79 serial plasma samples from 16 patients with operable stage II/III E/GEJ cancer undergoing treatment with neoadjuvant nivolumab, followed by nivolumab plus chemo-radiation and surgery as part of the CA209-906 trial. Liquid biopsies were evaluated pre-treatment, after each of two cycles of neoadjuvant nivolumab, and after concurrent nivolumab and chemoradiation immediately prior to surgery, for an average of 4 time points per patient. Deep sequencing of matched leukocyte DNA and whole exome sequencing (WES) of pre-treatment tumors was performed. The origin of plasma variants was determined by comparison to tumor WES (tumor-derived) and leukocyte TEC-Seq (clonal hematopoiesis (CH)-derived or germline) and their clonal dynamics over time were evaluated. Resected tumors were reviewed by central pathology and percent residual tumor was estimated. Patients were followed for an average of 2 years post-surgery. Results: Eight of 16 patients had detectable circulating tumor-derived DNA (ctDNA) at any time point. Additionally, 13 CH-derived mutations were detected in plasma of 8 patients. The number of CH-derived mutations was correlated with increasing patient age. Identification and removal of CH-derived mutations via comparison to matched leukocyte sequencing allowed for accurate assessment of kinetics of bona fide tumor-derived mutations in plasma. Tumor mutation burden as determined by tumor WES was not associated with pathological response (mean baseline mutations per exome 90 vs 81 for patients with residual disease &amp;gt;20% and &amp;lt;20% respectively). Detectable ctDNA at the last pre-surgery time point was found in 3 patients and was associated with residual tumor &amp;gt;20% (50% vs 23% with or without detectable ctDNA respectively). ctDNA clearance, defined as detectable ctDNA at one or more earlier time points that subsequently becomes undetectable before surgery, occurred in 5 patients and was associated with improved pathologic response (80% of patients with ctDNA clearance had residual tumor &amp;lt;=20% and no evidence of disease progression). Furthermore, of the three patients who did not have ctDNA clearance, two subsequently developed disease progression. Conclusion: Comprehensive analyses of ctDNA from E/GEJ patients undergoing neoadjuvant immunotherapy with concurrent chemoradiation revealed ctDNA dynamics that were associated with pathologic response and disease recurrence. These approaches may be used to identify patients at high risk for disease progression. Citation Format: Jenna VanLiere Canzoniero, Vincent Lam, Zineb Belcaid, Mara Lanis, Lamia Rhymee, Blair Landon, Archana Balan, Kristen Marrone, Patrick Forde, Benjamin Levy, David Ettinger, Heather Schneider, Hanika Rodavia, Richard Battafarano, Stephen Yang, Stephen Broderick, Jinny Ha, Blair Jobe, Ali Zaidi, Elizabeth Thompson, Julie Brahmer, Victor Velculescu, Ronan Kelly, Josephine Feliciano, Valsamo Anagnostou. Liquid biopsy approaches for determining pathologic response to neoadjuvant immunotherapy in esophageal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 538.

Does Combined Fractionated Stereotactic Radiotherapy and Immunotherapy Change the Outcome of Recurrent High-Grade Gliomas?

BackgroundRadiotherapy (RT) with immune checkpoint inhibitors (ICI) has yielded good responses in many cancers. We aimed to report the results of combined fractionated stereotactic radiotherapy (FSRT) and ICI in patients with recurrent high-grade glioma.MethodologyPatients were treated with FSRT and nivolumab which were continued until progression or toxicity. The Response Assessment in Neuro-oncology and Immunotherapy Response Assessment in Neuro-oncology criteria were used to assess treatment response on magnetic resonance imaging. Treatment-related toxicity was noted in all patients.ResultsA total of eight patients were included. Recurrence was detected after a median of 5.8 months following the first RT, all in the treatment field. FSRT (3 × 8 Gy) was applied with neoadjuvant, concurrent, and adjuvant nivolumab. After a median follow-up of 21.3 months from diagnosis and 12.6 months from recurrence, one patient was alive and seven succumbed to the disease. The median overall survival was 20.9 months after diagnosis and 12.9 months after recurrence. The median progression-free interval was 2.3 months after FSRT. The local control (LC) rate was 62.5% with a median local recurrence-free survival of nine months. Progression in other regions of the brain was observed in four patients with a median progression-free survival of 2.1 months. Acute toxicity was not observed. ICI-related grade 3 late pneumonitis was observed in two patients, and grade 1 late thyroid toxicity in two patients. One patient with pneumonitis also developed osteoporosis and radiation necrosis.ConclusionsA high LC rate was achieved with concurrent FSRT and ICI with a severe late toxicity rate of 25%. This combination can be an option in recurrent high-grade gliomas.

Efficacy of concurrent cetuximab (CTX) and nivolumab (NIVO) in previously untreated recurrent and/or metastatic (R/M) head and neck squamous cell carcinoma (HNSCC).

6017 Background: Current standard of care for patients (pts) with previously untreated R/M HNSCC that are incurable is either pembrolizumab (pembro) with/without chemotherapy depending on the Programmed Death-Ligand 1 (PD-L1) combined positive score (CPS). We evaluated the combination of CTX and NIVO for its efficacy. Methods: Pts were treated with CTX 500 mg/m2 IV on Day (D) -14 as a lead-in followed by CTX 500 mg/m2 IV and NIVO 240 mg/m2 IV on D1 and D15 every 28-D cycle (C). Pts with CTX infusion reaction or who did not receive C1D1 for any reason were non-evaluable and replaced. NIVO dose reduction was not allowed. Results: Fifty-four evaluable pts were analyzed. Median age was 62 (42-85). ECOG performance status at baseline was 0 (20, 37%), 1 (30, 56%), and 2 (4, 7%). Primary sites were oral cavity 19 (35%), oropharynx 22 (41%), hypopharynx 3 (6%), larynx 9 (17%), and unknown primary 1 (2%). p16 status is positive 22 (41%), negative 29 (54%), and unknown 3 (6%). PD-L1 CPS is &lt; 1 in 6 (11%), &gt;1 in 26 (48%), and unknown 22 (41%). Median follow up time for overall survival (OS) was 12.2 months. The most common grade 3 treatment-related adverse events (TRAEs) occurring in ≥2 pts were hypomagnesemia 2 (4%), hypophosphatemia 2 (4%), fatigue 4 (7%), and rash-acneiform 4 (7%). The only grade 4 TRAEs were hypomagnesemia in 1 (2%) and CTX infusion reaction in 1 (2%). The most common grade 3 immune-related adverse event (IRAE) occurring in ≥2 was fatigue 2 (4%). No grade 4 IRAEs is observed. Median progression-free survival (PFS) and OS were 7.8 and 14.5 months, while 1-year PFS and 1-year OS were 39% and 61%, respectively. There were no statistically significant differences in either PFS and OS based on tumor p16 or PD-L1 status. Conclusions: The clinical trial met its primary endpoint of 1-year OS. Our data indicate the combination of CTX and NIVO is safe and effective in pts with previously untreated incurable R/M HNSCC. Clinical trial information: NCT03370276.

Longitudinal analysis of dynamic changes of T-lymphocytes during multimodal treatment of patients with inoperable stage III NSCLC.

e20503 Background: Acute lymphocytopenia is associated with poor survival in solid cancers treated with multimodal therapy. A prospective analysis of peripheral blood mononuclear cells (PBMCs) during multimodal treatment in inoperable stage III NSCLC patients was performed to assess a correlation of T-lymphocytes changes with 6-months progression-free survival rates (PFS6M). Methods: Twenty patients at median age of 65.5 years (range 33-77), 85% male, 55% with adenocarcinoma and 40% with squamous cell carcinoma, were prospectively enrolled in this study. Eighteen (90%) patients received platinum-based concurrent chemo-radiotherapy (cCRT); seven (35%) patients additional concurrent and/or sequential immune check-point inhibition (four patients nivolumab and three durvalumab); patients treated with nivolumab received induction chemotherapy. Thoracic irradiation (TRT) was applied in all patients with median cumulative dose in equivalent 2Gy fractions (EQD2) of 64Gy (range: 52-65Gy). Peripheral blood was collected 5-10 days before treatment begin (A1), on the last day of TRT (RTend), and during follow-up. Samples were analyzed using polychromatic flow cytometry. Results are reported for three time-points: A1, RTend, and 6 months after TRT (C3) or the last sample available before that time-point. Results: From A1 to RTend, 16 (80%) patients experienced severe T-cell (CD3+, CD3+CD4+, CD3+CD8+) depletion, including 3 (15%) patients who received two doses of concurrent nivolumab. T-lymphocyte nadir was independent of the absolute numbers of PBMCs before treatment begin. In two patients, T-cell count remained stable, and increased in two other patients. No correlation of dynamic changes from A1 to RTend with PFS6M was observed. From RTend to C3, T-lymphocytes recovered in 11 (55%) patients; in 6 (30%) T-cell count further decreased or remained at very low levels. For total CD3 T-cells, CD3+CD4+ and CD3+CD8+ subsets, progressive disease in the first six months after TRT was associated with a decrease of median values (P = 0.03 for total CD3+ and CD3+CD4+, P = 0.08 for CD3+CD8+ T-cells). In contrast, an increase of all medians was associated with PFS6M (P = 0.007 for total CD3+, P = 0.002 for CD3+CD4+, P = 0.06 for CD3+CD8+ T-cells). Conclusions: There is a significant difference between patients with regards to T-lymphocytes recovery after the end of TRT, which is predictive for PFS6M, with poor median recovery observed in patients with early progress.

Re-irradiation with concurrent and maintenance nivolumab in locally recurrent and inoperable squamous cell carcinoma of the head and neck: A single-center cohort study

BackgroundThe rate of loco-regional recurrences for locally advanced head and neck squamous cell carcinoma (HNSCC) following standard treatment reaches up to 50%, accompanied by a probability of 20% to develop a second primary tumor in the head and neck region. MethodsTen patients with inoperable, in-field recurrence of HNSCC following previous primary or adjuvant radiotherapy (RT) in combination with concurrent platinum-based chemotherapy were re-irradiated with 60 Gray in 30 fractions between December 2017 and January 2020 with concurrent and maintenance nivolumab administration. Data were retrospectively collected and compared with patients who underwent re-irradiation (ReRT) with concurrent cisplatin following propensity score matching (PSM). Local progression-free survival (LPFS) and overall survival (OS) were visualized using Kaplan-Meier method (log-rank test). ResultsAll patients completed ReRT. Median number of applied courses of nivolumab was 12 (range, 3–38). OS rate was 50% at 12 months and the median OS was 11 (range, 2–23) months. Six and 12 month LPFS rates were 60% and 30%, respectively. Median LPFS was 8 (range, 2–19) months. OS and LPFS rates were not inferior to those of patients treated with concurrent cisplatin. No unexpected radiation-related toxicity occurred. A total of four patients developed any-grade immune-related adverse events of which two presented with grade 3 toxicities. One patient died within 3 weeks after ReRT. Higher blood levels of CRP (p = 0.004), lower levels of hemoglobin (p = 0.029) and higher neutrophil/lymphocyte ratio (p = 0.004) were associated with impaired LPFS. Higher recursive portioning analysis (RPA) class was associated with impaired LPFS (p = 0.022) and OS (p = 0.024). ConclusionThe combination of ReRT and nivolumab for locally recurrent HNSCC was feasible without occurrence of unexpected toxicities. Combined radioimmunotherapy might offer an effective treatment option for carefully selected pre-irradiated patients ineligible for salvage surgery.