Concurrent Immune Checkpoint Inhibitors Research Articles

Sequential vs. concurrent systemic therapies in combination with FOLFOX-HAIC for locally advanced hepatocellular carcinoma: a single-center, real-world cohort study

BackgroundTri-combination therapy based on hepatic arterial infusion chemotherapy (HAIC) of infusion fluorouracil, leucovorin, and oxaliplatin (FOLFOX-HAIC) plus immune checkpoint inhibitors (ICIs) and tyrosine kinase inhibitors (TKIs) for the locally advanced hepatocellular carcinoma (HCC) patients have been proven effective. However, whether it was best for these HCC patients to start with the most potent therapeutic pattern was still under debate. This retrospective study evaluated the efficacy and safety of FOLFOX-HAIC combined with systemic therapies in the patterns of sequential and concurrent schedules.MethodsThis real-world study included 117 unresectable HCC patients who initially received either FOLFOX-HAIC monotherapy (HAIC group, n = 44) or concurrent ICIs and TKIs (ConHAIC group, n = 73) from March 2020 and June 2022, during the period of FOLFOX-HAIC monotherapy in HAIC group, patients in the HAIC group (n = 30) experienced progressive disease (PD) would have their treatment pattern converted from the FOLFOX-HAIC monotherapy to the combination of FOLFOX-HAIC plus ICIs and TKIs sequentially (SeqHAIC group). The progression-free survival (PFS) and overall survival (OS), as primary outcomes, were compared between patients in the SeqHAIC and ConHAIC groups.ResultsThe median follow-up time of the SeqHAIC group was 24.92 months (95% CI, 12.74–37.09 months) and of the ConHAIC group was 17.87 months (95% CI, 16.85–18.89 months) and no significant difference was observed in both PFS (HR, 1.572; 95% CI, 0.848–2.916; p = 0.151) and OS (HR, 1.212; 95% CI, 0.574–2.561; p = 0.614) between the SeqHAIC and the ConHAIC groups. As for the tumor responses, there was no significant difference between the two groups regarding tumor responses, overall response rates (p = 0.658) and disease control rates (p = 0.641) were 50.0%, 45.2%, and 83.3%, 89.0% for the SeqHAIC and the ConHAIC groups, respectively.ConclusionOur study revealed that sequential systemic ICIs and TKIs in combination with FOLFOX-HAIC provides similar long-term prognosis and better tolerability compared to concurrent therapy for locally advanced HCC patients. Prospective studies with a larger sample size and longer follow-up are required to validate these findings.

Intention-to-treat outcomes of patients with hepatocellular carcinoma receiving immunotherapy before liver transplant: the multicenter VITALITY study

The use of immune checkpoint inhibitors (ICI) in patients with advanced hepatocellular carcinoma (HCC) has become widespread with encouraging outcomes in the neoadjuvant setting. Safety and intention to treat (ITT) outcomes in the peri transplant setting are currently based on small and heterogenous single center reports. This first multiregional US study (2016-2023) included 117 consecutive HCC patients assessed for LT and treated preoperatively with ICIs. Intention to treat ITT and survival analyses were conducted with evaluation of post LT rejection rates. In total, 86 (73.5%) patients exceeded MC and 65 (75.6%) were successfully downstaged (DS) within a median of 5.6 months. 43 (36.7%) underwent transplantation, including 18 (15.4%) within MC and 23 (19.7%) initially beyond and DS. Overall, 94% of the cohort received concurrent ICIs and locoregional therapies. No grade 4-5 adverse events occurred on the waiting list. The 3-year cumulative probability of dropout was 28% for those within MC and 48% for those beyond. Independent predictors of dropout included: being beyond MC (p<0.001), AFP doubling from baseline (p=0.014) and radiographic responses (p<0.001). The 3-year ITT survival was 71.1% (73.5% within MC vs 69.7% beyond MC, p=0.329), with 3-year post LT survival rate of 85%. Post-LT rejection occurred in 7 patients, six received their last dose of ICI less than 3 months prior to LT, resulting in one graft loss. The first multicenter evaluation of HCC patients receiving ICI pre-LT demonstrates favorable survival and safety outcomes, justifying continued utilization and further evaluation of this strategy in clinical practice. High tumor burden, doubling of AFP levels, and radiographic response were identified as predictors of unfavorable oncologic outcomes. The first multicenter evaluation of pre-transplant immune-checkpoint-inhibitors in hepatocellular carcinoma to show promising intention-to-treat survival, safety and rejection rates. Immune-checkpoint-inhibitors, either alone or combined with LRT, demonstrate reliable efficacy. This preoperative strategy could be particularly beneficial for high-risk patients, including those requiring downstaging or with elevated AFP levels despite locoregional treatment. These findings fill current knowledge gaps and offer reassuring evidence for the feasibility of pre-transplant use of immune-checkpoint-inhibitors, pending results from ongoing trials.

Pre-stereotactic radiosurgery neutrophil-to-lymphocyte ratio predicts post-stereotactic radiosurgery survival of patients with brain metastases concurrently treated with immune checkpoint inhibitors.

Treatment with immune checkpoint inhibitors (ICIs) has shown clinical benefit for a wide range of cancer types. The neutrophil-to-lymphocyte ratio (NLR) reportedly correlates with survival time or progression-free survival in patients treated with ICIs. However, NLR has not yet been assessed in patients with brain metastases (BMs) receiving stereotactic radiosurgery (SRS) combined with concurrent ICIs. The authors investigated the predictive impact of NLR on the survival data of patients with BMs who received SRS with concurrent ICIs. The clinical records of patients who had undergone SRS with concurrent ICIs for BMs between January 2015 and August 2023 were retrospectively analyzed. NLR was calculated using the data obtained from the last examination prior to SRS. The optimal NLR cutoff value was identified by receiver operating characteristic (ROC) curve analysis for time-to-event data (overall survival [OS] ≤ 18 months). OS and intracranial disease progression-free survival (IC-PFS) rates were compared between the two NLR groups. Of the 185 eligible patients included, 132 were male. The median (IQR) patient age was 69 (61-75) years. The primary cancers were lung, genitourinary, skin, breast, gastrointestinal, and others in 132, 23, 22, 2, 2, and 4 patients, respectively. The post-SRS median OS and IC-PFS times for the entire cohort were 18.4 (95% CI 14.0-23.1) months and 9.2 (95% CI 6.9-10.8) months, respectively. ROC curve analysis identified the optimal NLR cutoff value for 18-month OS to be 5.0 (area under the curve 0.64, Youden index 0.31). Kaplan-Meier analysis revealed that patients with high NLR (> 5) had a significantly shorter OS (median survival time 10.9 months for 48 patients vs 22.2 months for 137 patients, HR 2.0, 95% CI 1.3-3.0, p < 0.001). Similarly, a significant difference in median IC-PFS was noted: 4.8 months with high NLR versus 10.7 months with low NLR (HR 1.7, 95% CI 1.2-2.5, p = 0.003). The authors found elevated pre-SRS NLR (> 5) to be associated with shorter OS and IC-PFS after SRS with concurrent ICIs for BMs. NLR is a simple, cost-effective, and widely accessible biomarker, which can thus be used for managing patients with BMs receiving SRS concurrently with ICIs. Further investigation in other large datasets is, however, required to validate these findings.

Transarterial chemoembolization for renal cell carcinoma patients with liver metastases in the era of immunotherapy: A case series

Treatment for renal cell carcinoma (RCC) has changed rapidly in the past decade with the widespread implementation of immune checkpoint inhibitors (ICIs) as first-line therapy in metastatic disease. The presence of liver metastases is a poor prognostic indicator but also has the potential to be a target for localized therapy. However, there is limited knowledge on the dynamics and long-term effects of combining liver-directed transarterial chemoembolization (TACE) with ICI therapy. We identified four patients with metastatic RCC (mRCC) and liver metastases who were treated concurrently with ICIs and TACE to metastatic liver lesions from our institutional database. We assessed treatment radiological responses and toxicity in this cohort. Liver-directed TACE with concurrent ICI was associated with radiological response or stabilization in all the liver lesions in the four patients in this cohort with a median time to locoregional liver metastasis progression-free survival of 8.3 months (range 6.0–11.1). The concurrent administration of ICI therapy and TACE to liver lesions was well tolerated with no new safety signals and no immune-related toxicities. Combining TACE with ICI in patients with mRCC showed promising response with limited toxicity. Future studies are warranted to clarify treatment timing and validate benefits.

Efficacy and safety of concurrent immune checkpoint inhibitors combined with radiotherapy or chemoradiotherapy for advanced non-small cell lung cancer: A systematic review and single-arm meta-analysis.

The recent usage of immunotherapy combined with chemoradiotherapy has improved survival in advanced non-small cell lung cancer (NSCLC) patients. However, determining the most effective therapy combination remains a topic of debate. Research suggests immune checkpoint inhibitors (ICIs) post-chemoradiotherapy enhance survival, but the impact of concurrent ICIs during chemoradiotherapy on rapid disease progression is unclear. This meta-analysis aims to assess the effectiveness and safety of concurrent ICIs with radiotherapy or chemoradiotherapy in advanced non-small cell lung cancer. We searched PubMed, Embase, the Cochrane Library, and Web of Science for relevant studies, extracting data on overall response rate (ORR), progression-free survival (PFS), overall survival (OS), and adverse events (AEs). The analysis included ten studies with 490 participants. Stage III NSCLC ORR was 81.8%, while Stage IV ORR was 39.9%. One-year PFS and OS for Stage III were 68.2% and 82.6%, compared to 27.9% and 72.2% for Stage IV. Common adverse events included anemia (46.6%), nausea (47.6%), rash (36.4%), and radiation pneumonitis (36.3%). Our meta-analysis shows concurrent ICIs with chemoradiotherapy are effective and safe in advanced NSCLC, particularly in stage III patients at risk of progression before starting ICIs after chemoradiotherapy. The findings support further phase III trials. The review protocol was registered on PROSPERO (CRD42023493685) and is detailed on the NIHR HTA programme website.

Real-world safety and efficacy of concurrent immunotherapy and thoracic chemoradiotherapy: A multi-institutional analysis.

e23262 Background: Despite the success of Immune checkpoint inhibitors (ICIs) as consolidation following concurrent chemoradiotherapy (CCRT), 22% to 30% of patients still cannot be treated with durvalumab due to progression or adverse events (AEs) during or after CCRT. Concurrent ICIs with CCRT would offer the opportunity to receive ICIs and may provide treatment benefit to a greater proportion of patients. In this study, we performed a multicenter investigation to evaluate the safety and efficacy of ICIs and chemotherapy with concurrent thoracic radiotherapy. Methods: All patients from three institutions who underwent ICIs and concurrent thoracic radiotherapy were included. The rate of 12-month progression-free survival (PFS) was estimated using the Kaplan-Meier method and evaluated with 95% CIs calculated using the Greenwood formula. Therapy-related pneumonitis (TRP) and esophagitis (TRE) were defined per CTCAE v5.0. Statistics utilized logistic regression modeling and receiver operating characteristic (ROC) analysis. Results: 69 patients (median [range] age, 62 [52-76]; 61 [88.4%] male; median follow-up 30.4 months) were collected, including 18 (26.1 %) cases of non-small cell lung cancer (NSCLC), 26 (37.7 %) cases of small cell lung cancer (SCLC), and 25 (36.2 %) cases of esophageal cancer (EC). The 12-month PFS rates in NSCLC, SCLC and EC were 72.2%, 69.2% and 72.0%, respectively. The median PFS in NSCLC and SCLC was 24.3 and 13.1 months, and not reached (mean 29 months) for EC. The incidences of all-grade TRP and TRE were 60.7% and 57.7%, respectively. Grades 1-5 TRP occurred in 15.9%, 30.4%, 8.6%, 1.4%, and 0, respectively. Grades 1-5 TRE occurred in 20.2%, 28.9%, 8.6%, 0, and 0, respectively. On multivariable analysis, age and MLD significantly predicted for any-grade and grade ≥2 TRP. Only age significantly predicted for grade ≥3 TRP. ROC analysis was able to pictorially model RP risk probabilities for a variety of MLD and age thresholds. Conclusions: This real-world study can be helpful for understanding the true efficacy and toxicity of ICIs and chemotherapy with concurrent thoracic radiotherapy given the lack of robust clinical data. Close monitoring should be recommended in this patient population during RT and follow-up.

Palliative Quad Shot Radiation Therapy with or without Concurrent Immune Checkpoint Inhibition for Head and Neck Cancer.

Patients with recurrent and metastatic head and neck cancer (HNC) have limited treatment options. 'QuadShot' (QS), a hypofractionated palliative radiotherapy regimen, can provide symptomatic relief and local control and may potentiate the effects of immune checkpoint inhibitors (ICIs). We compared outcomes of QS ± concurrent ICIs in the palliative treatment of HNC. We identified patients who received ≥three cycles of QS from 2017 to 2022 and excluded patients without post-treatment clinical evaluation or imaging. Outcomes for patients who received QS alone were compared to those treated with ICI concurrent with QS, defined as receipt of ICI within 4 weeks of QS. Seventy patients were included, of whom 57% received concurrent ICI. Median age was 65.5 years (interquartile range [IQR]: 57.9-77.8), and 50% patients had received prior radiation to a median dose of 66 Gy (IQR: 60-70). Median follow-up was 8.8 months. Local control was significantly higher with concurrent ICIs (12-month: 85% vs. 63%, p = 0.038). Distant control (12-month: 56% vs. 63%, p = 0.629) and median overall survival (9.0 vs. 10.0 months, p = 0.850) were similar between the two groups. On multivariable analysis, concurrent ICI was a significant predictor of local control (HR for local failure: 0.238; 95% CI: 0.073-0.778; p = 0.018). Overall, 23% patients experienced grade 3 toxicities, which was similar between the two groups. The combination of QS with concurrent ICIs was well tolerated and significantly improved local control compared to QS alone. The median OS of 9.4 months compares favorably to historical controls for patients with HNC treated with QS. This approach represents a promising treatment option for patients with HNC unsuited for curative-intent treatment and warrants prospective evaluation.

Synergistic effects of immune checkpoint inhibitors in combination with stereotactic radiosurgery for patients with lung cancer and brain metastases: a propensity score-matched analysis.

Stereotactic radiosurgery (SRS) is the mainstay treatment for brain metastases (BMs) from lung cancer. In recent years, immune checkpoint inhibitors (ICIs) have been applied to metastatic lung cancer and have contributed to improved outcomes. The authors investigated whether SRS with concurrent ICIs for lung cancer BMs prolongs overall survival (OS), improves intracranial disease control, and raises safety concerns. Patients who underwent SRS for lung cancer BMs at Aizawa Hospital between January 2015 and December 2021 were included. Concurrent use of ICIs was defined as no more than 3 months between SRS and ICI administration. The two treatment groups, which had a similar likelihood of receiving concurrent ICIs, were generated by propensity score matching (PSM; match ratio 1:1) based on 11 potential prognostic covariates. Patient survival and intracranial disease control were compared between the groups with and without concurrent ICIs (ICI + SRS vs SRS) by time-dependent analyses, taking into account competing events. Five hundred eighty-five patients with lung cancer BM (494 with non-small cell lung cancer and 91 with small cell lung cancer) were eligible. Of those patients, 93 (16%) received concurrent ICIs. Two groups, each with 89 patients (ICI + SRS group and SRS group), were generated by PSM. The 1-year survival rates of the ICI + SRS and SRS groups after the initial SRS were 65% and 50% and the median survival times were 16.9 and 12.0 months, respectively (HR 0.62, 95% CI 0.44-0.87, p = 0.006). The 2-year cumulative neurological mortality rates were 12% and 16%, respectively (HR 0.55, 95% CI 0.28-1.10, p = 0.091). The 1-year intracranial progression-free survival rates were 35% and 26% (HR 0.73, 95% CI 0.53-0.99, p = 0.047). The 2-year local failure rates were 12% and 18% (HR 0.72, 95% CI 0.32-1.61, p = 0.43) and the 2-year distant recurrence rates were 51% and 60% (HR 0.82, 95% CI 0.55-1.23, p = 0.34). Severe adverse radiation events (Common Terminology Criteria for Adverse Events [CTCAE] grade 4) occurred in 1 patient in each group, and CTCAE grade 3 toxicities were observed in 3 patients in the ICI + SRS group and in 5 in the SRS group (OR 1.53, 95% CI 0.35-7.7, p = 0.75). The present study found that SRS with concurrent ICIs for patients with lung cancer BMs was associated with longer survival and durable intracranial disease control, with no apparent increase in treatment-related adverse events.

Immune checkpoint inhibition and single fraction stereotactic radiosurgery in brain metastases from non-small cell lung cancer: an international multicenter study of 395 patients.

Approximately 80% of brain metastases originate from non-small cell lung cancer (NSCLC). Immune checkpoint inhibitors (ICI) and stereotactic radiosurgery (SRS) are frequently utilized in this setting. However, concerns remain regarding the risk of radiation necrosis (RN) when SRS and ICI are administered concurrently. A retrospective study was conducted through the International Radiosurgery Research Foundation. Logistic regression models and competing risks analyses were utilized to identify predictors of any grade RN and symptomatic RN (SRN). The study included 395 patients with 2,540 brain metastases treated with single fraction SRS and ICI across 11 institutions in four countries with a median follow-up of 14.2months. The median age was 67years. The median margin SRS dose was 19Gy; 36.5% of patients had a V12 Gy ≥ 10 cm3. On multivariable analysis, V12 Gy ≥ 10 cm3 was a significant predictor of developing any grade RN (OR: 2.18) and SRN (OR: 3.95). At 1-year, the cumulative incidence of any grade and SRN for all patients was 4.8% and 3.8%, respectively. For concurrent and non-concurrent groups, the cumulative incidence of any grade RN was 3.8% versus 5.3%, respectively (p = 0.35); and for SRN was 3.8% vs. 3.6%, respectively (p = 0.95). The risk of any grade RN and symptomatic RN following single fraction SRS and ICI for NSCLC brain metastases increases as V12 Gy exceeds 10 cm3. Concurrent ICI and SRS do not appear to increase this risk. Radiosurgical planning techniques should aim to minimize V12 Gy.

Combination Immunotherapy with Partial Versus Whole Tumor Radiotherapy in a Preclinical Melanoma Tumor Model

Partial tumor radiotherapy (PTRT) with immune checkpoint inhibition (ICI) is currently the subject of clinical trials and may be used clinically for large volume tumors when the full gross tumor volume (GTV) cannot be safely treated with full dose. PTRT delivers RT to a portion of the GTV, underdosing or not treating the remainder of the GTV, hypothesizing that ICI-mediated tumor infiltrating lymphocyte (TIL) infiltration will produce adequate disease control in un- or under-irradiated GTV. Standard treatment is whole tumor radiotherapy (WTRT), and potential differences in disease control between PTRT and WTRT with ICI have not been robustly assessed. We hypothesized that PTRT with ICI and WTRT with ICI will demonstrate similar tumor regression, and both RT regimens will demonstrate superior tumor regression as compared to ICI alone. B78 melanoma flank tumors were generated in C57B/L6 mice, with randomization at tumor size of 1 cm to experimental cohorts of PTRT + ICI and WTRT + ICI and control groups of no RT ± ICI. Custom lead shields were fabricated to deliver 16 Gy single fraction PTRT (50% tumor treatment) and WTRT, with dosimetry confirmation via radiochromic film. ICI was delivered through I.P. injection of murine anti-CTLA4 and anti-PD-L1 at days 0, 3, and 6 post-RT. Tumor regression was assessed via differences in tumor volume at ten days post completion of ICI, and mean cohort tumor volumes were compared with ANOVA (α <0.05). Variances between individual cohorts were assessed via t-test (α <0.05). Treatment cohorts demonstrated significant variance in tumor volume at ten days following treatment completion (p = 0.007, Table 1). WTRT + ICI demonstrated superior tumor regression when compared to PTRT + ICI (p = 0.006), ICI alone (p = 0.002), and control cohorts (p = 0.013). There was no difference in tumor regression between PTRT + ICI and ICI alone (p = 0.709), and PTRT + ICI did not achieve significant regression when compared to control (p = 0.083). Tumor regression did not differ between cohorts receiving no RT ± ICI (p = 0.103). Our results in this ICI resistant melanoma model demonstrated superior tumor regression with WTRT + ICI as compared to PTRT + ICI and ICI alone, suggesting that even with concurrent ICI, PTRT may not be sufficient treatment for melanoma. PTRT + ICI tumor regression was similar to ICI alone, suggesting that PTRT may not overcome immune resistance in the unirradiated tumor volume. Further investigation of optimal RT regimens to potentiate ICI response is warranted and correlative studies examining spatial immunomodulation in unirradiated and irradiated portions of the same tumor are underway.

Immune Checkpoint Inhibition and Single Fraction Stereotactic Radiosurgery in Non-Small Cell Lung Cancer Brain Metastases: An International Multicenter Study of 395 Patients

Brain metastases most commonly arise from non-small cell lung cancer (NSCLC). In recent years, immune checkpoint inhibitors (ICI) have demonstrated improvements in overall survival (OS) in NSCLC. However, concerns remain about the risk of radiation necrosis (RN) when ICI are administered with stereotactic radiosurgery (SRS). Logistic regression was used to evaluate prognostic factors associated with the development of any grade RN and symptomatic RN. Cumulative incidence of RN was evaluated using competing risks analysis and the Fine and Gray model, where the null hypothesis was rejected for p < 0.05. There were 395 patients with 2,513 brain metastases treated across 11 international institutions included in the analysis. The median follow-up was 14.2 months. Median patient age was 67 years (Interquartile Range [IQR]: 61-73), 53.4% were male, the median Karnofsky Performance Status was 80 (IQR: 80-90), and 88.6% has active extracranial disease at the time of SRS. The median margin dose was 19 Gy (IQR: 18-20), 97.5% of patients were treated on the Gamma Knife ®, 3.8% underwent prior whole brain radiation therapy (WBRT). The median V12 Gy was 5.2 cm3 and 36.5% of patients had a V12 Gy ≥ 10 cm3, anti-PD-1 agents were administered in 91.6% of patients. A V12 Gy ³ 10 cm3 was associated with an increased risk of developing any grade RN; odds ratio (OR): 2.12, p = 0.04 and OR: 2.18; p = 0.03 on univariable and multivariable analysis, respectively. Similarly, a V12 Gy ≥ 10 cm3 was associated with an increased risk of developing symptomatic RN; OR: 3.80, p = 0.003 and OR: 3.95; p = 0.003 on univariable and multivariable analysis, respectively. Receipt of concurrent ICI and prior WBRT were not statistically significant. At 1-year, the cumulative incidence of any grade and symptomatic RN was 4.8% and 3.8%, respectively. The cumulative incidence of any grade RN was 3.8% vs. 5.3% for the concurrent and non-concurrent groups at 1-year, respectively (p = 0.35). The cumulative incidence of symptomatic RN was 3.8% vs. 3.6% for the concurrent and non-concurrent groups at 1-year, respectively (p = 0.95). The risk of any grade and symptomatic RN following SRS and ICI administration for NSCLC brain metastases increases as the V12 Gy exceeds 10 cm3. Concurrent ICI and SRS does not appear to increase this risk. Radiosurgical planning techniques should aim to minimize the V12 Gy.

Combined Pulsed Radiotherapy (“QUAD SHOT” regimen) with Immune Checkpoint Inhibition (ICI) to Enhance Immune Response for LAHNSCC in Patients Considered Ineligible for Curative Intent Therapy

To utilize pulsed QUAD SHOT as an in-situ vaccine by stimulating the tumor microenvironment (TME) and excluding elective nodal sites, to enhance the immune response with concurrent ICI. Thirty-three patients (20 males and 13 females), with a median age of 81 years, seen at two community hospitals, determined to be ineligible for curative treatment, were treated. All pts received pulsed dose QUAD shot regimen to gross disease (44.4-59.2 Gy) spaced 3 weeks apart with addition of an approved ICI (Pembrolizumab or Cemiplimab). ERT was directed ONLY to Gross Primary + nodal disease. ICI was administered in most pts after the first QUAD shot to enhance immune response. ICI was continued adjuvantly until a > Grade 3 adverse event (AE) or progression of disease (POD). Pts with either advanced cutaneous or mucosal SCC were included (cSCC, mSCC). 39% presented with N1-2 adenopathy, and 24% presented with recurrent disease. PD-L1 status were not routinely obtained. The median number of ICI cycles delivered was 5 (range 2-24). All pts completed at least 3 QUAD shots. Overall LRC for all 33 pts was 69.7%, with a mean follow-up of 11 months (1-39). LRC for 33 pts at 1 and 2 years after the end of radiation were 61.07% and 55.52%, respectively. The percentage of pts free from elective regional recurrences at 1 and 2 years was 87.13% for both cSCC and mSCC groups. Overall, 6 pts (18%) experienced distant failure. Freedom from distant failure at 1 yr after QUAD shot completion by pathology was 100.00% for cSCC and 77.08% for mSCC. DFS for all 33 pts at 1 and 2 yrs were 59.39% and 37.12%, respectively. DFS at 1 year for cSCC was 100% and 53% for mSCC. Median DFS for the mSCC was 13.8 months. Overall survival for all 33 pts was 45.45% with a median OS time of 17.7 months. The 1 and 2 year OS rates were 65% and 33%. Overall toxicity was low and manageable. Gr 3 mucositis occurred in 1 patient and 5 (15%) developed Gr 2 AE's. Gr 3/4 IMAR's were observed in 3 pts and included infusion reaction, colitis, and fatigue/FTT and were discontinued. 4 pts required post QUAD PEG's unrelated to radiation toxicity and due to POD. In elderly, frail, or comorbidly ill patients with LAHNC, the addition of ICI to involved field QUAD shot regimen nearly tripled the median OS rate from prior publications with QUAD shot alone from 5.7 months to 17 months in our series. The low percentage of failure in the elective nodal beds was particularly encouraging based on our hypothesis. This approach represents the next step in an evolution away from conventional RT approaches that engender greater toxicity and warrants further study.

Predictors of Hepatotoxicity in Patients with Metastatic Solid Tumors Treated with Immune Checkpoint Inhibition (ICI) and Liver-Directed SBRT

Liver-metastasis-directed SBRT (LM-SBRT) alone provides durable local control for liver metastases with low rates of toxicity when adhering to established dose constraints. Whether these constraints are sufficient in the context of concurrent ICI is not established. To determine whether LM-SBRT contributes to hepatotoxic adverse events (HAE) in patients receiving ICI, we analyzed potential predictors of HAE in a prospectively evaluated cohort of clinical trial patients treated with both SBRT and ICI. Patients with metastatic solid tumors were included from three trials of multi-site SBRT with ICI given concurrently or shortly after SBRT provided they received all study treatments and were monitored for adverse events. ICI agents included pembrolizumab alone or dual agent ICI with nivolumab and either cabiralizumab, urelumab, or ipilimumab. LM-SBRT was delivered to 45 Gy in 3 fr with mean liver dose (MLD) limited to 16 Gy and <700 cc of liver receiving 17.1 Gy. HAE were defined using CTCAE 4.0 as: elevation of AST, ALT, bilirubin or alkaline phosphatase; autoimmune hepatitis; hepatic failure; or cholecystitis. HAE were included if rated at least possibly related to treatment by the trial monitoring committee. Cumulative incidence (CI) of HAE was modeled with death as a competing risk. Competing risks regression was performed using Fine-Gray modeling. Two hundred thirteen patients were evaluable. Median follow-up was 10 months. Median age was 61, 90 had liver metastases at treatment, 65 received SBRT to a liver lesion, 15 had underlying liver disease (cirrhosis or hepatic steatosis) and 13 patients had a primary liver cancer. Dual agent ICI was given to 97 patients. Table 1 shows CI at 6 months of grades 1-4 HAE in all patients, LM-SBRT patients and non-liver SBRT patients (NL-SBRT). None experienced grade 5 HAE. There was no significant difference in CI of any grade of HAE between LM-SBRT and NL-SBRT patients. This was also true when comparing LM-SBRT patients to NL-SBRT patients with <0.1 Gy MLD. ICI dose reduction or cessation due to HAE occurred in 4 patients, none of whom received LM-SBRT. On univariate analysis, underlying liver disease and dual agent ICI were significantly associated with grade 2+ HAE while age, LM-SBRT, MLD, primary liver cancer and presence of liver metastases at treatment were not. On multivariate analysis, underlying liver disease and dual agent ICI remained significantly associated with grade 2+ HAE (HR: 6.7, 95% CI 2.3 - 19.1; 4.7, 95% CI 1.7 - 13.0). LM-SBRT and MLD were not significant on MVA. LM-SBRT did not significantly increase the risk for hepatotoxicity in patients receiving ICI when respecting the above dose constraints. Risk for hepatotoxicity appears to be driven by dual agent ICI and underlying liver disease.

Patterns and outcomes of palliative radiation therapy with immunotherapy in locally recurrent head and neck squamous cell carcinoma.

e18015 Background: Immune checkpoint inhibitors (ICI) have been shown to improve outcomes in patients with recurrent or metastatic (R/M) head and neck squamous cell carcinoma (HNSCC). Radiation therapy (RT) is commonly incorporated into R/M HNSCC treatment for symptom management and disease control. RT is a potential immunostimulatory treatment modality that may enhance the antitumor activity of ICI; however, ideal sequencing of RT and ICI in the palliative treatment setting is not defined. The objective of this study was to describe the patterns and outcomes of RT and ICI in locally recurrent HNSCC. Methods: All adults (≥ 18 years) with HNSCC who received palliative ICI for R/M disease from 2015-2021 were identified from the institutional electronic medical record via ICD codes under an IRB approved protocol. Patients who received ICI for non-HNSCC, had synchronous primary tumors, or had history of hematologic malignancy or immunodeficiency were excluded. Patients without documentation of clinical outcomes after palliative RT were excluded. Retrospective data were collected and underwent descriptive analysis. Results: We identified 26 patients who received palliative ICI and RT for locally recurrent HNSCC. Twelve underwent palliative RT while on ICI. In this group, there were 0 patients with complete response (CR), five with partial response (PR), two with stable disease (SD), and four with progression of disease (PD) in the target lesion. There were 10 grade 3 events. Fourteen patients had RT separately from ICI: 6 before and 8 after receiving ICI. In this group, there was one patient with CR, six with PR, one with SD, and six with PD in the target lesion. There were 3 grade 3 events. Most common grade 3 events in both groups were: dysphagia, mucositis, and voice change. The most common modalities of RT were SBRT, IMRT, and 3D conformal; 7 patients underwent SBRT, 19 underwent IMRT/3D conformal, with similar responses in target lesions. Conclusions: These data suggest that concurrent ICI and palliative RT for locally recurrent HNSCC is effective in the target lesions, but has an increase in toxicities. Although there was a small number of patients who underwent concurrent ICI and RT, the disease control rate (DCR) in this group was 58%, which is promising. Similarly, the DCR for patients receiving ICI and RT separately was 57%. Further study on the optimal type and sequence of palliative RT in this patient population is warranted.

Concurrent immune checkpoint inhibition and selective immunosuppressive therapy in patients with immune-related enterocolitis

PurposeImmune checkpoint inhibitor (ICI) therapy is often suspended because of immune-related enterocolitis (irEC). We examined the effect of resumption of ICIs with or without concurrent selective immunosuppressive therapy (SIT) on...

Kidney Disease Patient Representation in Trials of Combination Therapy With VEGF-Signaling Pathway Inhibitors and Immune Checkpoint Inhibitors: A Systematic Review

Kidney Disease Patient Representation in Trials of Combination Therapy With VEGF-Signaling Pathway Inhibitors and Immune Checkpoint Inhibitors: A Systematic Review

Concurrent/sequential versus sequential immune checkpoint inhibition in inoperable large stage III non-small cell lung cancer patients treated with chemoradiotherapy: a prospective observational study

Purpose/aimThe international standard for patients with large inoperable stage III NSCLC is durvalumab consolidation after concurrent chemoradiotherapy (CRT). In this single centre observational study based on individual data, we prospectively evaluated the role of concurrent/sequential versus sequential immune checkpoint inhibition (ICI).Methods and patientsIn total, 39 stage III NSCLC patients were prospectively enrolled, 11 (28%) patients were treated with simultaneous and consolidation therapy with PD-1 inhibition (nivolumab) (SIM-cohort) and 28 (72%) patients received PD-L1 inhibition (durvalumab) as consolidation treatment up to 12 months after the end of CRT (SEQ-cohort).ResultsFor the entire cohort, median progression-free survival (PFS) was 26.3 months and median survival (OS), locoregional recurrence-free survival and distant metastasis-free survival were not reached. For the SIM-cohort, median OS was not reached and PFS was 22.8 months, respectively. In the SEQ-cohort, neither median PFS nor OS were reached. After propensity score matching, PFS at 12/24 months were 82/44% in the SIM-cohort and 57/57% in the SEQ-cohort (p = 0.714), respectively. In the SIM-cohort, 36.4/18.2% of patients showed grade II/III pneumonitis; in the SEQ-cohort 18.2/13.6% after PSM (p = 0.258, p = 0.55).ConclusionBoth concurrent/sequential and sequential ICI show a favorable side effect profile and promising survival in treated patients with inoperable large stage III NSCLC. Concurrent ICI showed a numerical non-significant improvement regarding 6- and 12-months PFS and distant control compared to sequential approach in this small study. However, concurrent ICI to CRT was associated with a non-significant moderate increase in grade II/III pneumonitis.

Patterns of Failure Outcomes for Combination of Stereotactic Radiosurgery and Immunotherapy for Melanoma Brain Metastases

BACKGROUND: Previous series have demonstrated central nervous system activity for immune checkpoint inhibitors (ICIs) and shown improved local control between stereotactic radiosurgery (SRS) and ICI for lung cancer brain metastases. OBJECTIVE: To assess whether the addition of ICI to SRS for melanoma brain metastasis improves outcomes when compared with historical control group treated in the era before ICI availability. METHODS: In this single institution retrospective series, outcomes of 24 patients with melanoma receiving concurrent ICI and SRS were compared with 111 historical controls treated before ICI era. Overall survival (OS) was estimated using the Kaplan-Meier method. Cumulative incidence of local and distant failures was estimated using a competing risk model that accounted for baseline differences using propensity score adjustments. RESULTS: The median OS time was improved in patients receiving ICI compared with the historical control group (17.6 vs 6.6 months, hazard ratio [HR] = 0.056, P = .0005). Cumulative incidence at 1 year for local failure in the historical control and ICI groups was approximately 12.5% and 6.5%, respectively (HR = 0.25, P = .19), while cumulative incidence of distant brain failure in the historical control and ICI groups was approximately 48% and 28%, respectively (HR = 0.326, P = .015) CONCLUSION: Distant brain failure and OS were improved in patients receiving concurrent ICI with SRS compared with historical controls. Local failure trended in the same direction; however, owing to small sample size, this did not reach statistical significance. While these data remain to be validated, they suggest that patients with brain metastasis may benefit from concurrent use of ICI with SRS.

Efficacy and clinicogenomic correlates of response to immune checkpoint inhibitors alone or with chemotherapy in non-small cell lung cancer

The role of combination chemotherapy with immune checkpoint inhibitors (ICI) (ICI-chemo) over ICI monotherapy (ICI-mono) in non-small cell lung cancer (NSCLC) remains underexplored. In this retrospective study of 1133 NSCLC patients, treatment with ICI-mono vs ICI-chemo associate with higher rates of early progression, but similar long-term progression-free and overall survival. Sequential vs concurrent ICI and chemotherapy have similar long-term survival, suggesting no synergism from combination therapy. Integrative modeling identified PD-L1, disease burden (Stage IVb; liver metastases), and STK11 and JAK2 alterations as features associate with a higher likelihood of early progression on ICI-mono. CDKN2A alterations associate with worse long-term outcomes in ICI-chemo patients. These results are validated in independent external (n = 89) and internal (n = 393) cohorts. This real-world study suggests that ICI-chemo may protect against early progression but does not influence overall survival, and nominates features that identify those patients at risk for early progression who may maximally benefit from ICI-chemo.

Concurrent Administration of Immune Checkpoint Inhibitors and Single Fraction Stereotactic Radiosurgery in Patients With Non-Small Cell Lung Cancer, Melanoma, and Renal Cell Carcinoma Brain Metastases

Stereotactic radiosurgery (SRS) and immune checkpoint inhibitors (ICI) are highly effective treatments for brain metastases, particularly when these therapies are administered concurrently. However, there are limited data reporting the risk of radiation necrosis (RN) in this setting. Patients with brain metastases from primary non-small cell lung cancer, renal cell carcinoma, or melanoma treated with SRS and ICI were considered. Time-to-event analyses were conducted for any grade RN and symptomatic RN (SRN) with death incorporated as a competing risk. As a secondary analysis, recursive partitioning analysis (RPA) was used for model development, and a loop of potential models was analyzed, with the highest-fidelity model selected. Brain V12 Gy thresholds identified on RPA were then incorporated into the competing risks analysis. Concurrent SRS and ICI administration. Six hundred fifty-seven patients with 4182 brain metastases across 11 international institutions were analyzed. The median follow-up for all patients was 13.4 months. The median follow-up was 12.8 months and 14.1 months for the concurrent and nonconcurrent groups, respectively (P=.03). The median patient age was 66 years, and the median Karnofsky Performance Status was 90. In patients with any grade RN, 1- and 2-year rates were 6.4% and 9.9%, respectively. In patients with SRN, 1- and 2-year rates were 4.8% and 7.2%, respectively. On RPA, the highest-fidelity models consistently identified V12 Gy as the dominant variable predictive of RN. Three risk groups were identified by V12 Gy: (1) < 12 cm3; (2) 20 cm3 ≥ V12 Gy ≥ 12 cm3; (3) V12 Gy > 20 cm3. In patients with any grade RN, 1-year rates were 3.7% (V12 Gy < 12 cm3), 10.3% (20 cm3 ≥ V12 Gy ≥ 12 cm3), and 12.6% (V12 Gy > 20 cm3); the 2-year rates were 7.5% (V12 Gy < 12 cm3), 13.8% (20 cm3 ≥ V12 Gy ≥ 12 cm3), and 15.4% (V12 Gy > 20 cm3) (P < 0.001). In patients with any SRN, 1-year rates were 2.4% (V12 Gy < 12 cm3), 8.9% (20 cm3 ≥ V12 Gy ≥ 12 cm3), and 10.3% (V12 Gy > 20 cm3); the 2-year rates were 4.4% (V12 Gy < 12 cm3), 12.4% (20 cm3 ≥ V12 Gy ≥ 12 cm3), and 13.1% (V12 Gy > 20 cm3; P< 0.001). There were no statistically significant differences in rates of any grade RN or SRN when accounting for therapy timing for all patients and by V12 risk group identified on RPA. The use of SRS and ICI results in a low risk of any grade RN and SRN. This risk is not increased with concurrent administration. Therefore, ICI can safely be administered within 4-weeks of SRS. Three risk groups based on V12 Gy were identified, which clinicians may consider to further reduce rates of RN.