High Tumor Research Articles

Relationship between immune phenotype and treatment selection of Chemo-IO vs. IO-only in TPS-high NSCLC using hypothetical test-and-control group generation based on survival data extracted from phase III trials.

e13569 Background: Immunotherapy has become the treatment of choice for the first-line treatment of unresectable NSCLC with high PD-L1 tumor proportion score (TPS). However, the optimal treatment regimen, particularly when to add chemotherapy, remains unclear. To evaluate whether an immune microenvironment biomarker could help guide the treatment regimen, we have explored computational hypothetical analysis applying historical proportion of inflamed immune phenotype (IIP) to published outcome data of clinical trials. Methods: R package “IPDfromKM” was used to reconstruct raw time-to-event outcomes from Kaplan-Meier (KM) curves. Data from KN-189 and KN-407 for anti-PD1 with chemotherapy (Chemo-IO), and KN-024 and KN-042 for anti-PD1 (IO-only) in the first-line treatment of NSCLC were included for analysis. Overall survival (OS) data were computed from KM of pts with PD-L1 TPS of ≧ 50% from these studies (KN-189 n=132, KN-407 n=73, KN-024 n=154, KN-042 n=299). It was assumed that Lunit SCOPE IO classified pts into IIP or non-IIP at a ratio of 57% vs. 43%, based on previous analysis. One hundred hypothetical sets of Chemo-IO and IO-only groups satisfying hazard ratio (HR) of IIP to non-IIP as 0.81 and 0.61 (± 0.025) while maintaining the proportion of IIP were randomly generated. A total of 10,000 (100 x 100) combinations of cohorts were analyzed to test our hypothesis of superiority of Chemo-IO over IO-only in non-IIP as well as non-superiority of Chemo-IO over IO-only in IIP. Results: Patient-level OS data for a total of 205 pts with Chemo-IO and 453 pts with IO-only were reconstructed. The median OS was favorable in Chemo-IO vs IO-only (HR 0.73, 95% confidence interval [CI] 0.54-0.99, p = 0.045). From 10,000 hypothetical combinations of cohorts, the median HR of Chemo-IO compared to IO-only was 0.61 (interquartile range [IQR] 0.60-0.63) in non-IIP group, whereas that was 0.86 (IQR 0.84-0.89) in IIP group (Table). The upper 95% bound of HR was < 1 for 8,611 combinations of non-IIP groups, but > 1 for all possible combinations of IIP groups. Given a non-superiority margin of 1.37(=1/0.73), 8,306 combinations were positive for the upper 95% bound of HR < 1.37. Overall, 6,917 matched combinations supported our hypothesis. Conclusions: From the computational analysis, 69.17% cases of hypothetical combinations support that Chemo-IO would be superior to IO-only in non-IIP group, whereas Chemo-IO would not be superior to IO-only in IIP group, implying a potential value of confirmatory biomarker analysis in providing evidence for regimen selection. [Table: see text]

Use of immunotherapy with check point inhibitors in soft tissue sarcoma: Analysis from single institution.

e23566 Background: Traditional treatments for soft tissue sarcomas include surgery, chemotherapy, and radiation. Effectiveness of Check point inhibitors for sarcoma has been unsatisfactory thus far. Major clinical trials PEMBROSARC and SARC028 revealed median PFS of 2 and 4.5 months, respectively. The FDA has approved three immunotherapy (IO) therapies for sarcoma. Atezolizumab was approved for alveolar soft part sarcoma. Dostarlimab is approved for sarcoma with DNA mismatch repair deficiency (dMMR), Sarcoma patients with high microsatellite instability (MSI-H), dMMR, or tumor mutational burden can receive pembrolizumab. A single-institution analysis of soft tissue sarcoma patients with IO is presented in this paper. Methods: All soft tissue sarcoma patients who have received IO from January 2021 to now have been included. At our institute, a total of seven patients received IO for soft tissue sarcoma. Observations were made regarding their fundamental characteristics and the progression free survival (PFS). The data was not statistically examined due to the small sample size and the heterogeneity of the data. Results: 2 of 7 trial patients were lost to follow-up. Recurrent autoimmune hepatitis terminated IO for another patient. Most of the patients are elderly with the median age of 78. Given their comorbidities and age, IO was chosen as the first line for 5 patients. Median PFS was 5.8 months. High PDL1 ( > / = 5%) patients had a median PFS of 5.6 months, while low PDL1 patients had 4.5 months. However, one patient with low PDL1 had PFS of 7 months. 5/7 patients didn’t have IO related side effects. Two patients developed Autoimmune (AI) hepatitis. Conclusions: The limited sample size prevented definitive conclusions from being drawn. Despite the unsatisfactory outcomes, it is worth mentioning that IO provided a certain degree of PFS in older patients with comorbidities who are not suitable candidates for chemotherapy. Based on limited data, patients with high PDL1 status appear to benefit more. IO alone has not shown promising results. In clinical trials, IO is being tested with chemotherapy and Tyrosine kinase inhibitors. The findings from these trials will provide valuable insights into the potential benefits of combination therapy. [Table: see text]

Use of Oncotype vs. Breast Cancer Index (BCI) for extended endocrine therapy decisions: A single center analysis in stage IA hormone receptor positive breast cancer.

e13083 Background: Extended Endocrine Therapy (EET) for hormone receptor positive HER-2 negative early-stage breast cancer reduces late recurrence risks but raises concerns about toxicity. Biomarker tests like the Breast Cancer Index (BCI) are vital for identifying patients who could benefit from continued ET, reassuring others against unnecessary extension. This study evaluates prognostic implications for both Oncotype Dx (Recurrence score, RS) and BCI amidst concerns about added testing costs in patients with early stage, estrogen receptor (ER) positive breast cancer. Methods: This is a single institution retrospective review of Stage IA ER positive HER-2 negative breast cancer patients who underwent both Oncotype Dx and BCI testing from January 2021 to December 2023. Pearson's correlation coefficient (r) was used to assess the linear relationship between the assays (p<0.05 for significance), analysis was performed with SAS software, version 9.4. Results: Fifty-eight patients with Stage IA ER positive HER-2 negative breast cancer who had both Oncotype and BCI results were identified (100% female; mean age 72.2 years [54-87]). After a median followed up of 72 months (63-75), no systemic or locoregional recurrences were reported. A low positive correlation between Oncotype and BCI was observed across the entire cohort (r=0.4058; p=0.0016). However, subgroup analysis showed no significant correlations: Oncotype <11 (n=17; r=0.2415; p=0.3504), Oncotype ≤18 (n=43; r=0.0914; p=0.5600), Oncotype <26 (n=51; r=0.2530; p=0.0733); Oncotype ≥26 (n=7; r=-0.5634; p=0.1878). Correlation was also not found in patients with Grade 1 tumor (n=16; r=0.3138; p=0.2365). Thirty-nine patients (67.24%) had their treatment recommendation changed based on BCI results. Side effects from ET affected 15 patients (25.86%) and included arthralgias (60%, n=9), hot flashes (26.67%, n=4), depression (13.33%, n=2), insomnia (6.67%, n=1), and others (53.3%, n=8). Twenty-two patients (37.93%) developed new osteopenia, and 6 (10.34%) new osteoporosis while on EET. Eight patients (13.79%) had ET interruption during their treatment course. Conclusions: Despite inclination towards cost-saving measures, Oncotype DX may be more useful to give prognosis in the early adjuvant period whereas BCI is more useful to evaluate late recurrence risk. Low or high Oncotype scores and tumor grade may not align with BCI findings. Considering the importance of managing toxicity against the risk of late recurrence, incorporating BCI testing can enhance EET recommendations, even for Stage I, node-negative, ER positive patients.

A phase II study of lurbinectedin with or without avelumab in small cell carcinoma of the bladder (LASER).

TPS4629 Background: Small cell carcinoma of the bladder (SCCB) is a rare, aggressive malignancy accounting for <1% of all bladder malignancies. Given its rarity, few prospective randomized trials have been completed in SCCB. Most therapeutic evidence comes from retrospective case series and due to its histologic similarity to small cell lung cancer (SCLC), current guidelines recommend bladder cancers with any component of small cell histology be treated similarly to SCLC. Lurbinectedin is a novel alkylating agent which recently received accelerated approval from the FDA as a second line treatment for SCLC after demonstrating an overall response rate (ORR) of 35.2% and median duration of response (DoR) of 5.3 months (Trigo et al., Lancet Oncol, 2020). Avelumab is an anti-PD-L1 antibody FDA approved as maintenance treatment for patients with locally advanced or metastatic urothelial cancer (UC) without progression on frontline chemotherapy. Case reports have demonstrated that second line options in SCLC, including immunotherapy, appear to have some efficacy in SCCB. The purpose of this study is to assess the efficacy of lurbinectedin, either alone or in combination with avelumab, in participants with SCCB or other high grade neuroendocrine tumors (HGNETs) of the urinary tract. Methods: LASER (NCT06228066) is a phase II, multisite, open label, nonrandomized study with two cohorts. Eligible patients must have pathologically confirmed SCCB or other HGNETs of the urinary tract. Patients with mixed histologies, with any component of neuroendocrine tumor, are eligible. Patients must have received or be ineligible/refused frontline platinum/etoposide therapy. Participants in Cohort 1 must have received prior immune checkpoint inhibitors (ICIs) or be ineligible for treatment with ICI. These patients will receive lurbinectedin 3.2mg/m2 IV every 21 days. Participants in Cohort 2 must be ICI naïve but eligible to receive them. These patients will receive lurbinectedin 3.2mg/m2 IV and avelumab 800mg IV every 21 days. The primary endpoint for both cohorts is ORR, with key secondary endpoints including clinical benefit rate, PFS, OS, and DoR. The study will be conducted using a Simon minimax two stage design to rule out an ORR of 5% in favor of an ORR of 25% or greater in each cohort. If 1 of the first 12 patients has a response accrual will continue up to 16 evaluable patients per cohort. Accrual ceiling will be set at 35 patients. Exploratory objectives include analyzing peripheral immune subsets, DNA and RNA sequencing of tumors, and measurement of ctDNA and CTCs. Clinical trial information: NCT06228066 .

Linking the companion diagnostic function of cancer genome profiling to therapy: Investigation of TMB-high predictors.

e13033 Background: Based on the companion diagnostic function of the Comprehensive Cancer Genome Profiling (CGP) test in Japan, pembrolizumab is the standard treatment for patients with Tumor Mutational Burden (TMB)-high (H) solid tumors. In this report, we attempted to extract predictive factors of TMB-H from CGP test results. Methods: We carried out a retrospective cohort study of 42 patients with malignant breast tumors (excluding circulating tumor DNA in the blood) who underwent CGP testing between June 1, 2019, and November 30, 2023, at our hospital and affiliated institutions. We analyzed the association between clinicopathological factors, the number of analyzed cancer-related gene mutations (SNV, InDel), and TMB-H using univariate and multivariate statistical analysis. Results: Of the 42 cases (27 positive and 15 negative for estrogen receptor (ER), respectively), seven (16.7%) were TMB-H. Samples significantly associated with TMB-H according to univariate analysis were submitted as pathology specimens (non-primary (16.7%) vs. primary (0%), p = 0.011), ER (positive (16.7%) vs. negative (0%), p = 0.044), letrozole (LET) (yes (11.9%) vs. no (4.8%), p = 0.008), and previous treatment (after 6th line (14.3%) vs. before (2.4%), p = 0.041). Multivariate analysis showed that LET had a significant effect on TMB-H in Aromatase inhibitor agents (LET + Anastrozole + Exemestane) (LET: OR, 19.9; 95% CI, 2.2–183.5; p = 0.008) and the number of cancer-related gene mutations (PIK3CA+TP53) were significantly affected (PIK3CA: OR, 3.8; 95% CI, 1.1–13.2; p = 0.032. TP53: OR, 0.08; 95% CI, 0.01–0.66; p = 0.015). Single regression analysis showed a significant association between the number of PIK3CA mutations and LET. (β, 0.31; SE, 0.11; p = 0.008). Conclusions: ER positivity, history of LET use, prior therapy after the 6th line, and submission of pathology specimens from non-primary tumors to CGP testing are predictive factors for TMB-H. In multivariate analysis, the history of LET use and the number of PIK3CA mutations were significantly associated with TMB-H. Research shows that PIK3CA mutations are most frequent in patients who have undergone preoperative endocrine therapy with LET (Breast Cancer Res Treat. 2020 Nov;184(1):123–133.), suggesting that an increased number of PIK3CA mutations due to LET contributed to TMB-H. Although immune checkpoint inhibitors (ICIs) are not indicated for ER-positive breast cancer, TMB-H may be a predictor of ICI efficacy in such cases. The limitations of our research were the small sample size, and the study population only included Japanese. For the next steps needed to continue in this research, clinical trials should take place to test whether TMB-H is a predictor of ICIs in a wider population of ER-positive breast cancer.

Contrasting comprehensive genomic profiles of adenocarcinomas of the appendix in younger versus older patients.

3626 Background: Adenocarcinoma of the appendix (AAC) is a rare form of intestinal malignancy that can pursue an aggressive clinical course. Little is known about the clinical and biologic features of this disease when it presents in young patients under 40. Methods: 1,840 cases of clinically advanced AAC were selected and analyzed by hybrid capture based comprehensive genomic profiles (CGP) to evaluate all classes of genomic alterations (GA). MSI high status and tumor mutation burden (TMB) were determined from sequencing results and PD-L1 was measured by immunohistochemistry (Dako 22C3). Results: 135 (7.3%) of the AAC were identified in patients of 39 years of age or younger (“younger”). The mean age of the younger patients was 32.9 years and for the 40 and over (“older”) patients it was 60.4 years. The slight female gender preponderance was higher in the older patients than the younger patients (Table). The GA per sample were similar. The younger patients had a significantly higher frequency of KRAS GA (71.1% vs 60.4%; p=.017) and TP53 GA (56.3% vs 41.3%; p=.0008). The KRAS G12C mutation frequency was similarly low in both cohorts. Targetable GA in BRAF and ERBB2 were infrequent in both groups as were GA in PIK3CA, PTEN and FBXW7. GA in the APC gene was significantly more frequent in the older patients (10.8% vs 3.7%; p=.007). Biomarkers of immune-oncology (IO) drug efficacy were infrequently identified in both groups including MSI-High status, TMB levels and PD-L1 expression. Conclusions: At a 7.3% incidence, AAC is a relatively infrequent form of gastrointestinal malignancy in young patients. The data analysis shows significant differences in the genomics found in younger and older patients suffering from this disease. These results can have a crucial impact on current and future clinical trials used to design novel treatments. Further exploration into this subject can change the overall approach and even treatment guidelines for this type of cancer. [Table: see text]

REPLACE: A phase III, randomized, open-label trial to evaluate the safety and efficacy of regorafenib and pembrolizumab versus locoregional therapy (LRT) with transarterial chemoembolization (TACE) or transarterial radioembolization (TARE), for the first-line treatment of intermediate-stage hepatocellular carcinoma (HCC) with beyond up-to-7 criteria.

TPS4200 Background: Intermediate-stage HCC represents a heterogeneous population, posing unique challenges for therapeutic management. With the advent of effective systemic therapies for unresectable HCC, the treatment landscape for intermediate-stage extends beyond LRT, particularly in patients with high tumor burden. The growing evidence about the benefit of systemic therapy in intermediate-stage HCC led to the inclusion in some recent guidelines of systemic therapy as the first choice of treatment in TACE-unsuitable patients with intermediate-stage HCC. Despite these recommendations, no randomized clinical trial has been published comparing LRT with TACE/TARE versus systemic therapy in patients with intermediate-stage HCC and high tumor burden. Methods: REPLACE is a phase III, multicenter, randomized, open-label trial that will compare the efficacy and safety of LRT with TACE/TARE versus systemic therapy, for the first-line treatment of intermediate-stage HCC with beyond up-to-7 criteria. Eligible participants will be randomized 1:1 to receive regorafenib (90 mg orally q.d. on days 1 to 21 of a 4-week cycle), and pembrolizumab (400 mg i.v. on day 1 of a 6-week cycle) or LRT with TACE or TARE, and will be stratified according to geographic region (Asia vs. non-Asia), ECOG Performance Status (0 vs 1) and Albumin-Bilirubin (ALBI) grade (1 vs 2). Patients must have intermediate-stage HCC with beyond up-to-seven criteria (Up-to-7 criteria = largest tumor diameter (cm) + number of tumors ≤7), measurable disease per RECIST 1.1, disease not amenable to curative treatment but amenable to LRT with TACE or TARE, no prior systemic or LRT for HCC, except for successful resection and/or ablation completed ≥ 6 months prior to randomization. Patients will be treated until progressive disease, unacceptable toxicity, or other treatment discontinuation criteria is met. The primary endpoint is progression free survival (PFS), assessed locally by the Investigator using mRECIST for HCC. Secondary endpoints include PFS assessed locally by the Investigator using RECIST 1.1; PFS centrally assessed using mRECIST and RECIST 1.1; overall survival; overall response rate according to RECIST v.1.1 and mRECIST based on the Investigator’s and central assessment; time to unTACEable progression; duration of response; safety and tolerability of the trial treatments, and patient reported outcomes for health-related quality of life. The estimated enrollment is 496 patients from approximately 14 countries. Recruitment started in October 2023 and is currently ongoing. Clinical trial information: NCT04777851 .

Tumor purity as confounder for the determination of tumor mutational burden (TMB).

e14656 Background: TMB determination is a prerequisite to stratify advanced cancer patients for pembrolizumab based on the histology-agnostic FDA approval. The accuracy of TMB measurement is challenged by low tumor purity resulting in a lower number of detected somatic variants for a fixed threshold of variant allele frequency (VAF) and a lower measured TMB level as a consequence. Methods: We derived a mathematical formula describing the influence of tumor purity on the VAF of somatic variants, in which the DNA copy number of the corresponding region of the tumor genome is a parameter. We simulated the effect of tumor purity in a cohort of 4,900 tumors from the TCGA project with tumor purity of at least 80%. TMB was calculated as the number of missense mutations with VAF greater or equal than 5%. Tumors were classified as TMB-high when harboring at least 199 missense mutations. This cutpoint corresponds to 10 mut/Mb as derived in the TMB bridging study. We compared tumors with a simulated tumor purity of 70%, 60%, ..., and 10% with tumors with a tumor purity of 80%, which served as reference. Results: The median of TMB in the pan-cancer cohort was reduced by 2%, 10%, and 32% for tumor purity of 60%, 40%, and 20% compared to the reference of 80%. For the 10% tumors with the worst estimation, TMB was reduced even by 12%, 35%, and 77% or more, respectively. In the pan-cancer cohort, the sensitivity to detect high TMB was 98%, 90%, and 62% for tumor purity of 60%, 40%, and 20%, respectively. For head and neck cancer, lung adenocarcinoma, lung squamous cell carcinoma, and cutaneous melanoma, the sensitivity to detect high TMB was 80%, 89%, 92%, and 91%, respectively, for tumors of tumor purity 40%. Conclusions: High tumor purity is critical for accurate determination of the TMB and to reach a high sensitivity concerning the selection of patients for immunotherapy. As shown by the simulations, the sensitivity to detect high TMB is close to 100% for tumor purity of at least 60%, while a substantial proportion of patients that could receive immunotherapy is missed for tumors with purity of 40% or less. Potential ways out of the TMB underestimation include increasing the sequencing coverage and lowering the VAF threshold for mutation calling or using clonal TMB with an adapted cutpoint instead of total TMB as biomarker for immunotherapy guidance.

Immune checkpoint inhibition for the treatment of metastatic breast cancer with high tumor mutational burden: Real world clinical and genomic correlates of response.

1078 Background: Pembrolizumab has received tumor-agnostic approval for the treatment of unresectable/metastatic solid tumors carrying a tumor mutational burden (TMB) >10 mut/Mb. The registrational KEYNOTE-158 study, however, did not include any patients with metastatic breast cancer (MBC). Here we present a retrospective study of patients with TMB-high MBC treated with immune checkpoint inhibition (ICI) and report real-world efficacy endpoints, including progression free survival as well as clinical and genomic characteristics that may be associated with duration of response. Methods: All patients with MBC treated with an ICI at MSK and with TMB-high tumors (>10 mut/Mb) assessed by tumor-normal targeted sequencing (MSK-IMPACT) were included. Clinicopathological and demographic data were obtained via the MSK Breast Cancer Translational Program. Mutational signatures were determined using the Signature Multivariate Analysis (SigMA) algorithm. Real world progression free survival (PFS) was determined clinically and analyzed using Kaplan-Meier estimates. Univariate and multivariate analyses were performed using Cox-proportional hazards models. Results: Of 688 patients with TMB-high breast cancer at MSKCC, 87 had received ICI-based therapy for estrogen receptor positive (ER+), triple negative breast cancer (TNBC), and HER2+ MBC. Of those, 45 patients were treated with ICI monotherapy (29 ER+, 11 TNBC, 5 HER2), 31 were treated with ICI + chemotherapy (12 ER+, 19 TNBC), and 11 were treated with combinations of ICI and targeted therapy (8 ER+, 1 TNBC, 2 HER2). Median age at time of ICI treatment across all patients was 60. ICI was the median 5th line therapy for all patients (range 1-16). Median PFS of ICI for all patients was 3.17 months (95%CI 2.27-5.5). Multivariable analysis did not show statistically significant differences in PFS based upon treatment regimen (monotherapy vs. chemoIO HR 1.03, 95%CI 0.54-1.96, p= 0.92, monotherapy vs combination IO HR 1.66, 95%CI 0.69-4.02, p=0.26), ER status (ER- vs ER+, HR 1.20, 95%CI 0.63-2.28, p=0.57), or HER2 status (HER2- vs HER2+, HR 1.63, 95%CI 0.51-5.20, p=0.41. However, longer PFS was significantly associated with TMB>30 (HR 0.35, 95%CI 0.13-0.92, p=0.03) and dominant APOBEC signature score (APOBEC- vs APOBEC+, HR 0.49, 95%CI 0.25-0.98, p=0.04). Shorter PFS was significantly associated with later treatment line at the time of ICI exposure (continuous, HR 1.22, 95%CI 1.11-1.36, p=0.0001). Conclusions: In this heavily pretreated real-world cohort, ICI in TMB high MBC shows modest clinical activity. Our analysis suggests that ICI may be more effective in MBC patients that are less heavily pre-treated, have TMB>30, and have a predominantly APOBEC mutational signature. Further translational work is necessary to explore the mechanisms of these findings.

A phase 2, multicenter study of TILs treatment in advanced tumors with alterations in the SWI/SNF complex: The TILTS study.

TPS2674 Background: Tumors associated with SWI/SNF complex (SWI/SNFc) mutations, mainly SMARCA4 and SMARCB1 loss, are a heterogeneous group of malignancies with rhabdoid features that typically affect young patients (pts). These are aggressive malignancies with poor prognosis for which no standard treatment is available. Despite not having a high tumor mutation burden, tumor infiltrating lymphocytes (TILs) are usually present in high numbers. The biologic reasons for this feature are not clearly understood but might be associated to changes in gene expression due to aberrant chromatin remodeling. However, these TILs indicate that tumor antigens are recognized by lymphocytes unveiling a vulnerability that can be exploited by immunotherapy. The objective of the TILTS study is to develop a personalized adoptive cell therapy using TILs in pts affected by these tumors. Methods: Single arm, multi center, phase 2 study of TILs in pts with advanced tumors associated with SWI/SNFc mutations. Pts are treated at 3 centers in Spain: Catalan Institute of Oncology (ICO), Barcelona, Vall d'Hebron Institute of Oncology (VHIO), Barcelona, and Centro Integral Oncológico Clara Campal (HM CIOCC), Madrid. Primary endpoint is overall response rate (ORR) by RECIST 1.1. Secondary endpoints include toxicity evaluation, duration of response (DOR), progression-free survival (PFS) or overall survival (OS). After informed consent is obtained, tumor resection is performed. Total volume of tumor resected should be at least 1.5 cc to assure TIL isolation. Eligible pts enter the treatment phase. TILs are produced under GMP conditions. During the TILs manufacturing process, pts are allowed to receive standard treatment if clinically indicated. Before TIL infusion, pts receive non-myeloablative preconditioning lymphodepletion with daily intravenous (IV) cyclophosphamide (60 mg/kg; IV x2 doses) and daily fludarabine (25 mg/m2; IV x5 doses). Infusion of autologous TILs is given on Day 0 followed by administration of IL-2 at 600,000 international units (IU)/kg every 8-12 hours for a maximum of 6 doses. After 4 weeks, a new tumor biopsy is optional. First image evaluation is performed after 8 weeks from TIL infusion. Pts without progression enter the follow-up phase. An ancillary translational study will explore mechanisms of immunogenicity, antigen recognition, TILs anti-tumor activity, and changes in the stool microbiome and specific TCR population during treatment. Also, tumor immune microenvironment will be analyzed. Clinical trial information: 2023-504632-17-00 . [Table: see text]

Results of a phase 2 study of evorpacept (E, ALX148), cetuximab (C), and pembrolizumab (P) in patients with refractory microsatellite stable metastatic colorectal cancer (MSS CRC).

3530 Background: Single-agent anti-PD-1/PD-L1 drugs are ineffective in MSS CRC. E is an engineered protein (high-affinity CD47-blocker fused to an inactive IgG Fc region), which blocks the CD47/SIRPα innate immune inhibitory phagocytosis checkpoint expressed on CRC and phagocytes, respectively. Preclinical evidence suggests ECP may be effective in MSS CRC. Methods: This phase 2, single-arm, two-stage, multicenter, investigator-initiated trial of E (15 or 10 mg/kg weekly at dose level [DL] 1 and -1, respectively), C (400 mg/m2 then 250 mg/m2 weekly), and P (200 mg every 3 weeks) in 21-day cycles enrolled patients with MSS CRC, regardless of tumor sidedness and RAS/BRAF status, refractory to ≥ 2 prior lines of therapy, including EGFR inhibitor if indicated (NCT05167409). All patients in both Stage 1 (safety run-in) and Stage 2 (expansion) received ECP until progression or unacceptable toxicity. The co-primary objectives were to determine the recommended dose (RD) of E with CP and objective response rate (ORR) by RECIST v1.1 (by one-sided exact test with α=0.05, H0 p ≤ 3% [historical controls], HA p ≥ 15%; power is 87% with N=48). Results: The safety-evaluable population included 16 patients, of whom 69% were male and median age 53 years. The primary tumor was in the right, left, and transverse colorectum in 31%, 31%, and 6% of patients, and was unknown in 31%. Mutations in KRAS, NRAS, and BRAF genes were present in 38%, 6%, and 0% of patients. The median number of prior lines of therapy was 3, including prior EGFR inhibitor in 44%. In Stage 1, 9 and 3 patients were enrolled at E DL1 and DL-1, respectively. E DL1 was established as the RD for Stage 2, in which 4 patients were enrolled. The most common any-grade treatment-emergent adverse events were headache (32%), fatigue (26%), anemia (21%), diarrhea (21%), dyspnea (16%), abdominal pain (16%), nausea/vomiting (16% each), and acneiform rash (16%). There were two on-study deaths assessed as related to all three study drugs (hemophagocytic lymphohistiocytosis and cytokine release syndrome; 1 each). While both are known associations with checkpoint inhibitors, other significant factors contributing to these event outcomes included cancer progression with high tumor burden in the former and patient decision to transition to comfort care in the latter. In the safety-evaluable population, ORR was 6.3% (1 ongoing partial response, 95% confidence interval [CI] 0.2-30.2%), disease control rate was 12.5% (95% CI 1.6-38.4%), median progression-free survival was 2.6 months (mo; 95% CI 2.1-2.9 mo), and median overall survival was 10.9 mo (95% CI 3.3 mo-infinity). Formal hypothesis testing was not performed. Conclusions: Further dose optimization of ECP is needed to establish a RD in the refractory MSS CRC population. While initial activity was seen, at the DLs evaluated, criteria for study termination were met. Clinical trial information: NCT05167409 .

Trophoblast cell-surface antigen 2 is a biomarker and potential therapeutic target in human colon cancer.

e15514 Background: Trophoblast cell-surface antigen 2 (TROP2), a transmembrane glycoprotein in epithelial cells, is implicated in malignant progression, notably in breast cancer therapy. However, the clinicopathologic aspects of TROP2 in colorectal cancer (CRC) are unclear. This study aims to explore the association between TROP2 expression and clinicopathological features in CRC and investigate the inhibitory effects of the anti-TROP2 antibody-SN-38 conjugate (ADC-TROP2) on colon cancer cells. Methods: A retrospective analysis of 1296 CRC patients who underwent colorectomy at Renji Hospital, Shanghai Jiaotong University School of Medicine, was conducted. Immunohistochemistry determined the expressions of TROP2, HER2, and PD-L1 in colon cancer tissues. Statistical analyses, including the chi-square test and Cox proportional hazards model, assessed associations. Sacituzumab Govitecan (ADC-TROP2 drug) cytotoxicity on human cancer cells was determined using the MTT method. Results: TROP2 was predominantly expressed at the cell membrane of cancer tissues, with 50% of cases TROP2-positive. The overexpression of TROP2 (staining extension 2+ or 3+) were found in 356 (27.5%) cases. The clinicopathological features of all 1296 patients based on the TROP2 expression in their cancer cells were summarized in Table 1. Compared to TROP2 negativity expression, the high TROP2 expression was significantly associated with the advantaged tumor stage (III/IV, P = 0.022), high tumor invasion depth (T3/T4, P = 0.002), lymph node metastasis (N1/N2, p = 0.026), HER-2 expression (2+/3+, p = 0.013) ,PD-L1 CPS (CPS≤5,P = 0.007). Sacituzumab Govitecan exhibited stronger inhibition in TROP2-positive human CRC cells in TROP2-negative CRC cells compared to TROP2-negative cells and the control SN-38 agent. Conclusions: TROP2 expression positive in 50% of CRC cases is associated with with advantaged tumor stage, high tumor invasion depth, lymph node metastasis. Sacituzumab Govitecan demonstrates potent targeting of TROP2-positive CRC cells, suggesting TROP2 as a potential biomarker for clinical prognosis and therapeutic targeting in colon cancer. [Table: see text]

Ex vivo assessment of cellular mass response for personalized therapy selection of hyperthermic intraperitoneal chemotherapy (HIPEC) agents.

3132 Background: Despite progress in the development of HIPEC protocols for the treatment of peritoneal carcinomatosis, agent selection remains largely empiric with few biomarkers for guiding treatment. Ex vivo assessment of drug response using single-cell mass measurements offers a promising option for therapy selection. Previously, we have shown that mass response testing (MRT) is a malignancy- and drug-agnostic means of assessing drug response (1) and can predict a patient’s clinical response to therapy in a range of solid and hematological malignancies (2). Methods: Tissue specimens were collected from patients with peritoneal carcinomatosis as part of an ancillary study for a HIPEC clinical trial (NCT04847063) to explore the feasibility of performing MRT with these specimen types. Briefly, after overnight shipment of viable tumor tissue, tumor cells were isolated and treated with various therapies ex vivo. Single-cell mass distributions of vehicle and drug-treated populations were compared to determine the functional activity of each agent. Results: MRT was attempted for 60 patients with metastatic disease, 10 of whom had peritoneal carcinomatosis and ultimately received HIPEC. The HIPEC cases included histologies such as peritoneal mesothelioma (n=4), colorectal cancer (n=3), ovarian cancer (n=2), and small bowel adenocarcinoma (n=1). In total, 8 out of 10 peritoneal specimens had a sufficiently high tumor cell count, viability, and purity to perform MRT. These specimens displayed clear and statistically distinguishable mass response patterns of response and non-response to several different agents commonly used for HIPEC treatment such as cisplatin, oxaliplatin, doxorubicin, and mitomycin C. Study design:These feasibility results serve as the foundational data for launching a single-site phase II interventional study at the NCI’s Center for Cancer Research. The study will evaluate the potential benefit of personalized treatment regimens determined by MRT for patients with peritoneal carcinomatosis, particularly mesothelioma, a context where therapeutic options have relative equipoise in clinical efficacy. Tumor biopsies will be obtained via laparoscopy prior to HIPEC and submitted to a CLIA-certified lab for MRT to assess the responses of various clinically acceptable agents. The HIPEC regimen will be selected based on these MRT results returned within two days of sample collection. Enrolled patients will then undergo cytoreduction and HIPEC, and progression-free and overall survival will be monitored. As a single-arm, non-randomized trial, patient responses will be compared with a matched synthetic control to assess the impact of MRT on efficacy of HIPEC regimens. Conclusions: MRT is feasible for peritoneal carcinomatosis tissues, with future studies focusing on its role in guiding HIPEC treatment. 1. Nat Comm Bio,2022. 2. JCO PO, 2024. Clinical trial information: NCT04847063 .

Outstanding safety and efficacy data of IMC002, an autologous CLDN18.2-targeting CAR-T, in CLDN18.2+ advanced solid tumors.

e16012 Background: Claudin 18.2 (CLDN18.2) is a promising therapeutic target for advanced solid tumors with CLDN18.2 expression. IMC002 is an autologous CLDN18.2-targeting CAR-T cell directed by a CLDN18.2-specific VHH, the specificity of which was confirmed by a membrane proteome array assay. Preclinical studies showed that IMC002 exhibited high tumor specificity, anti-tumor efficacy, and excellent safety profile in both cell and animal models. Methods: This is an open label first in human Phase 1 dose escalation study to evaluate the safety and efficacy of IMC002 in advanced solid tumors with CLDN18.2 expression which is defined as CLDN18.2 expression of ≥1+ membrane staining intensity in ≥10% tumor cells. Accelerated titration followed by Bayesian optimal interval design was adopted with a total of 4 dose levels planned at 1, 3, 5 and 7 million (mil) CAR-T cells/kg respectively. All patients (pts) were given a single dose of IMC002 infusion after lymphodepletion chemotherapy. Dose limiting toxicity (DLT) was evaluated during the 28-day period after IMC002 infusion. Safety, anti-tumor activity, pharmacokinetics and pharmacodynamics were explored in this study. Here, we present preliminary safety and efficacy data for the pts dosed with up to 3 mil CAR-T cells/kg. Results: As of January 17, 2024, 3 advanced unresectable gastric cancer pts received IMC002 infusion, 1 patient at 1 mil CAR-T cells/kg and 2 pts at 3 mil CAR-T cells/kg. No DLT or SAE was reported. Manageable CRS (grade 1) was reported in all 3 pts. Other adverse events related to cell therapy included grade 1-2 lipase increase (3/3), diarrhea (1/3), pruritis (1/3) and γ-GGT increase (1/3). All adverse events recovered quickly. Preliminary efficacy data showed that best overall response of the 3 pts was all stable disease as evaluated by RECIST 1.1. The two pts at the dose level of 3 mil CAR-T cells/kg underwent successful radical surgery at week (W) 11 and 44 after IMC002 infusion respectively. Pathological complete response (pCR) was achieved in the patient with surgery at W44. Distinct CAR-T cell expansion in peripheral blood was observed in all 3 pts, with the peak number of CAR+ cells reaching on day 7-11 in the peripheral blood after the infusion. Moreover, CAR-T cell infiltration was detected in the W11 and W44 surgical samples. Significant elevations of serum levels of IFN-γ, IL-10, IP-10, IL-2 and IL-6 were observed in the 3 pts. The trial is ongoing. Conclusions: IMC002 showed a favorable safety profile, encouraging anti-tumor activities with observed pCR and persistent expansion in the tumor tissue at the low dosage levels in pts with advanced CLDN18.2+ gastric cancer. In addition, our trial has successfully provided a surgical treatment opportunity after CAR-T therapy downstaging of unresectable gastric cancers. Clinical trial information: NCT05472857 .

Nivolumab plus ipilimumab (N+I) in patients (pts) with solid tumors with high tumor mutational burden (HTMB): Results from the Targeted Agent and Profiling Utilization Registry (TAPUR) Study.

3130 Background: TAPUR is a phase II basket study evaluating antitumor activity of commercially available targeted agents in pts with advanced cancers with genomic alterations. Results in a cohort of pts with advanced solid tumors with HTMB treated with N+I are reported. Methods: Eligible pts had measurable disease, ECOG performance status (PS) 0-2, adequate organ function, and no standard treatment (tx) options or prior immune checkpoint inhibitor tx. PD-L1 expression testing was not required. Genomic testing was performed in CLIA-certified, CAP-accredited site selected labs. HTMB was defined a priorias ≥9 mutations/megabase (Muts/Mb) via a qualifying test for TAPUR or approved by the Molecular Tumor Board. Pts received I at 3 mg/kg every 3 weeks (wks) for 4 doses with N at 1 mg/kg IV every 3 wks for 4 doses. N alone was then continued at 240 mg every 2 wks or 480 mg every 4 wks until disease progression. Low accruing histology-specific cohorts with HTMB were collapsed into 1 cohort for analysis. Primary endpoint was disease control (DC) per investigator defined as complete (CR) or partial (PR) response per RECIST v. 1.1, or stable disease (SD) of at least 16 wks duration (SD16+). The hypothesized null DC rate of 15% was evaluated by a 1-sided exact binomial test (α= 0.10; 86% power based on alternative DC rate of 35%). Secondary endpoints were progression-free survival (PFS), overall survival (OS), objective response (OR), duration of response (DOR), duration of SD, and safety. DOR is time from documented OR to progressive disease (PD); duration of SD is time from tx start to PD. Results: 26 pts with 13 tumor types with HTMB were enrolled. Table shows demographics and outcomes. Tissue tumor mutational burden (TMB) ranged from 8 to 374 Muts/Mb (median= 16). 1 CR (small intestine; TMB= 48 Muts/Mb; DOR= 36 wks), 7 PR (biliary tract, site unspecified [3], soft tissue sarcoma, uterus, vagina; median TMB= 17 Muts/Mb; median DOR= 20 wks [range, 5-231]) and 1 SD16+ (pancreas; TMB= 26 Muts/Mb; duration of SD= 26 wks) were observed for a DC rate of 35% (1-sided 90% CI: 22 to 100) and OR rate of 31% (95% CI: 14 to 52). The null hypothesis was rejected (p=0.011). Notably, 1 pt (uterus, 374 Muts/Mb) is still on tx with an ongoing 66-wk PR as of Jan 2024. Most pts, including 8/9 with DC, were microsatellite stable. 10 pts had ≥1 grade 3 tx-related adverse event (AE) or serious AE. Conclusions: N+I showed antitumor activity in pts with advanced solid tumors with HTMB. Additional study is warranted to confirm the efficacy of N+I in pts with HTMB. Clinical trial information: NCT02693535 . [Table: see text]

A machine learning algorithm based on multi-omics biomarkers for the detection of tumor microsatellite instability.

1554 Background: Microsatellite instability (MSI) occurs via defects in mismatch repair (MMR) and is characterized by high tumor mutational burden (TMB) and a robust inflammatory response. Accurate MSI-high classification of immune-evasive tumors is vital due to the effectiveness of immune checkpoint inhibitor (ICI) therapy, such as pembrolizumab, which is FDA approved for all MSI-high tumors irrespective of anatomic origin. Detection methods of MSI-status vary widely, including immunohistochemistry (IHC), polymerase chain reaction (PCR), and next-generation sequencing (NGS). We developed a machine learning (ML) model to predict MSI status in patients with solid tumors using comprehensive genomic and immune profiling (CGIP), independent of direct sequencing data from microsatellite sites. Methods: We analyzed samples from 1,838 patients with colorectal cancer (CRC) by CGIP, which included DNA panel testing (523 genes) for pathogenic single nucleotide variants (pSNV) and determination of TMB (mut/Mb), and RNA sequencing (397 genes) for gene expression (GEX). The Boruta algorithm was used to select key genomic and GEX changes associated with MSI status. A distributed gradient boosting algorithm created a predictive model that was trained on 70% of the cohort. The model was tested on the remaining CRC cohort (Test), and in the PanCancer Atlas CRCs (TCGA), endometrial adenocarcinomas (EMCA), and CRC with indeterminate MSI testing by CGIP. Performance of the trained model was assessed using sensitivity, specificity, and positive (PPV) and negative (NPV) predictive value. Results: Feature selection identified 79 genes with pSNVs, 63 GEX changes, and TMB as informative for MSI prediction. The model showed high predictive accuracy in differentiating MSI-H tumors. Of the 39 cases that failed MSI component of CGIP (Indeterminate), 17 had MMR IHC results available, of which 1 demonstrated loss of MLH1/PMS2 and the other 16 showed intact (normal) expression. Testing of this cohort identified 3 cases as MSI-high, at least one of which was confirmed by IHC. No cases with intact MMR protein IHC were identified as MSI-high by the algorithm. Conclusions: Our ML-driven approach accurately assessed MSI status of CRC and EMCA using CGIP data. This approach also identified potential cases with MSI-high status where direct sequencing of microsatellites failed. This study highlights a method to identify patients with potential MSI-high status for orthogonal screening with the MSI component of a test fails. [Table: see text]

Efficacy of cytotoxic chemotherapy in recurrent/metastatic adenoid cystic carcinoma (ACC).

6111 Background: Despite aggressive local therapy, many ACC patients (~50%) develop recurrent and/or metastatic (R/M) disease. However, there is no standard of care or FDA-approved systemic therapy for this population. Based on small phase II trials, mostly including multiple salivary gland histologies, cytotoxic chemotherapy is recommended for symptomatic patients with high tumor burden, but its efficacy and impact on survival in R/M ACC remain unsubstantiated. Methods: A retrospective cohort study was conducted at MD Anderson Cancer Center with an institutional ACC database (N=769). Patients diagnosed with R/M ACC and treated with single-agent or combination palliative-intent chemotherapy were included. The primary endpoints were overall response rate (ORR) and disease control rate (DCR) per RECIST 1.1. Secondary endpoints were median overall survival (mOS) and progression-free survival (mPFS) on chemotherapy for the entire cohort and stratified by growth pattern (solid v non-solid), line of therapy (1 v >2), chemotherapy regimen, and stage at diagnosis (M0 v M1). Results: 48 out of 115 patients who received chemotherapy were evaluated for response per RECIST.Median age at diagnosis was 43.6 years. 56% were male, 79% had M0 stage at diagnosis, 67% had minor salivary gland primary tumors, 52% had solid growth pattern, 31% had non-solid growth pattern, and 54% received first-line chemotherapy. The most common regimens were Platinum/Vinorelbine (38%), Platinum/Taxane (27%) and CAP (15%).The ORR and DCR rates were 12.5% and 56.3% respectively; 6 had partial response, 21 had stable disease, and 21 had progressive disease. The ORR and DCR rates were 20% and 52% for solid and 6.7% and 73.3% for non-solid growth pattern, respectively. The mOS from diagnosis was 7 years (95% CI, 3.5-10.7). The mOS on chemotherapy was 16 months (95% CI, 10.8-24.5). There was a significant difference in mOS between solid and non-solid growth pattern (10.8 v 24.1 months, p=0.015), but not by line of therapy, regimen, or stage at diagnosis. The mPFS on chemotherapy was 4.3 months (95% CI, 2.8-6.3 months). There was a significant difference in mPFS between solid and non-solid growth pattern (4.0 v 7.3 months, p=0.018), but not by line of therapy, regimen, or stage at diagnosis. Conclusions: In this largest to date real-world data on chemotherapy in ACC, response and survival outcomes were lower than historical data. The efficacy of chemotherapy may vary by growth pattern and other patient and tumor factors, which requires further investigation. Given the low ORR and overall slow-growing disease pattern, tumor volumetrics may be better than RECIST to assess treatment benefit.

Impact of intratumor heterogeneity (ITH) on survival outcomes in patients with non-small cell lung cancer (NSCLC) with high tumor mutational burden (TMB-H).

e20519 Background: Heterogeneity among cancer cells within a tumor significantly impacts cancer development and resistance to treatment. Currently, no standard measure exists for assessing ITH in routine clinical settings. In this study, we applied a quantitative metric to assess intratumor genetic diversity in NSCLC, using a large, multicenter database. Methods: We accessed the Tempus database for next-generation sequencing results from patients with NSCLC who underwent immune checkpoint inhibitor (ICIs) monotherapy as their first-line treatment. We calculated the mutant-allele tumor heterogeneity (MATH), defined as the ratio of the distribution's range to the median of mutant-allele fractions across tumor-specific mutated loci. The primary outcomes were progression-free survival (PFS) and overall survival (OS). Results: A total of 160 pembrolizumab Significant differences in PFS between high and low MATH groups (MATH-H and MATH-L, respectively), using the 50th percentile as the cutoff, were observed among patients with stage 4 adenocarcinoma who had TMB-H above the 25th percentile (Table). In this subgroup, with 27 patients in the MATH-H/TMB-H group and 22 in the MATH-L/TMB-H group, the MATH-H/TMB-H group showed improved PFS (median PFS 5.19 vs. 1.61 months; p = 0.02). Differences in PFS were also observed among patients with TP53, KEAP1, and MET mutations (p < 0.001, p = 0.02, and p = 0.004, respectively). TP53 mutations were found in 27.6% of the MATH-H group and 27.8% of the MATH-L group, KEAP1 mutations in 8.2% and 10.1%, respectively, and MET mutations in 5.1% and 8.9%, respectively. No significant PFS differences were found in groups with low TMB, other stages, or squamous histology. Conclusions: Our findings suggest that higher genetic diversity within stage 4 TMB-H lung adenocarcinoma, as quantified by MATH, might be linked to improved clinical outcomes among those who receive pembrolizumab as first-line therapy and supports further exploration of MATH as a predictive/prognostic biomarker. [Table: see text]

Therapeutic implications of acquired high tumor mutational burden (TMB-H) after targeted therapy (TT) in metastatic colorectal cancer (mCRC).

3542 Background: mCRC treated w/ TT can acquire a high number of mutations at progression. TMB is used as a proxy of neoantigen load for predicting benefit from immune checkpoint blockade (ICB). In TMB-H CRC, benefit to ICB is restricted to microsatellite unstable (MSI-H) hypermutated or POL-D/E ultramutated tumors. We asked whether TT can sensitize microsatellite stable (MSS) CRCs to ICB by inducing an acquired TMB-H state. Methods: We screened the MSK-IMPACT dataset for mCRC patients (pts) who received TT and underwent pre-treatment (pre-TT) and post-progression (post-TT) tissue or liquid biopsies (LBx). We included pts who received TT against EGFR, BRAF V600E, KRAS G12C, or HER2. DNA sequencing of tissue and LBx was performed w/ MSK-IMPACT and Guardant 360. MSI status was assessed with algorithms measuring somatic changes in length of repetitive sequences (e.g., MSIsensor). Due to known discrepancies between tissue TMB (tTMB) and blood TMB (bTMB), we defined acquired TMB-H as: 1) tTMB <10 mut/Mb or bTMB <20 mut/Mb pre-TT; 2) ≥5-fold increase in TMB post-TT; 3) tTMB ≥10 mut/Mb or bTMB ≥40 mut/Mb post-TT. Results: We identified 26 pts w/ paired samples that had been sequenced w/ determination of TMB. 4/26 (15%) met criteria for acquired TMB-H. None had detectable pathogenic mismatch repair or DNA damage repair alterations pre-TT. All 4 post-TT samples were LBx only. One pt’s tumor acquired a somatic MLH1 mutation and converted from MSS to MSI-H. In all cases, the majority of acquired mutations were subclonal w/ many at variant allele frequencies (VAF) of ≤1% (Table). After detection of acquired TMB-H, 2/4 pts received ICB. Pt 1 had RAS wild type mCRC w/ pre-TT tTMB 6.9. She received irinotecan + panitumumab for 25.8 months. Post-TT bTMB was 40.19 and met criteria for MSI-H. She received pembrolizumab and experienced clinical + radiographic progression of disease (POD) within 49 days. Pt 2 had KRASG12C-mutant mCRC w/ pre-TT bTMB 13.4 and tTMB 4.9. She received sotorasib + panitumumab for 3.2 months w/ post-TT bTMB 145.34. She received pembrolizumab + regorafenib and experienced clinical + radiographic POD within 37 days. Conclusions: In CRC, acquisition of TMB-H at progression w/ predominantly low VAF mutations suggests activation of enhanced mutagenesis due to therapeutic pressure from exposure to TT. In this context, TMB may not be an accurate reflection of tumor immunogenicity as it does not distinguish between clonal and subclonal alterations. Our data suggest that pts w/ acquired TMB-H following TT are unlikely to benefit from ICB. [Table: see text]

Immunotherapy for local/regional control of locally advanced orbital and periocular squamous cell carcinoma.

e18034 Background: Periocular squamous cell carcinoma can be of eyelid skin, ocular surface (bulbar) or palpebral conjunctival, or of lacrimal sac/nasolacrimal duct mucosal origin, is relatively rare, and presents unique anatomic considerations due to proximity to the eye and inherent risk to ocular structures associated with high dose radiation therapy. We herein report on 17 patients with orbital or periocular SCC who were treated with immunotherapy (IO) to decrease surgical morbidity or to avoid high dose radiation therapy. Methods: Retrospective review of all previously unreported patients with orbital, conjunctival, or periocular SCC who were treated with IO either in the neoadjuvant setting prior to surgery or for treatment of periocular SCC with perineural spread into the orbit and skull base. Results: 17 patients, 12 men and 5 women (Age range: 44-92; median=70 years old) with orbital (n=6), conjunctival (n=5), or lacrimal sac/duct (n=2) squamous cell carcinoma (SCC), or periocular SCC with perineural spread into the orbit and skull base (n=4) who were treated with IO either as single drug (n= 11) or in combination with chemotherapy (n= 6 ). In all patients either cemiplimab or pembolizumab was used. In 13 patients IO was used in the neoadjuvant setting prior to planned surgery. In 4 patients with perineural spread as they had non surgically resectable disease, IO was used to avoid high dose radiation therapy with its inherent significant risk of ocular toxicity. Overall, 3 patients achieved complete response, 10 patients achieved partial response, and 4 patients had stable disease, using RECIST criteria. One of 5 patients with conjunctival SCC also had nodal metastasis at presentation and achieved a dramatic complete response of both the conjunctival tumor and the nodal metastasis and managed to avoid surgery altogether. This patient had a very high tumor mutation burden (TMB). One patient developed diabetic ketoacidosis as a side effect of IO; otherwise the adverse effects were low grade. Conclusions: IO either as single drug or in combination with chemotherapy has a fairly high response rate in patients with ocular adnexal, conjunctival or orbital SCC and in patients with periocular SCC with perineural spread in the orbit and skull base. Future prospective trails using IO for orbital and ocular adnexal SCC should be planned and should aim to correlate molecular data such as TMB with response.