Metastatic Solid Malignancies Research Articles

Phase 1 study of LB1410, a bivalent TIM-3/PD-1 bispecific antibody, in patients with advanced solid tumors or lymphoma.

TPS2663 Background: Cancer immunotherapies targeting PD-1 or PD-L1 have been proven effective in causing durable antitumor immune responses with less toxicity in many types of tumors. However, the response rate of anti-PD-1/PD-L1 treatments is far from satisfactory and most patients show primary or acquired resistance to the treatments. Tim-3, one of the next generation of immune checkpoint targets, co-expressed on exhausted T cells with PD-1. It is also expressed by innate immune populations, including NK and DC. Dual blocking PD-1 and Tim-3 not only on T cells but also on DC, NK cells may achieve better clinical benefit. LB1410 is a recombinant humanized anti-PD-1/TIM-3 bispecific antibody (BsAb) developed by L&L Biopharma Co., Ltd. for the patients who are resistant to or refractory from PD-1/PD-L1 treatments. It blocked the immune checkpoint PD-1 and TIM-3-mediated immunosuppressive signal pathways simultaneously, showed better T/DC cell activity and in vivo anti-tumor efficacy compared to Tim-3 and PD-1 antibody combination in preclinical studies. Methods: This is a FIH, multicenter, non-randomized, open label, phase 1 study of LB1410 in Participants With Advanced Solid Tumor or Lymphoma（Keyplus-001）. The planned sample size is approximately 100 patients in two parts: part 1 dose escalation will evaluate safety, tolerability, pharmacokinetics (PK), pharmacodynamics, and determine the maximum tolerated dose (MTD) and/or the recommended phase 2 dose (RP2D), and Part 2 dose expansion will further characterize the safety profile and preliminary tumor response in several cohorts including NSCLC, CRC, EC etc. Enrollment criteria include adults with life expectancy of > 3 months, ECOG performance status 0-1，histologically or cytologically confirmed advanced and/or metastatic solid tumor malignancies or lymphoma for which standard treatment fails, or no standard treatment is available, or standard treatment is not applicable at this stage. Exclusion criteria include pregnancy, lactation, or breastfeeding, ongoing or recent evidence of significant autoimmune disease that required treatment with systemic immunosuppressive treatments. The primary endpoints are incidence of dose limiting toxicities and adverse events, MTD, and recommended phase 2 dose. Secondary objectives will evaluate PK parameters, preliminary antitumor activity, and immunogenicity of LB1410. Besides, the pharmacodynamics (PD) biomarkers related to LB1410 treatment, clinical activity will be explored. This clinical trial is in progress; cohorts 1 to 5 in dose escalation part have been completed. Clinical trial information: NCT05357651 .

Use of clinical pathways to identify patients with cancer who may benefit from serious illness conversations.

12027 Background: Treatment pathways are widely used to provide decision support and encourage guideline adherence. Pathways data may be used to identify patients for targeted interventions to improve cancer care. For example, pathways data may enable the identification of patients with poor prognoses for whom serious illness conversations (SICs) should be prioritized to ensure goal-concordant care. Methods: For patients starting new therapies at Dana-Farber, oncologists select a node in clinical pathways to indicate the line of treatment. Subspecialty oncologists identified “poor prognosis” nodes in pathways, defined as therapies for patients with expected survivals of < 12 months and for whom an SIC would be appropriate (e.g., 3rd-line treatment for metastatic colon cancer). Pathway node navigations for patients with metastatic solid tumor malignancies with poor prognosis nodes (n = 21 disease pathways) were combined with electronic medical record data to identify SIC documentation in an advance care planning module within 6 months of pathway navigation and patients’ dates of death if present. For each node, we calculated the median overall survival (OS), the proportion of patients with an SIC, and the proportion of patients who died before reaching the next node. Results: There were 10,132 navigations for 7,031 patients (median age 67 years, 52% female, 86% White) between 8/16/2019 and 1/4/2023. With each treatment line, patients’ median OS decreased and SIC rates increased (examples for 3 diseases in Table). Among patients who reached poor prognosis nodes, the median OS was 4.9 months, mean SIC rate was 43.8%, and 60.2% of patients died without reaching a subsequent node. For nodes immediately prior to poor prognosis nodes, the median OS was 7.1 months, the mean SIC rate was 25.2%, and 31.3% of patients died without reaching the next node. 46.3% of patients died without reaching a poor prognosis node. The proportion of patients having an SIC at death was 40.9% among all decedents, 50.8% for decedents reaching a poor prognosis node, and 29.3% for decedents who do not reach a poor prognosis node. Conclusions: Clinical pathways can be used as a scalable method to identify patients with metastatic solid tumors and poor prognoses. In our study, only half of patients who reached a poor prognosis node had an SIC before death and nearly half of decedents never reached a poor prognosis node, underscoring the importance of identifying this population to improve end-of-life care. A clinical trial using pathways to identify and deliver interventions to increase SICs is ongoing. [Table: see text]

Personalized Palliative and Survivorship Care for Patients With Metastatic Cancer Treated With Radiation Therapy.

While the benefits of early palliative care for patients with metastatic cancer are well established, cancer survivorship remains inadequately integrated into the care of patients with distant metastases. Moreover, the optimal model of care delivery is poorly defined. A prognostic model previously developed and validated at Good Samaritan University Hospital identified four groups of patients with metastatic solid tumor malignancy having very favorable, favorable, standard or unfavorable prognoses with median survival of 31, 14, 4 and 1 month, respectively. This framework holds promise for the personalized delivery of supportive, palliative and survivorship care services in the context of radiation therapy. We review the published literature providing the rationale for a novel multidisciplinary care model where the radiation oncology Clinical Nurse Specialist identifies and coordinates interventions to address unmet physical and emotional issues faced by survivors with metastatic cancer with the goal of improving quality of life and overall survival.

Trial in progress: A phase 1, first-in-human, open-label, multicenter, dose-escalation and dose-expansion study of ASP3082 in patients with previously treated advanced solid tumors and KRAS G12D mutations.

TPS764 Background: Kirsten rat sarcoma (KRAS) G12D is a point mutation observed in various cancer types including pancreatic ductal cancer, colon adenocarcinoma, and lung cancers. ASP3082 is a novel small-molecule proteolysis-targeting chimeric degrader that binds to, and selectively targets, the KRAS G12D-mutated protein for degradation via recruitment of E3 ubiquitin ligase proteins. In preclinical studies, ASP3082 selectively degraded the KRAS G12D-mutated protein and showed growth inhibitory activity in KRAS G12D-mutated cancer cells but not in KRAS -wildtype cancer cells. Notable antitumor effects of ASP3082 have been demonstrated when intravenously administered weekly in mice xenografted with KRAS G12D-mutated cancer cells. Methods: This first-in-human, open-label, multicenter, phase 1 study evaluates the safety and tolerability of ASP3082 in patients with pancreatic cancer, colorectal cancer, non-small cell lung cancer or other solid tumors. Participants with unresectable, locally advanced, or metastatic solid tumor malignancy with documented KRAS G12D mutation are eligible for enrollment. Part 1 consists of dose-escalation cohorts of 3−12 patients receiving intravenous administration of ASP3082 in a 21-day cycle. Part 2 consists of random assignment of ≤20 patients into 2 cohorts with different ASP3082 dose levels to determine the recommended phase 2 dose. Additional tumor-specific expansion cohorts may enroll ≤20 participants per tumor type. Primary endpoints will evaluate safety and tolerability as noted by dose-limiting toxicities, adverse events, serious adverse events, laboratory test results, electrocardiograms, vital signs, physical exams, and Eastern Cooperative Oncology Group performance status. Secondary endpoints will evaluate objective response rate, duration of response, disease control rate per Response Evaluation Criteria in Solid Tumors version 1.1, pharmacokinetics of single and repeated doses of ASP3082, and changes in KRAS G12D in tumor samples. Exploratory objectives will evaluate potential biomarkers that may correlate with treatment outcomes. Tumor assessment follow-up will continue for ≤45 weeks or until progressive disease. Enrollment in Cohort 1 is complete, and enrollment to Cohort 2 began in September 2022. Clinical trial information: NCT05382559 .

Prophylactic Radiation Therapy vs. Standard-of-Care for Patients with High-Risk, Asymptomatic Bone Metastases: A Multicenter, Randomized Phase II Trial

<h3>Purpose/Objective(s)</h3> External beam radiotherapy (RT) is standard-of-care (SOC) for pain relief of symptomatic bone metastases. We aimed to test whether radiation for asymptomatic bone metastases prevents skeletal-related events (SRE). <h3>Materials/Methods</h3> We conducted a multicenter, randomized phase 2 trial (NCT03523351) of prophylactic RT to high-risk, asymptomatic bone metastases vs SOC. Patients were eligible if they were at least 18 years old with a metastatic solid tumor malignancy and more than 5 metastatic lesions, including at least one asymptomatic high-risk bone lesion, defined as: bulky disease (≥2cm in longest diameter), junctional spine or posterior spinal element disease, disease involving hip or sacroiliac joint, or disease in long bone involving 1/3-2/3 cortical thickness. Patients were stratified by histology and planned SOC (systemic therapy or observation) and randomly assigned in a 1:1 ratio to RT to all enrolled high-risk bone metastases or SOC alone. The primary outcome of SRE (defined as fracture, cord compression, or intervention with surgery or radiation) was analyzed from randomization to death or 12 months. A sample size of 66 was deemed necessary to achieve 80% power to detect a difference of 30% (experimental arm) versus 60% (SOC arm) using a two-sample, one-sided proportion test with alpha<0.05. We used the log-rank test for time-to-event analyses and Wilcoxon rank sum test to compare hospitalizations, brief pain inventory and quality of life (using EQ-5D-5L) between arms. <h3>Results</h3> Between May 8, 2018 and August 9, 2021, 78 patients with 122 bone metastases were enrolled and randomized to prophylactic RT (n=39) or SOC (n=39). The most common primary cancer types were lung (27%), breast (24%), and prostate (22%). Seventy-one patients (91%) were evaluable for the primary endpoint. At one year, SRE occurred in 1 of 62 lesions (1.6%) in the RT arm and 14 of 49 lesions (29%) in the SOC arm (p<0.001). There was a significant difference in time-to-SRE by type of high-risk feature (p=0.016), with most events occurring in junctional spine and bulky disease. There were significantly fewer patients hospitalized for SRE in the RT arm compared to the SOC arm (4 vs 0, p=0.045). At a median follow-up of 2.4 years, overall survival was significantly longer in the RT arm (HR 0.50, 95% CI 0.28, 0.91; p=0.02). Median OS among 11 patients with an SRE was 1.1 years compared to 1.5 years among 67 patients without an SRE. Pain was reduced at 3 months in the RT arm (p<0.05) compared to the SOC arm. EQ-5D-5L was similar between the groups at all time points. <h3>Conclusion</h3> Radiation delivered prophylactically to asymptomatic, high-risk bone metastases reduced skeletal-related events, meeting the primary endpoint of the study. Importantly, we observed an improvement in overall survival, with potential mechanisms of palliation or debulking warranting further investigation in a phase 3 trial.

Differences in the utilization of palliative care support services among patients with metastatic solid tumor cancer in a community oncology setting: A retrospective review.

82 Background: Palliative care has been underutilized in the setting of advanced cancer despite its established benefit in improving the quality of life in cancer patients. Few studies have evaluated socioeconomic disparities in receiving palliative care in the outpatient oncology setting. We aimed to evaluate for disparities in utilization of palliative care among patients with metastatic solid tumor malignancies at Tennessee Oncology, a large outpatient community oncology practice with an established palliative care program. Methods: We completed a retrospective review of medical records of 1513 patients that were seen in Tennessee Oncology clinics from 12/2020 to 12/2021. We compared the baseline characteristics of patients with metastatic solid tumor malignancies who did and did not receive palliative care. Chi-square and two-sample t-tests were used for data analysis with the 5% significance level using R statistical software. Results: Male patients utilized palliative care less often than female patients (17% versus 24% for females, p =.0002; 95% CI,.05-1.0). Of payer types, Medicare had the least palliative care utilization (14%) compared to commercial (25%) and other payers (23%). Utilization also varied by cancer type, with melanoma (9%), lung cancer (15%) and renal cancer (21%) being least likely to receive palliative care (p &lt;.00005; 95% CI,.19-1.0). We did examine racial differences in palliative care utilization, but those did not reach statistical significance. Conclusions: There are multiple disparities in the utilization of on-site palliative care support services among patients with metastatic solid tumor cancer in this outpatient community oncology setting. Further research is needed to gain insight into why this is, including an in-depth analysis of both patient and provider utilization/referral practices.[Table: see text]

Humoral and cellular responses to mRNA-based COVID-19 booster vaccinations in patients with solid neoplasms under active treatment

BackgroundPatients with cancer are at high risk for severe coronavirus disease 2019 (COVID-19) infection. Knowledge regarding the efficacy of the messenger RNA (mRNA) vaccines in actively treated cancer patients is limited as they had been excluded from the pivotal studies of these vaccines. We evaluated humoral and cellular immune responses in cancer patients after double vaccination and a booster dose and identified disease- and treatment-related factors associated with a reduced immune response. We also documented the number and outcome of breakthrough infections.Patients and methodsPatients with metastatic solid malignancies undergoing active treatment were included if they had received two doses of the severe acute respiratory syndrome coronavirus 2 mRNA vaccines BNT162b2 or mRNA-1273 and a booster dose. Other causes of immunosuppression and previous COVID-19 infections (positive anti-nucleocapsid titers) were exclusion criteria. Anti-spike antibodies, neutralizing antibodies (nAbs) and T-cell responses were assessed about 6 months after the two-dose vaccination and 4 weeks after the booster.ResultsFifty-one patients had pre-booster and 46 post-booster measurements. Anti-spike titers after two vaccine doses were highly variable and significantly lower in older patients, during treatment with chemotherapy compared to targeted and endocrine treatments and in patients with low CD4+ or CD19+ cell counts. The booster dose led to a significant increase in anti-spike antibodies and nAbs, achieving almost uniformly high titers, irrespective of baseline and treatment factors. The cellular immune response was also significantly increased by the booster, however generally more stable and not influenced by baseline factors and treatment type. Seventeen patients (33%) experienced breakthrough infections, but none required hospital care or died from COVID-19.ConclusionsAn mRNA vaccine booster dose is able to increase humoral and cellular immune responses and to overcome the immunosuppressive influence of baseline and treatment factors in cancer patients. Breakthrough infections were uniformly mild in this vaccinated high-risk population.

Abstract 281: Culture of circulating tumor cells isolated from cancer patients with metastatic disease

Abstract OBJECTIVE: The purpose of this study is to investigate the feasibility of using decellularized tissue ECM to culture circulating tumor cells (CTCs) collected from patients with metastatic solid tumor malignancies. BACKGROUND: Circulating tumor cells (CTCs) have been shown to recapitulate the heterogeneity and biology of patients’ cancers. However, there is a lack of technologies that can culture patient CTCs. Our group has previously shown that tumor cells cultured on decellularized tissue closely mimic the in vivo condition. Therefore, we hypothesized that we can utilized decellularized tissue as strata to culture CTCs. METHODS: Peripheral blood samples were collected from patients with metastatic disease who had not received any systemic therapy in the last six months or are progressing on systemic therapy. PMBC layer, which contains lymphocytes, monocytes, dendritic cells and CTCs (in metastatic patients) is separated from whole blood by Ficoll gradient. The cells are then mixed with decellularized lung or liver material and cultured using stemcell media. RESULTS: 26 subjects were enrolled in this study. We were able to generate cell colonies from 12 patients’ samples (either colonies on liver or lung strata). Of the patient samples that did not develop tumor colonies, 9/14 subjects had no metastatic tumors in either lung or liver. Colonies from the cultures were characterized by histological staining and SEM imaging. Of the samples that the tumor colonies were large enough for H&amp;E, we observed phenotypes that are indicative of tumor cell colony. Ongoing work aim to further validate the CTC cultures using genomic sequencing and RNAse CONCLUSION: We showed decellularizd organ technology can be utilized to generate CTC cultures. Citation Format: Nikhila Reddy Sultanpuram, Isaiah Kim, Hossein Sendi, Nicole Kanpe, Tilden Hagen, Kyle Wagner, Andrew Wang. Culture of circulating tumor cells isolated from cancer patients with metastatic disease [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 281.

Assessing Egyptian oncology patients’ perceptions of treatment goals: A multicenter study.

12133 Background: Management of metastatic solid malignancies is generally focused on prolonging life along with improvement of quality of life. Hence palliative intent treatment. The understanding of the disease nature and its treatment intent is variable among patients and it’s unclear what are the main contributing factors. Our study across multiple cancer centers in Egypt evaluated patients’ understanding of whether their treatment was for curative or palliative purposes and sought to identify factors associated with understanding of treatment intent. Methods: This was a survey based study of 489 consecutive patients with stage IV solid tumor malignancies at four different cancer centers in Egypt. Patients were given a questionnaire, during a routine visit. Requested information included primary site of malignancy, stage, duration of treatment, whether they think the treatment is curative, and whether they think the treatment will help them live longer and/or relieve cancer-related symptoms. Patients also provided basic demographic information such as age, gender, marital status, area of residence and education level. Their answers regarding cancer type, stage and length of treatment were compared with their medical records. Results: Median age was 53 with 67% females. Of the 489 patients, 48% finished at least middle school education. The primary malignancies consisted of 35% breast, 19% gastrointestinal/liver, 9% genitourinary, 9% lung, 8% ovarian/uterine, 11% others. 57% of patients had been on treatment for at least 6months. 45% of patients didn’t know they had a malignancy. 69% could not identify their disease stage, and only 19% of patients knew their cancer is stage 4. Only 11% of patients knew their treatment was not curative while 35% thought it was, and 53% did not know. Only 29% of patients believed their treatment would help them live longer and 62% believed the treatment would alleviate their symptoms. Younger patients were more aware of the Disease Nature (DN), however were less aware of the treatment intent (TI), compared to patients older than 60yo (P value 0.02). Urban residents answered more accurate DN questions compared to rural residents (P value 0.01), but both had similar limited understanding to TI (P value 0.2). Education level was the most consistent factor showing difference with higher level of education correlated with better understanding of DN and TI (P value 0.01). Conclusions: In our study, only 11% of patients receiving treatment with palliative intent reported understanding the intent was not curative. Factors influencing perception of treatment goals are many and include those specific to patients (education level), their cancers, and providers (educational materials). Ongoing studies will focus on identifying factors most strongly associated with a patient’s perceived TI with development of a knowledge score.

BIOM-04. SENSITIVE DETECTION OF LEPTOMENINGEAL DISEASE USING CELL-FREE DNA FROM CEREBROSPINAL FLUID

Abstract Leptomeningeal disease is a devastating complication of cancer that is frequently underdiagnosed due to the low sensitivity of cerebrospinal fluid cytology, the current gold-standard diagnostic method. We performed genomic sequencing on cerebrospinal fluid specimens obtained from patients with suspected or confirmed leptomeningeal disease to identify tumor-derived cell-free DNA. From the same fluid draw, cerebrospinal fluid cytology was assayed for comparison. 30 patients underwent cytology and cell-free DNA analysis. This study consisted of two patient populations: 22 patients with cytology-confirmed leptomeningeal disease without parenchymal tumors abutting their cerebrospinal fluid and 8 patients with parenchymal brain metastases with no evidence of leptomeningeal disease. The primary outcome was the diagnostic accuracy of cell-free DNA, defined as the number of correct diagnoses out of the total number of tests assayed. A total of 30 patients, 23 female and 7 male, with a median age of 51 participated in this study. Participants mostly presented with metastatic solid malignancies. In patients previously diagnosed with leptomeningeal disease via cytology with no parenchymal tumor abutting cerebrospinal fluid, cell-free DNA was accurate in diagnosis of leptomeningeal disease in 45 of 48 follow-up samples (94%; 95% CI, 83%-99%). Cytology was accurate in 36 of 48 follow-up samples (75%; 95% CI, 60%-86%). Cell-free DNA was significantly more accurate (P=.02) and sensitive (P=.02) than cytology in patients without parenchymal tumors abutting the cerebrospinal fluid. In three patients with parenchymal brain metastases abutting the cerebrospinal fluid and no suspicion for leptomeningeal disease, cytology was negative in all three patients; whereas, cell-free DNA was positive in all three. This study demonstrates the improved sensitivity and accuracy of cell-free DNA in diagnosing leptomeningeal disease with the exception of parenchymal tumors abutting cerebrospinal fluid. Overall, these results will lead to improved diagnosis of leptomeningeal disease and potentially earlier intervention and clinical trial enrollment.

Changes Over Time in COVID-19 Severity and Mortality in Patients Undergoing Cancer Treatment in the United States: Initial Report From the ASCO Registry.

PURPOSE:People with cancer are at increased risk for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. ASCO's COVID-19 registry promotes systematic data collection across US oncology practices.METHODS:Participating practices enter data on patients with SARS-CoV-2 infection in cancer treatment. In this analysis, we focus on all patients with hematologic or regional or metastatic solid tumor malignancies. Primary outcomes are 30- and 90-day mortality rates and change over time.RESULTS:Thirty-eight practices provided data for 453 patients from April to October 2020. Sixty-two percent had regional or metastatic solid tumors. Median age was 64 years. Forty-three percent were current or previous cigarette users. Patients with B-cell malignancies age 61-70 years had twice mortality risk (hazard ratio = 2.1 [95% CI, 1.3 to 3.3]) and those age > 70 years had 4.5 times mortality risk (95% CI, 1.8 to 11.1) compared with patients age ≤ 60 years. Association between survival and age was not significant in patients with metastatic solid tumors (P = .12). Tobacco users had 30-day mortality estimate of 21% compared with 11% for never users (log-rank P = .005). Patients diagnosed with SARS-CoV-2 before June 2020 had 30-day mortality rate of 20% (95% CI, 14% to 25%) compared with 13% (8% to 18%) for those diagnosed in or after June 2020 (P = .08). The 90-day mortality rate for pre-June patients was 28% (21% to 34%) compared with 21% (13% to 28%; P = .20).CONCLUSION:Older patients with B-cell malignancies were at increased risk for death (unlike older patients with metastatic solid tumors), as were all patients with cancer who smoke tobacco. Diagnosis of SARS-CoV-2 later in 2020 was associated with more favorable 30- and 90-day mortality, likely related to more asymptomatic cases and improved clinical management.

Stereotactic Body Radiation Therapy and Immunotherapy in Abdominal and Pelvic Lymph Node Metastases

This study characterizes the efficacy and safety of stereotactic body radiation therapy (SBRT) with immunotherapy in the treatment of abdominal and pelvic lymph node metastases, based on a pooled analysis of three prospective phase I trials. While SBRT is frequently utilized for metastases, its role in the treatment of abdominal and pelvic lymphadenopathy remains unclear. We hypothesize that local control will remain excellent for nodal SBRT, even with prioritization of organ-at-risk (OAR) constraints resulting in undercoverage of target metastases and with omission of elective treatment of regional nodal basins.Patients with widely metastatic solid malignancies were enrolled on three Phase I trials between 2016 and 2020 (total 213 patients). Patients were treated with multisite SBRT (up to 4 sites). Metastases > 65cc were partially treated. Immunotherapy was administered either concurrently or sequentially. Immunotherapy regimens included pembrolizumab, ipilimumab with nivolumab, urelumab with nivolumab, or cabiralizumab with nivolumab. The study cohort included patients who underwent SBRT to at least one lymph node in the abdomen or pelvis, including the inguinal regions. Local control (LC) of irradiated metastases and regional control (RC) of the corresponding nodal basin were determined per RECIST 1.1 guidelines. Overall survival (OS) was calculated using the Kaplan-Meier method. For each irradiated lesion, the mean dose, V95%, and V100% to the ITV and PTV were recorded.A total of 39 patients (mean age 59.2 years) underwent SBRT to 56 abdominal or pelvic lymph node metastases with median follow-up of 16.2 months. The median prescription dose was 45 Gy in 3 fractions. Median lesion volume was 17.0cc. Lymph node sites included 24 para-aortic/retroperitoneal (43%), 9 pelvic (16%), 11 inguinal (20%), 10 gastrohepatic/porta hepatis (18%), and 2 other (4%). Across all patients, the 1-year LC was 90.4%. Even without elective treatment of the corresponding nodal basins, 1-year RC was 81.9% (with only one isolated regional failure without concomitant distant progression). Median OS was 25 months, while 1-year and 2-year OS were 69.9% and 53.2%, respectively. ITV mean dose, V95%, and V100% were 47.3 Gy, 95.3%, and 89.5%, respectively (reported as medians across all 56 metastases). PTV mean dose, V95%, and V100% were 45.5 Gy, 84.2%, and 75.0%, respectively. The overall incidence of grade 3+ toxicity was 10.3%. The incidence of grade 3 colitis was 2.6% and grade 3 hepatitis was 2.6%, with no grade 4-5 colitis/hepatitis events.In this pooled analysis of three prospective trials, SBRT to abdominal or pelvic lymph node metastases with immunotherapy is associated with acceptable toxicity and high rates of LC, even with target undercoverage to meet OAR constraints. This suggests a potential for this approach in clinical practice and study in future trials.

1029TiP Phase II trial of pembrolizumab (pembro) and brentuximab vedotin (BV) in patients with metastatic solid malignancies after progression on prior programmed cell death protein (PD)-1 inhibitors (SGN35-033)

Intratumoral regulatory T-cells (Tregs) contribute to resistance to checkpoint inhibitors through various mechanisms (Saleh 2019). Intratumoral Tregs have a unique phenotype expressing higher levels of CD30 than other T-cells and non-tumor infiltrating Tregs in several malignancies including non-small cell lung cancer (NSCLC; De Simone 2016, Vasanthakumar 2017). BV (ADCETRIS®), a CD30-directed antibody-drug conjugate, has been shown to reduce Tregs in clinical trials of classical Hodgkin’s lymphoma and cutaneous T-cell lymphoma, to be uniquely toxic to CD30-expressing Tregs, and to allow for expansion of co-cultured CD8 T-cells in vitro (Romano 2019, Heister 2018 [AACR]).

1150TiP A phase II, open-label, multi-dose study of [89Zr]Zr-Df-IAB22M2C (CD8 cell PET tracer) PET/CT in patients with selected advanced or metastatic solid malignancies scheduled to receive standard of care immunotherapy, as single agent or in combination

Immunotherapy (IOT) of cancer depends on intratumoral CD8+ cells that can overcome multiple obstacles to their localization and function. CD8+ cell content and its changes with treatment are important to understand tumor immunobiology, prognosis, and to guide therapy.

LMD-22. Clinicopathological spectrum of leptomeningeal metastases: A 3 year retrospective study

ObjectivesCytological examination of cerebrospinal fluid is a widely used cost effective, simple procedure and a reliable routine diagnostic test. CSF cytology helps in detection of inflammatory diseases of the CNS, diagnosis of subarachnoid haemorrhage and the identification of malignant cells in metastatic or rarely primary CNS malignancies.Leptomeningeal metastases (LM) is estimated to occur in 5% of all patients with cancer. It has a higher propensity to occur in solid tumours compared to haematological malignancies.In view of poor prognosis, early diagnosis may aid in appropriate tumour staging and aggressive therapeutic intervention.MethodsAll the samples of CSF received in the Department of Laboratory for cytological examination and reported as ‘positive for malignant cells’ during the year January 2018 to December 2020were included in the study. All the cases were routinely evaluated on Neubauer’s chamber, direct smear and a cytospin preparation stained using MGG stain. The clinical records and any further ancillary testing performed were retrospectively analysed.Results87cases with LM were identified over 3 year duration. Mean age of presentation was 43 years. Metastatic solid malignancies (56%) had a higher incidence of leptomeningeal metastases compared to haematolymphoid malignancies (40%) and CNS medulloblastomas(2%). Most common solid tumour with involvement of CSF was adenocarcinoma lung (51%) followed by breast carcinoma (37%). Of all the cases of adenocarcinoma lung with LM, EGFR mutant NSCLC were 40% while 8% showed ALK gene rearrangement. Amongst the haematological malignancies, acute leukaemia’s constituted 67% of cases while systemic NHLs were 34%. Most of the cases (97%) presented with neurological symptoms during the course of treatment while 3 cases (3%) showed LM at the time of first presentation.ConclusionsWith appropriate clinicoradiological correlation, CSF cytology remains the gold standard for identification of malignant cells in cases with already known primary tumour (leptomeningeal dissemination of the disease). In this study, clinical features of both solid and haematolymphoid malignancies were evaluated. The group of solid malignancies included adenocarcinomas lung, breast, gastrointestinal tract and renal cell carcinoma. With the availability of EGFR TKIs and ALK inhibitors, overall survival of the patients may be prolonged with therapeutic interventions despite limited CSF and CNS penetration of these drugs.

Limited evolution of the actionable metastatic cancer genome under therapeutic pressure.

Genomic profiling is critical for the identification of treatment options for patients with metastatic cancer, but it remains unclear how frequently this procedure should be repeated during the course of the disease. To address this, we analyzed whole-genome sequencing (WGS) data of 250 biopsy pairs, longitudinally collected over the treatment course of 231 adult patients with a representative variety of metastatic solid malignancies. Within the biopsy interval (median, 6.4 months), patients received one or multiple lines of (mostly) standard-of-care (SOC) treatments, with all major treatment modalities being broadly represented. SOC biomarkers and biomarkers for clinical trial enrollment could be identified in 23% and 72% of biopsies, respectively. For SOC genomic biomarkers, we observed full concordance between the first and the second biopsy in 99% of pairs. Of the 219 biomarkers for clinical trial enrollment that were identified in the first biopsies, we recovered 94% in the follow-up biopsies. Furthermore, a second WGS analysis did not identify additional biomarkers for clinical trial enrollment in 91% of patients. More-frequent genomic evolution was observed when considering specific genes targeted by small-molecule inhibitors or hormonal therapies (21% and 22% of cases, respectively). Together, our data demonstrate that there is limited evolution of the actionable genome of treated metastases. A single WGS analysis of a metastatic biopsy is generally sufficient to identify SOC genomic biomarkers and to identify investigational treatment opportunities.

Real-world pan-cancer landscape of frameshift mutations (FSM) and their role in predicting responses to immune checkpoint inhibitors (ICI) in patients (pts) with tumors with low tumor mutational burden (TMB).

2599 Background: Pembrolizumab was recently approved in tumors with TMB ≥10 mut/Mb. FSM can complement TMB in predicting ICI responses. We obtained a real-world dataset of genomic alterations from 250,813 samples to examine the distribution of TMB and FSM across a variety of malignancies. We then conducted a multi-institutional retrospective review of pts treated with ICI. Methods: Database samples were sequenced by Foundation Medicine using hybrid capture genomic profiling to evaluate all classes of genomic alterations in at least 315 genes. The clinical cohort included pts with metastatic solid malignancies who received ICI and had undergone commercial next-generation sequencing (NGS). Pts were classified into four distinct groups: TMB-L ( &lt; 10mut/Mb)/ FS-A (absent FSM), TMB-H (≥10mut/Mb)/ FS-A, TMB-L /FS-P (present, ≥1 FSM) and TMB-H/FS-P. Progression-free survival (PFS), overall survival (OS), and response rate (RR) were compared between the groups. Results: 246,252 MSS and 4,561 MSI-High samples were segregated by histology and divided into four distinct groups based on the TMB and FSM. For the MSS cohort the distribution was: TMB-L/FS-A (N = 111,065, 45%), TMB-H/FS-A(N = 15,313, 6%), TMB-L /FS-P (N = 98,389, 40%) and TMB-H/FS-P (N = 21,485, 9%). In the ICI-treated clinical cohort, there were 230 pts in 12 histology groups; 212 had information on TMB and FSM. The most common primary sites were GI (N = 39), melanoma (N = 37), GU (N = 32) and H&amp;N cancer (N = 21). 159 pts received single ICI and 53 dual ICI. 196 tumors were MSS, 11 MSI, and 5 unknown. Group distribution: TMB-L/FS-A 80 pts (38%), TMB-L/FS-P 57pts (27%), TMB-H/FS-A 36pts (17%), TMB-H/FS-P 39pts (18%). FS-P was associated with higher RR 23.81 vs. 12.8 % (p = 0.02). Regardless of TMB, the median PFS for FS-P vs. FS-A was 7.9 and 4.0 mo, respectively (p &lt; 0.01). TMB-L/FS-P had superior PFS (5.1 mo) compared to TMB-L/FS-A (3.6 mo) group (p &lt; 0.01). The 15-month PFS probability was 12% for TMB-L/FS-A vs. 38% for TMB-L/FS-P. No statistically significant difference was detected in OS between the groups. From the pan-cancer cohort, histologies with more than 40% of samples in the TBM-L/FS-P (MSS) group were: CRC, RCC, PDAC, biliary, breast, esophageal, and endometrial cancers. Additional genomic data will be presented. Conclusions: FSM are frequently found on commercial NGS testing in tumors that are MSS and TMB-L. The presence of FSM may complement TMB in predicting benefit from immunotherapy. If validated in additional cohorts, FSM presence could be utilized to identify pts that may benefit from ICI, particularly for tumors with low TMB.

Phase 1 trial of a novel, first-in-class G protein-coupled estrogen receptor (GPER) agonist, LNS8801, in patients with advanced or recurrent treatment-refractory solid malignancies.

3084 Background: The G protein-coupled estrogen receptor (GPER) is a broadly expressed G protein-coupled receptor that is tumor suppressive. LNS8801 is an oral, highly selective small molecule agonist of GPER. GPER activation results in c-Myc depletion, inhibition of tumor proliferation, and enhancement of tumor immune recognition. Preclinically, LNS8801 demonstrates potent single-agent and combinatorial anti-cancer activity and can overcome established resistance to standard-of-care anti-cancer therapies including immune checkpoint inhibitors. Methods: The primary objective of this phase 1/1B first-in-human, open-label, multicenter study (NCT04130516) was to determine the safety and tolerability and recommended phase 2 dose (RP2D) of LNS8801 in patients (pts) with locally advanced or metastatic solid tumor malignancies, both as monotherapy and in combination with the anti-PD-1 antibody, pembrolizumab. Dose levels were escalated in a 3+3 fashion and included 10, 40 and 125 mg dosed 3/7, 125 mg daily, and 125 and 250 mg twice daily. Dose limiting toxicity (DLT) was defined via NCI CTCAE v5.0 during the first 21 days of treatment. An increase in prolactin over the initial 12 hrs of dosing was measured to assess systemic GPER signaling. Tumor c-Myc expression was measured as a surrogate of treatment-related biologic response. Radiographic response (RECIST v1.1) was evaluated every 8 weeks until progression. Results: 33 pts (19 M/14 F) with median age 58.8 y and 4 (1-9) prior therapies enrolled. Median duration of treatment was 66 d (1–367+). With monotherapy (n = 28), no DLTs, treatment-related SAEs, or treatment-related study discontinuations were observed up through the maximum administered dose (250 mg bid). Possibly related AEs were grade 1 or 2 and did not correlate with dose level. Exposure was above that predicted for efficacy and t1/2 was ̃10 hr at all doses. Of 26 evaluable monotherapy pts, 8 (27%) experienced stable disease (SD) for up to a year. All SD pts had a prolactin response. Among tumors expressing GPER, c-Myc depletion was observed in 100% (5/5) of paired pre and on-treatment biopsies. In the combination cohort (n = 5), 2/2 evaluable pts demonstrated net tumor reductions on initial f/up scans, including one RECIST partial response. Based on PK/PD data, 125 mg daily has provisionally been identified as the monotherapy and combination RP2D. Conclusions: LNS8801 is well tolerated and demonstrates signals of anti-tumor activity when administered both as monotherapy and in combination with pembrolizumab. Confirmation of RP2Ds and updated efficacy data will be presented in June. A phase 2A expansion study to evaluate these RP2Ds in clinical settings of high unmet need is now in development. Clinical trial information: NCT04130516.

A phase 1 study of SGN-B6A, an antibody-drug conjugate targeting integrin beta-6, in patients with advanced solid tumors (SGNB6A-001, Trial in Progress).

TPS3144 Background: The extracellular matrix (ECM) plays an important role in solid tumor pathogenesis and is a major focus of research and therapeutic targeting. Integrin beta-6 is a cell surface receptor that interacts with the ECM to mediate cellular adhesion. Integrin beta-6 is overexpressed in numerous solid tumors and its expression is a negative prognostic marker in cancers including colorectal, non-small cell lung, gastric, and cervical cancers. SGN-B6A is an investigational vedotin, an antibody-drug conjugate directed against integrin beta-6 to selectively deliver the cytotoxic agent monomethyl auristatin E, which binds tubulin and induces apoptosis. In multiple xenograft models, treatment with SGN-B6A resulted in tumor growth delay and regression in tumor volume when compared to non-binding control. Methods: SGNB6A-001 (NCT04389632) is a phase 1, first-in-human, open-label, multicenter study designed to evaluate the safety, tolerability, pharmacokinetics (PK), and antitumor activity of SGN-B6A in adults with select advanced solid tumors. Primary objectives are to evaluate the safety and tolerability of SGN-B6A in patients with advanced solid tumors, identify the maximum tolerated dose, and identify a recommended dose and schedule. The study has 2 parts: dose escalation (Part A) and dose expansion with multiple disease-specific cohorts and a biology cohort (Part B). SGN-B6A will initially be given by intravenous infusion on Days 1, 8, and 15 of 21-day cycles. The dose escalation (Part A) will be conducted using the modified toxicity probability interval method to determine a dose that demonstrates a dose-limiting toxicity rate of 25% with a 5% margin. The dose and schedule for Part B will be determined based on evaluation of safety, PK, and pharmacodynamic biomarkers. Response evaluations will be based on RECIST v1.1. Patients must be ≥18 years old and have histologically or cytologically confirmed metastatic or unresectable solid malignancy within one of the following tumor types: non-small cell lung cancer, head and neck squamous cell cancer, breast cancer, esophageal cancer, ovarian cancer, cutaneous squamous cell cancer, exocrine pancreatic adenocarcinoma, bladder cancer, cervical cancer, or gastric cancer. After an appropriate dose and schedule are determined in Part A, safety and preliminary antitumor efficacy of SGN-B6A will be evaluated in indication-specific cohorts (Part B). This study is ongoing in sites across North America and Europe. Clinical trial information: NCT04389632.

COM701 with or without nivolumab: Results of an ongoing phase 1 study of safety, tolerability and preliminary antitumor activity in patients with advanced solid malignancies (NCT03667716).

2504 Background: COM701 is a novel first in class humanized IgG4 monoclonal antibody that binds with high affinity to poliovirus receptor related immunoglobulin domain containing (PVRIG), blocking its interaction with its ligand, PVRL2. Blocking of PVRIG leads to enhanced activation of T/NK cells and in mouse models inhibits tumor growth. We report new and updated results on safety/tolerability/pharmacokinetics and antitumor activity from this ongoing study including final results in dose escalation combination cohort, monotherapy expansion cohort (MEC). Methods: We enrolled a total of 51 DLT-evaluable pts: Arm A (COM701 mono dose escalation), 16 pts in 8 cohorts (0.01 – 20 mg/kg IV Q3/4 wks); Arm B (COM701 0.3 – 20 mg/kg + nivolumab (NIVO) 360 mg/480 mg IV Q3/Q4 wks), 15 pts in 5 cohorts; 20 pts in MEC (NSCLC, OVCA, breast, endometrial and CRC) at the recommended dose for expansion(RDFE), 20 mg/kg IV Q4 wks. Key inclusion criteria: Age ≥18 yrs, histologically confirmed metastatic solid malignancy, has exhausted available standard tx, ECOG 0-1, prior ICI permissible (except prior tx with a PVRIG inhibitor). Key exclusion criteria: active autoimmune disease requiring systemic tx, hx inflammatory lung disease. Primary objectives – safety/tolerability of COM701 ± NIVO (AEs, CTCAE v4.03), PK, RDFE. Key secondary/exploratory objectives - antitumor activity of COM701 ± NIVO (RECIST v1.1), evaluation of PVRL2 expression in tumor biopsy, blood cytokines and immunophenotyping. Results: No DLTs were reported in Arms A or B. COM701 PK profile similar in Arm A, 20 mg/kg IV Q4 wks (cohort 8) and Arm B cohort 5 (COM701 20 mg/kg + NIVO 480 mg; all IV Q4 wks). Frequency of TEAEs in safety population (N=54 pts): pts on COM701 mono (N=38)- No AE (4), Grade≤2 (21), G3 (11), G4 (1), G5 (1, PD), pts on combo (N=16) - Grade≤2 (8), G3 (7), G5 (1, PD). Serious TEAE: pts on COM701 mono 11/38, pts on combo 6/16. Most frequent AEs in Arm A: Grade ≤2 fatigue 12/38 pts (31%), nausea 9/38 (23%); Arm B: fatigue 7/16 pts (44%) and AST increased 4/16 pts (25%). Antitumor activity - in Arm A (cohort 8), a pt with platinum resistant primary peritoneal cancer had confirmed PR ongoing 14 months. In Arm B (COM701 10 mg/kg + NIVO 480 mg, all IV Q4 wks), a pt with anal SCCA; confirmed CR, ongoing 18 months, last tx with prior PD on NIVO. In addition, a pt with renal cell CA had confirmed SD [ongoing 13 months, COM701 0.3 mg/kg + NIVO 360mg; IV Q3 wks],] In MEC, 30% (6/20 pts) had best response of SD [1-endometrial, 3 NSCLC, 2 OVCA], 2 pts [NSCLC, OVCA] ongoing at 6/4 months. Overall 16pts had prior tx-refractory disease, 9(56%) had best response of ≥SD. Of 18 pts with prior tx with ICI, 13 (72%) had best response of ≥SD. Datacut 14Dec2020. Conclusions: COM701 ± NIVO well tolerated with no new safety signals. Encouraging signal of antitumor activity including in pts with prior tx with ICI or prior tx-refractory disease. Clinical trial information: NCT03667716..