Early-phase Trials Research Articles

ATRT-09. Outcome and therapeutic interventions in relapsed and refractory ATRT – The EU-RHAB perspective

Abstract Currently an internationally accepted consensus treatment for relapsed/refractory ATRT is missing. Little is known about relapse patterns, prognostic factors and outcome. In a recently published cohort of 143 ATRTs from the EU-RHAB registry, progression on therapy or relapse occurred in 64% (n=91). Previously published strategies for treatment failure have been restricted to individual, mostly clinically guided, attempts or early phase trials with limited sample sizes. We present a cohort of 55 patients with relapsed/refractory ATRT identified between 2015 and 2021 (total ATRT recruited n=147). Median age was 19 months; in 27.3% (n=15) a germline mutation was identified. A total of 43/55 tumors were subgrouped [60.5% SHH (n=26), 14.0% MYC (n=6), 23.3% TYR (n=10), one patient with SHH+TYR]. Salvage therapy was applied to 83.6% (46/55). Sixty therapy attempts with 17 different regimens subclassified into conventional chemotherapy, epigenetic, targeted or metronomic therapy were applied to 40/55 patients. Median overall survival (OS) was 20±1.8 weeks following the first event, median time to progression was 11±1.8 weeks. 12 months OS was 23.1%. No significant differences in survival were noted between different molecular subgroups; neither was germline mutation in SMARCB1 prognostic. Patients <12 months (n=9;16.4%) had a significantly reduced OS compared to older patients. (9±6.0wks vs. 22±3.2wks, p<0.05) Those who received therapy according to metronomic approaches such as MEMMAT (8/55;14.5%) survived longer than patients treated with other regimens, including epigenetic and targeted therapy. (72±36.8wks vs. 25±6.2wks, p<0.05) Our data provide valuable insights into a vulnerable group of patients deserving evidence based clinical management and access to clinical trials of all phases. Prospectively we aim to merge the results with data from other, international cohorts to generate more robust and valuable results.

LGG-42. Thromboembolic toxicity observed with concurrent trametinib and lenalidomide therapy

INTRODUCTION: Event-free survival of pediatric low-grade glioma (pLGG) is poor, and patients often require multiple treatment strategies. The hallmark of pLGGs are genetic aberrations of the mitogen-activated protein kinase pathway, which lead to constitutive pathway activation. MEK and RAF inhibitors target this pathway and are efficacious in early phase trials in recurrent pLGGs. However, not all patients respond to monotherapy, and many experience progression after completion of therapy. Evaluating combination therapies that may enhance efficacy or prolong disease stabilization is warranted. Lenalidomide is an immunomodulatory agent with an anti-tumor effect demonstrated in phase 1 trials in recurrent pediatric central nervous system (CNS) tumors. OBJECTIVE: To describe our institutional experience using concurrent trametinib and lenalidomide in the treatment of primary pediatric central and peripheral nervous system (PNS) tumors. METHODS: Retrospective review of patients’ medical records. RESULTS: Four patients with locally recurrent primary CNS or PNS tumors, three with WHO grade II pilomyxoid astrocytomas and one with a plexiform neurofibroma, were treated with trametinib and lenalidomide concurrently. Two patients developed severe thromboembolic events. One patient was treated with combination therapy for seven months until trametinib and lenalidomide were held after urgent ventriculoperitoneal shunt revision. Shortly following shunt revision, he experienced near-complete vision loss. MRI of the brain demonstrated a left posterior watershed territory hypoxic-ischemic injury. In a second patient, after four months of combination therapy, surveillance echocardiogram showed an incidental finding of severe biventricular dysfunction with a left ventricular ejection fraction (LVEF) of 17.7% and two mural thrombi in the left ventricular apex. She started losartan and enoxaparin and discontinued trametinib and lenalidomide. Her LVEF normalized four months later, and the mural thrombi resolved. CONCLUSIONS: Given the severe thromboembolic events experienced by these patients treated with concomitant trametinib and lenalidomide, this combination requires further investigation, and we urge caution if used concurrently.

Coping with Diffuse Intrinsic Pontine Glioma in Children - Findings from an Interview Study on Bereaved Parents.

Diffuse midline glioma (DMG) is the most common malignant glioma in early childhood with median survival of only eleven months. This retrospective interview study investigates specific coping strategies and needs of affected parents. 13 interviews with parents of seven children who died from DMG at the age of five to 16 years were conducted in 2016. The used method is a problem-oriented guided interview with consecutive content and evaluating structuring analysis according to Mayring. Major inductive category was whether the parents had talked to their children about their upcoming death. All parents stated overall satisfaction and comfort regarding their palliative care. Lack of psycho-social support in families was successfully addressed by involving palliative care. Retrospective interview studies in this context are feasible. Early involvement of the palliative care team may relieve burden from affected parents. Open communication about death proved helpful for all involved parties, it may facilitate acceptance of terminal illness and alleviate guilt in parents.Concepts for an open and empowering communication within families and between treatment site and families need continuing adjustment. The Palliative care team may also have a key role regarding early phase trials and molecular studies.

Targeting EGFR Exon 20 Insertion Mutation in Non-small cell Lung Cancer: Amivantamab and Mobocertinib.

To evaluate clinical data regarding the use of amivantamab and mobocertinib for epidermal growth factor receptor (EGFR) exon 20 insertion mutation non-small cell lung cancer (NSCLC) and assess their potential impact on the care of patients. A comprehensive literature search of PubMed and Clinicaltrials.gov was conducted using the terms amivantamab, Rybrevant, JNJ-61186372, mobocertinib, Exkivity, TAK-788. Relevant English-language clinical trials were evaluated. Amivantamab and mobocertinib were Food and Drug Administration (FDA) approved based on phases 1 and 2 studies. Amivantamab demonstrated an overall response rate (ORR) of 40% and median progression-free survival (PFS) of 8.3 months. Patients commonly experienced rash (86%), paronychia (45%), and stomatitis (21%). Mobocertinib demonstrated an ORR of 28% and median PFS of 7.3 months in phase 1/2 study. Patients frequently experienced diarrhea (91%), rash (45%), and paronychia (38%). Cardiac monitoring is recommended with mobocertinib due to risk of QTc prolongation and cardiac failure. For NSCLC patients who possess an EGFR exon 20 insertion mutation, amivantamab and mobocertinib are indicated as second-line therapy. Ongoing studies are evaluating these therapies as first-line monotherapy and as part of combination regimens in multiple cancer types. Dosage forms, drug interactions, and patient comorbidities should be considered when deciding which of the 2 agents may be most appropriate. Amivantamab and mobocertinib target an uncommon NSCLC mutation that has historically marked a poor prognosis because of innate resistance to previously approved EGFR tyrosine kinase inhibitors. Promising results from early phase trials supported accelerated FDA approval.

Do early phase trials predict clinical efficacy in subsequent phase III biomarker-enriched randomized trials?

3152 Background: Efficacy endpoints of randomized controlled trials (RCT) are commonly used as the basis of regulatory drug approvals. Recently, promising results in early phase trials have resulted in approval of biomarker-targeted therapies. We examined if early phase trial results were associated with efficacy in subsequent biomarker-enriched RCTs. Methods: All cancer drug RCTs conducted between January 2006 and March 2021 were identified through Clinicaltrials.gov. Trials were eligible if a biomarker was used to select a patient population for treatment with a targeted agent. Associated early phase trials were included if they matched the RCT in treatment setting and patient population. Trials pairs were compared using objective response rate (ORR) and progression-free survival (PFS). We assessed difference in endpoints using summary measures (e.g., average, range). We examined whether early phase trials results were associated with RCT results using logistic regression. Results: The search yielded 2,157 unique phase III RCTs and 27 RCTs met eligibility criteria pairing with associated early phase trials, where 17 RCTs met their primary endpoint. The most common biomarkers were EGFR+ (n = 8), HER2+ (n = 5) and PD-L1 (n = 5). Based on average difference of trial pairs, ORR was similar between trials (1.59%, 95% CI = -2.5-5.6, p = 0.50) and median PFS was slightly higher in early phase trials (1.95 months, 95% CI = 0.91-2.99, p < 0.05). On an individual pair basis, there was large range of variability in the difference between early phase trials and RCTs for ORR (range = -23.9-20.2%) and median PFS (range = -0.8-7.4 months). The probability of the RCT meeting its primary endpoint is 50% or 95%, when the early phase trial ORR is 41.2% (95% CI = 35.2-47.1%) or 77.7% (95% CI = 71.7-83.6%), respectively. Conclusions: Through comparison of early phase trials and subsequent phase III RCT, we found that, overall, ORR has minimal bias in early phase trials, and median PFS appears to be slightly overestimated. Substantial variability in results for trial pairs suggests that, on an individual basis, results in early phase trial can be inconsistent with results in subsequent RCT. Early phase trial results may be associated with RCTs meeting their primary endpoint when ORR is very high; however, caution must be exercised when using early phase trials as representative of RCTs for decision-making as the predictive ability of early phase trials is limited.

Trends in early phase clinical trials: A tale of exponential economic growth and access.

e18504 Background: There has been exponential economic growth in the BRIC (Brazil, Russia, India and China) nations in recent years, and outsourcing of clinical trials to these countries has occurred in tandem. Our study aimed to assess the current status of early phase oncology clinical trial recruitment in the BRIC countries, to assess the impact of these emerging economies and global markets in health care. Methods: We reviewed the open-access clinical trial registry, clinicaltrials.gov, for registered interventional recruiting early phase trials (Phase I/II) in the BRIC countries in adults and analyzed each country separately and collectively. We extracted descriptive data and established a database and proceeded to perform literature review and examine trends in early phase clinical trials. Results: We identified 888 recruiting early phase clinical trials in BRIC countries; China had 95% (842/888) of the trials, Brazil 1.5% (13/888), Russia 3.4% (30/888) and India 0.34% (3/888). For tumor specific studies, gastrointestinal (17%, 148/888), lung 11% (94/888) and breast (17%, 53/888) cancers were the most studied. Most trials were industry-sponsored (76%, 675/888); and most conducted in a single country (95%, 846). Industry-sponsored studies comprised 96% in China (635/842), 87% in Russia (26/30), 92% in Brazil (12/13), 67% (2/3) in India. Overall, immunotherapy agents in single and combination treatment strategies were the most common agent under investigation, with novel therapies such as CAR T-cell therapy (eg. CAR-T/TCR NK-CAR CAR-T/TCR-T Cell) being increasingly used in China (168 single agent trials, 30 trials in combination: 24% of trials in China). In contrast, CAR T-cell therapy trials were not yet in BRIC nations outside of China. Combination studies were frequent (33%, 293/888), and included a variety of combination strategies utilizing targeted therapies, immunotherapies, chemotherapies, antibody drug conjugates and novel biologics. Conclusions: Despite the economic explosion and shift of non-oncology clinical trials to BRIC nations, US and Europe continue to dominate in the design and conduct of early phase clinical trials in hematology and oncology. However, there has been exponential growth in early phase trial testing in China, which now accounts for 18.5% of the world’s population and has the majority (95%) of trials in BRIC nations. Contrastingly, India, which accounts for 17.7% of world’s population, has < 1% of BRIC nation trials. In keeping with trends in the US and Europe, there is a dominance of industry-sponsored studies in BRIC countries. Globally, early phase trials are increasing in their complexity with ongoing interest in immune modulation as a treatment strategy.

Mesenchymal Stem/Stromal Cells in Progressive Fibrogenic Involvement and Anti-Fibrosis Therapeutic Properties.

Fibrosis refers to the connective tissue deposition and stiffness usually as a result of injury. Fibrosis tissue-resident mesenchymal cells, including fibroblasts, myofibroblast, smooth muscle cells, and mesenchymal stem/stromal cells (MSCs), are major players in fibrogenic processes under certain contexts. Acknowledging differentiation potential of MSCs to the aforementioned other types of mesenchymal cell lineages is essential for better understanding of MSCs’ substantial contributions to progressive fibrogenesis. MSCs may represent a potential therapeutic option for fibrosis resolution owing to their unique pleiotropic functions and therapeutic properties. Currently, clinical trial efforts using MSCs and MSC-based products are underway but clinical data collected by the early phase trials are insufficient to offer better support for the MSC-based anti-fibrotic therapies. Given that MSCs are involved in the coagulation through releasing tissue factor, MSCs can retain procoagulant activity to be associated with fibrogenic disease development. Therefore, MSCs’ functional benefits in translational applications need to be carefully balanced with their potential risks.

Endogenous clues promoting remyelination in multiple sclerosis.

The introduction some 30 years ago of β-interferon, followed by a panel of immunomodulators and immunosuppressants has led to a remarkable improvement in the management of multiple sclerosis (MS) patients. Despite these noticeable progresses, which lower the number of relapses and thereby ameliorate patients' quality of life, preventing long-term progression of disability is still an unmet need, highlighting the necessity to develop therapeutic strategies aimed at repairing demyelinated lesions and protecting axons from degeneration. The capacity of human brain to self-regenerate demyelinated lesion has opened a field of research aimed at fostering this endogenous potential. The pioneer electron microscopic evidence by Périer and Grégoire [Périer O, Grégoire A. Electron microscopic features of multiple sclerosis lesions. Brain 1965; 88:937-952] suggesting the capacity of human brain to self-regenerate demyelinated lesion has opened a field of research aimed at fostering this endogenous potential. Here we review some recently identified mechanisms involved in the remyelination process, focusing on the role of electrical activity and the involvement of innate immune cells. We then provide an update on current strategies promoting endogenous myelin repair. Identification of therapeutic targets for remyelination has opened an active therapeutic field in MS. Although still in early phase trials, with heterogenous efficacy, the door for myelin regeneration in MS is now opened.

Two checkpoint inhibitor combinations in patients with cutaneous melanoma: A systematic review of clinical trials.

e21530 Background: Melanoma is a cancer of melanocytes and has the potential to metastasize to distant organs. Immune checkpoint inhibitors (ICI) enhance the immune response against cancer cells. Programmed cell death protein-1 (PD-1), PD-ligand-1 (PD-L1), cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), and lymphocyte-activation gene (LAG-3) are the common targets of ICI. Blocking two pathways can have an additive/synergistic effect. This systematic review will assess the efficacy of two ICI combinations in cutaneous melanoma. Methods: A search was performed on PubMed, Embase, and clinicaltrials.gov. We used the following mesh and Emtree terms, “Melanoma” AND “Immune checkpoint inhibitors,” from the inception of literature till 01/15/2022. We screened 11,287 articles and included 4 randomized clinical trials (N = 1,948) and 6 single-arm clinical trials (N = 438) in this review. We excluded preclinical trials, case reports, case series, review articles, observational studies, meta-analysis, and irrelevant clinical trials. Results: In 10 clinical studies (N = 2,386), two ICI combinations were assessed in adult patients with melanoma. Nivolumab (nivo) + ipilimumab (ipi), relatlimab (rela) + nivo, pembrolizumab (pemb) + ipi, lag525 + spartalizumab (spa), fianlimab (fian) + cemiplimab (cem) and single drug/placebo were used to treat 560, 365, 223, 42, 48, and 1,148 patients, respectively. 2,119, 70, and 197 patients had advanced untreated, PD-1/L1 refractory, and resectable stage III/IV melanoma. The response rates (RR) and survival rates are given in table. Conclusions: Two ICI combinations of nivo, ipi, and rela were more effective than monotherapy in patients with untreated advanced melanoma. In early phase trials, combinations of ipi, nivo, pemb, lag525, spa, fian, and cem were effective in advanced melanoma. Nivo, ipi, and rela were effective in patients with resectable melanoma. Pemb+ipi was effective in patients with PD-1/L1 refractory melanoma. More randomized double-blinded clinical trials are needed to confirm these results.[Table: see text]

Baseline tumor size as prognostic index in patients with cancer receiving experimental targeted agents.

3063 Background: Several studies showed that high baseline tumor size (BTS) is associated with worse outcomes in cancer patients treated with immunotherapy (IO). However, the prognostic impact of BTS for patients receiving targeted therapies (TT) remains uncertain. Methods: We collected clinical data for patients with solid tumors consecutively treated within early phase trials at our institution from 01/2014 to 04/2021. Treatments were categorized as IO-based (if any IO-agent was included) or TT-based (biomarker-matched or not). BTS was calculated as the sum of RECIST 1.1 baseline target lesions. Progression-free survival (PFS), overall survival (OS) and objective-response rate (ORR) were compared between patients with high BTS (> median) and low BTS (≤median). Results: 444 patients were eligible for the analysis (220 IO, 151 TT biomarker-matched, 73 TT biomarker-unmatched). Median age was 56 years (interquartile range, IQR 48-64) and median BTS was 69 mm (IQR 40-100). Most represented tumor types were breast (49%), lung (9%), melanoma (5%) stomach, colorectal, head and neck and ovarian (4% each). Patients with low BTS were more often female (p < 0.001), had a better performance status (PS, p = 0.008), lower LDH (p < 0.001), lower neutrophile/lymphocyte ratio (NLR, p < 0.001) and higher albumin (p = 0.003). OS was significantly longer for patients with low BTS (16.6 vs 8.2 months, p < 0.001), including when restricting at those receiving IO (12 vs 7.5 months, p = 0.005). Among patients receiving TT, those with lower BTS experienced longer PFS (4.7 vs 3.1 months, p = 0.002) and OS (20.5 vs 9.9 months, p < 0.001) as compared with those with high BTS. However, BTS was only prognostic among patients receiving biomarker-matched TT, with improved PFS (6.2 vs 3.3 months, p < 0.001) and OS (21.2 vs 6.7 months, p < 0.001) in the low-BTS subgroup, despite a similar ORR (28% vs 22%, p = 0.57). BTS was instead not prognostic among patients receiving unmatched TT, with similar PFS (3.7 vs 4.4 months, p = 0.30), OS (19.3 vs 11.8 months, p = 0.20) and ORR (33% vs 28%, p = 0.78) in the two BTS groups. Multivariate analysis confirmed that BTS was independently associated with PFS (p = 0.03) and OS (p < 0.001) but not with ORR (p = 0.11), regardless of tumor site, treatment category, PS, NLR, sites of metastases and number of prior lines. Conclusions: Patients receiving biomarker-matched TT experience longer PFS and OS if having a lower BTS, whereas response rate is not affected by this variable. This difference may reflect the faster emergence of molecular mechanisms of resistance among patients with higher baseline burden. Lower BTS is also confirmed to be associated with longer survival among patients receiving experimental IO. BTS has instead no prognostic value among patients receiving unmatched TT.

Addition of tyrosine kinase inhibitors (TKIs) in patients (pts) with unresectable hepatocellular carcinoma (HCC) who progress on first-line immunotherapy (IO).

e16193 Background: Atezolizumab plus bevacizumab is now standard first-line therapy for advanced HCC. Early phase trials in HCC and phase III trials in other solid tumors testing IO and TKI have shown greater antitumor activity with the combination than with either agent alone. Cancer and vascular endothelial cells release VEGF, which not only increases angiogenesis, promoting tumor growth, but also induces an immunosuppressive tumor microenvironment (TME). Preclinical studies suggest that TKIs with anti-VEGF activity have immunomodulatory potential, enabling the infiltration and activation of effector T cells to the TME. Experimental models of HCC with combination of IO plus TKI also reverted immune escape mechanisms mediated by β-catenin, Wnt, and TGFβ activation and by Treg or neutrophil infiltration. At our institution, pts who were treated with IO alone in the front line often had a TKI added on progression of disease (PD). We aimed to evaluate whether the addition of a TKI could rescue IO failure. Methods: We conducted an IRB-approved retrospective chart review of pts with unresectable HCC at Mount Sinai Health System who received IO from 1/2017 to 6/2021 and who subsequently received a TKI on PD. We assessed the objective response rate (ORR), median progression-free survival (mPFS) and overall survival (mOS). Follow-up CT/MRI imaging studies were conducted every 2-3 months after addition of TKI. Results: Of 277 pts who received first-line IO during the study period, 46 evaluable pts subsequently had TKIs added to IO upon PD. Pts were predominantly male (37/46), with median age 63 years, and 38 had cirrhosis. Etiologies of HCC were as follows: 9 HBV, 22 HCV, 15 alcohol-related, 7 NASH-associated. All pts received first-line nivolumab. TKIs added were lenvatinib (44/46) and sorafenib (2). At the start of IO, most pts (31/46) had Child Pugh class A liver disease and performance status ECOG 0 (31/46). TKIs were added upon PD and after a median of 5.8 months (range 2.1-28.1 months) from IO initiation. ORR of IO plus TKI was 15% (7/46; 2 complete responses and 5 partial responses). 16 pts had stable disease, and 13 had PD. Among the 11/46 pts who initially responded to first-line IO, 2 achieved a response with TKI. There were 5 responses among the 35/46 non-responders to first-line IO. TKI-related grade 3-4 adverse events, including liver toxicity, rash, and encephalopathy, led to discontinuation in 7/46 pts. mOS after adding TKI was 9.5 months (95% CI: 6.1-13.7) and mPFS was 5.4 months (95% CI: 3.6-9.7). The mOS and mPFS of adding TKI after PD did not differ between IO initial responders and non-responders. Overall, mOS from IO initiation was 17.6 months (95% CI: 14.5-24.4). Conclusions: Adding a TKI after PD on single agent IO in pts with advanced HCC did not add a signal of clinical benefit compared with reported outcomes from second-line TKIs alone.

Large scale clinical trials: lessons from the COVID-19 pandemic

BackgroundThe COVID-19 pandemic has presented substantial new challenges to clinical and research teams. Our objective was to analyse the experience of investigators and research delivery staff regarding the research response...

A phase II/III trial of chemotherapy plus cetuximab versus chemotherapy plus bevacizumab versus atezolizumab plus bevacizumab following progression on immune checkpoint inhibition in recurrent/metastatic head and neck cancers: ECOG-ACRIN EA3202.

TPS6098 Background: There is no standard treatment beyond progression on first-line pembrolizumab (P) in patients with R/M HNSCC. Vascular endothelial growth factor (VEGF) modulates anti-tumor immunity via proliferation of inhibitory T regulatory and myeloid-derived suppressor cells, inhibition of dendritic cell maturation and suppression of effector T cell responses. Efficacy data from other disease sites and from early-phase trials done in HNSCC suggests promising clinical activity of VEGF and PD-1 inhibitor combination therapy. We have thus designed a Phase II/III, randomized, multi-arm trial to evaluate the efficacy of atezolizumab (A) and bevacizumab (B) beyond progression on P in patients with R/M HNSCC. Methods: EA3202 is enrolling patients with CPS ≥1% R/M HNSCC previously treated with P either alone or in combination with other checkpoint inhibitors without progression for at least 12 weeks. In phase II, patients will be randomized to one of three treatment arms: platinum doublet chemotherapy (C) plus cetuximab (E) for six cycles followed by E maintenance (control arm), C + B for six cycles followed by B maintenance, or A + B. Therapy in each arm will continue until progression, toxicity, or for a total period of two years. Patients will be stratified by p16 status, CPS score (≥ 20 vs. < 20), distant metastases (M0 vs M1), and disease progression pattern with first-line P (while on P vs. after discontinuation). 216 patients will be enrolled. The primary endpoint for phase II is progression-free survival (PFS). Each experimental arm will be compared to the control arm at a one-sided alpha level of 0.10. Pre-specified rules will be used to pick a winner among the two experimental arms, which will then advance to phase III against the control arm. 214 patients will be enrolled in phase III for a total sample size of 430 patients. The primary endpoint for phase III is overall survival (OS) which will be compared using a stratified log-rank test. Secondary endpoints include OS in the two phase III arms among the CPS ≥ 20 cohort and comparison of grade 3 or higher treatment-related adverse events between the two arms. A total of 277 OS events will be required for full information for phase III evaluation to give a nominal ̃90% power at one-sided alpha level 0.0125. 144 patients enrolled in phase II (from the control and selected experimental arms) will be included in the phase III analysis. With this design the overall study power is at least 80% under a true 40% hazard reduction for PFS and 35% hazard reduction for OS. Blood and tumor tissue will be banked. EA3202 was activated in December 2021. It is the first randomized study to compare systemic treatments for R/M HNSCC in the immunotherapy era and will define the best second-line treatment approach beyond P. Clinical trial information: NCT05063552.

Racial, ethnic, and socioeconomic survival disparities among children with high-risk neuroblastoma treated on upfront Children’s Oncology Group clinical trials.

10005 Background: Racial and socioeconomic disparities have not been comprehensively investigated in high-risk neuroblastoma (HR NBL). Prior Children’s Oncology Group (COG) investigations have demonstrated population-based disparities in late relapse rates among Black children, and trial-based disparities in relapse and survival among children living in poverty receiving post-consolidation immunotherapy. It is unknown whether these disparities persist in upfront trials for newly diagnosed patients. We leveraged COG data to investigate race, ethnicity, and socioeconomic disparities in a cohort of children with HR NBL treated on upfront clinical trials from 2007-2016. Methods: Retrospective cohort study of children enrolled on upfront COG HR NBL trials ANBL0532, ANBL09P1, and ANBL12P1. Race and ethnicity were the primary exposures categorized as: Black Non-Hispanic (BNH); Hispanic; Other Non-Hispanic (ONH); or White Non-Hispanic (WNH). Poverty was the secondary exposure, defined as household (public insurance only vs others), area (census-defined high-poverty ZIP code with >20% of population living below 100% Federal Poverty Level (FPL) vs <20% below 100% FPL), and rural (Census-defined rurality measures linked to ZIP code). Overall (OS) and event-free (EFS) survival from time of trial enrollment were plotted by Kaplan-Meier methods; associations with race/ethnicity and poverty were evaluated by log-rank tests. Results: Among 696 children, 16% were BNH, 11% Hispanic, 4% ONH, and 69% WNH. One-third (33%) of children were household poverty-exposed, 26% area poverty-exposed, and 15% rural-exposed. Tumor stage and biology did not differ by race/ethnicity or poverty measures. Five-year OS differed significantly by race/ethnicity (47% Hispanic vs. 50% ONH vs. 61% WNH vs. 62% BNH; p=0.047). Five-year OS was inferior among children exposed to household-poverty (53% vs. 63%; p=0.036) and neighborhood-poverty (54% vs. 62%; p=0.050) compared to unexposed children. There was no difference in OS by rurality. Similar directionality in 5-year EFS outcomes by race/ethnicity and poverty were observed without statistical significance. Conclusions: Race/ethnicity and poverty-exposure are associated with inferior OS outcomes among children with HR NBL despite uniform planned treatment on upfront COG trials. Investigation of mechanisms driving these disparities, including disparate early phase trial enrollment are ongoing to inform targeted health equity interventions to improve outcomes.

TARGET National: A U.K.-wide liquid-based molecular profiling program to enhance recruitment to early-phase trials.

TPS3163 Background: Precision medicine programs have largely focused on tissue-based assays to screen patients for genomic variants amenable to experimental targeted therapies. Challenges faced in such studies include time taken to acquire archival biopsies and limitation in capturing tumor heterogeneity and clonal evolution. The TARGET study (Rothwell, Nature Medicine 2019) previously demonstrated feasibility of using ctDNA to match patients to early phase trials with the benefit of rapid turnaround of results. With an ever-increasing number of novel therapies in development targeting rare genomic alterations across different tumor types, ctDNA holds great promise in enhancing recruitment to studies with rapid and efficient comprehensive genomic profiling assays covering a broad range of variants. There is need to perform profiling at scale to identify rare alterations and to utilise networks for identification of suitable clinical trials across the country. ctDNA is not detectable in all patients (owing to differences across disease types/ burden), thus tissue analysis still plays an important role. Methods: TARGET National is an investigator-initiated multi-centre molecular profiling study. The primary endpoints are to establish a national framework to offer profiling from blood samples (or tissue if appropriate) for patients being considered for early phase clinical trials across the UK Experimental Cancer Medicine Centre (ECMC) Network, and to measure the number of patients receiving matched therapy (MT). Secondary endpoints include curating the genomic landscape of the early phase population in the UK, and outcomes for patients receiving MT versus unmatched. Enrolment began in July 2021 and >250 patients have been recruited across 9 ECMCs with plans to expand to 20 centres by Q3 2022. Planned enrolment is 6000 patients over 5 years. Patients must be ≥ 16 years old, provide written consent, have histologically confirmed advanced solid cancer, progressing disease and be considered fit enough to receive an experimental therapy. ctDNA is analysed with Foundation Medicine Liquid CDx with option for other providers. A multi-disciplinary national Molecular Tumor Board enables interpretation of genomic reports and identifies suitable clinical trials, supported by eTARGET; a bespoke clinical-genomic data capture solution including trial finding software. The study provides broad access to genomic profiling throughout the UK, increasing experience with ctDNA assays, and will improve opportunities for patients to participate in early phase research. The UK database will provide means for identification of rare genomic patient groups for new first-in-human studies, and the program provides a national infrastructure to collect additional samples for translational research and pre-clinical models to progress understanding of biological predictors of response and resistance. Clinical trial information: NCT04723316.

Increase in serum choline levels predicts for improved progression-free survival (PFS) in patients with advanced cancers receiving pembrolizumab

BackgroundRecent studies have demonstrated that T cells can induce vasodilation in a choline-acetyltransferase dependent manner, leading to an increase in T cell migration to infected tissues in response to viral...

Early circulating tumor DNA (ctDNA) kinetics using a tumor-naïve assay as a predictive biomarker in early-phase immunotherapy (IO) clinical trials.

2546 Background: ctDNA kinetics with tumor-informed assays can predict treatment outcome in patients (pts) treated with anti-PD1 IO ( Bratman et al, Nature Cancer 2020). We evaluated whether early ctDNA kinetics with a tumor-naïve assay were associated with clinical outcomes in advanced solid tumor patients treated on early phase IO trials. Methods: Advanced solid tumor pts treated with investigational IO agents at the Princess Margaret Phase I program were enrolled. Baseline (B) and pre-cycle 2 (C2) (3-4 weeks after first dose) plasma samples were prospectively collected via an institutional liquid biopsy program (LIBERATE, NCT03702309). ctDNA was assessed using the tumor-naïve 425-gene Geneseeq Prime panel in a clinical laboratory. Mutations in each gene detected in ctDNA were measured as Variant Allele Fraction (VAF). Mean VAF from all mutations was calculated. Radiological response was measured per RECIST criteria and correlated using ROC curves. Hyperprogression (HPD) was defined using VHIO criteria ( Matos et al, CCR 2020). Survival outcomes were estimated using the Kaplan Meier method. Results: From 12/2017 to 3/2020, 162 plasma samples from 81 pts with 25 different tumor types were collected. Pts were treated within 25 different IO phase I/II trials, 72% of which involved a PD-1/PD-L1 inhibitor. Median age was 58y (range 21 – 79), 54% female, 76% ECOG1. Sarcoma and colorectal (11%, each) followed by breast (8%) and melanoma (7%) were the most frequent tumors. Median follow up was 10.3 months (m) (1.8-46.9). CR 4% (n = 3), PR 6% (n = 5), HPD 11% (n = 9). Clinical benefit (CB) rate (CR+PR+SD > 6 months) was 20% (n = 16). ctDNA was detected in 122/162 samples (75.3%) (60 at B, 62 at C2). The most frequent mutations were TP53 (32%), PI3KCA (12%), PKHD1 (11%), and KRAS (9%). Mean VAF at B below median was not associated with OS (HR = 0.68 95%CI 0.4-1.16; p = 0.16) or PFS (HR = 0.93 95%CI 0.56-1.54; p = 0.77). Mean VAF change (difference between mean VAF at B and at C2) was associated with response (AUC = 0.99) and CB (AUC = 0.86). A decrease in mean VAF from B to C2 was seen in 24 pts (37.5%) and was associated with longer PFS (median PFS 2.7 vs 1.8 m; HR: 0.43, 95%CI 0.24-0.77; p < 0.01) and OS (median OS 10.8 vs 9.1 m; HR: 0.54; 95%CI 0.3-0.96; p = 0.03) compared to an increase in mean VAF. These differences were more marked if there was > 50% decrease in mean VAF from B to C2 (n = 11, 17%) compared to decrease < 50% or increase: median PFS 3.6 vs 1.8 m (HR: 0.29, 95%CI 0.13-0.62; p < 0.01) and median OS not reached vs 9.6 m (HR: 0.23, 95%CI 0.09-0.6; p < 0.01). No differences in mean VAF change were seen between HPD and PD pts. Conclusions: In a pan-cancer solid tumor early phase trial IO cohort, a decrease in ctDNA within 4 weeks of treatment was associated with increased CB, OS and PFS. HPD pts did not show greater increases in ctDNA. Tumor-naïve ctDNA assays may be useful to identify early treatment benefit in phase I/II trials with IO.

Preliminary results from an early phase trial of in situ immunization of lymphoma with a virus likeparticle containing a TLR9 agonist combined with anti-PD1 therapy (NCT03983668).

2639 Background: In situ immunization involves intratumoral (IT) injection of immunostimulatory agents to modify the tumor microenvironment with the goal of inducing an anti-tumor T cell response. Here, we report preliminary results of a clinical trial exploring in situ immunization with a virus like particle (VLP) combined with systemic pembrolizumab (Pembro) in lymphoma. The VLP, known as CMP-001 or vidutolimod (Vidu), is composed of the bacteriophage Qb capsid encapsulating the TLR9 agonist G10. Preclinical studies demonstrated generation of antibodies against the Qb capsid (anti-Qb) is necessary for Vidu to induce an anti-tumor response. In other cancers, early phase clinical trials of in situ immunization with Vidu, with and without systemic anti-PD1 therapy, have revealed early promising results. Methods: This trial included patients with relapsed lymphoma that have failed at least 1 line of therapy. The first dose of Vidu is given subcutaneously to stimulate anti-Qb that opsonizes the VLP. This is followed by IT Vidu administered weekly for seven doses, then at 3-week intervals. Pembro (200 mg fixed dose) is given intravenously every 3 weeks. Subjects continue treatment if they do not experience unacceptable toxicities and in the investigator’s opinion continued treatment is in the subject’s best interest. Fine needle aspirates for flow cytometric analysis are obtained prior to therapy and 4-6 weeks following initiation of therapy. Results: Six patients have enrolled to date (1 CR, 2 PR, 1 SD, 2 PD). The first 3 patients received 5mg Vidu per dose and the second cohort 7.5 mg per dose. Common side effects included chills, rigors, mild headache, and fatigue. These typically resolved within 4 hours after receiving the injection. Conclusions: In situ immunization with Vidu plus systemic anti-PD1 is a promising therapy in lymphoma. The ability to generate anti-Qb that opsonizes the VLP appears to be necessary for Vidu to induce an immune and therapeutic response. Accrual and correlative studies are continuing with the modification that generation of functional-Qb after the first dose of Vidu is required before patients receive IT therapy. Clinical trial information: NCT03983668. [Table: see text]

Evaluation of an automated artificial intelligence (AI)/ natural language processing (NLP) engine to match patients (pts) with advanced solid cancers to biomarker-driven early phase (EP) clinical trials.

e13513 Background: The increasing complexity of precision medicine in oncology creates significant challenges in identification of pts for biomarker-driven clinical trials. Worldwide expansion of genomic testing will identify more pts with potentially actionable alterations, but the manual task of matching pts to clinical trials requires laborious interpretation of fragmented medical information and knowledge of suitable trial eligibility criteria. Inspirata’s Trial Navigator (TN) solution uses AI and NLP to automatically extract relevant information from both patient medical records and trial protocols to identify appropriate trials. We conducted a retrospective study to evaluate the ability of TN to match pts referred to the Guy’s Hospital EP trials unit. Methods: Anonymised referral letters and genomic reports for pts referred from Jan 2019 to Dec 2020 were used. A subset was used to train TN to extract relevant variables for matching against eligibility criteria for all UK Experimental Cancer Medicine Centre (ECMC) Network trials open within 160 km of Guy’s Hospital at the time of referral, favouring biomarker-matched studies. Finally, TN was tasked with finding 5 ECMC trial matches for 40 referred pts. Matches were scored for eligibility and tumour and/ or biomarker suitability using a quality index (QI): 0, ineligible; 1, generic match; 2, tumour match; 3, biomarker match; 4, tumour and biomarker match. Results: Of 40 pts, most common tumour groups included gastrointestinal (55%), HNSCC (20%) and gynae (10%). TN was able to correctly identify at least 1 suitable trial (median = 4) for 39/40 pts (97%). Selection biomarkers were available for 27 pts, of whom 21 (78%) were matched to at least one appropriate biomarker-directed trial, 5 (12%) were matched to biomarker-agnostic trials and one was not correctly matched due to exclusion for progressive CNS metastases. Of 13 pts without biomarker information, 11 (84%) were matched to at least 1 tumour-appropriate trial and 2 to tumour-agnostic trials. Of all 200 trial matches, 134 (67%) were appropriately matched, of which 80 (59%) were external to Guy’s Cancer centre. Conclusions: TN successfully matched 90% of these preselected cancer pts to an appropriate biomarker- or tumour-directed trial, indicating potential to improve access and recruitment to early phase cancer trials, including those external to the primary treating site with which referrers may not be familiar. A prospective multicentre evaluation of TN is warranted to further define improvements in trial recruitment and efficiency.[Table: see text]

Neoadjuvant Nivolumab plus Chemotherapy in Resectable Lung Cancer

BackgroundNeoadjuvant or adjuvant chemotherapy confers a modest benefit over surgery alone for resectable non–small-cell lung cancer (NSCLC). In early-phase trials, nivolumab-based neoadjuvant regimens have shown promising clinical activity; however, data from phase 3 trials are needed to confirm these findings.MethodsIn this open-label, phase 3 trial, we randomly assigned patients with stage IB to IIIA resectable NSCLC to receive nivolumab plus platinum-based chemotherapy or platinum-based chemotherapy alone, followed by resection. The primary end points were event-free survival and pathological complete response (0% viable tumor in resected lung and lymph nodes), both evaluated by blinded independent review. Overall survival was a key secondary end point. Safety was assessed in all treated patients.ResultsThe median event-free survival was 31.6 months (95% confidence interval [CI], 30.2 to not reached) with nivolumab plus chemotherapy and 20.8 months (95% CI, 14.0 to 26.7) with chemotherapy alone (hazard ratio for disease progression, disease recurrence, or death, 0.63; 97.38% CI, 0.43 to 0.91; P=0.005). The percentage of patients with a pathological complete response was 24.0% (95% CI, 18.0 to 31.0) and 2.2% (95% CI, 0.6 to 5.6), respectively (odds ratio, 13.94; 99% CI, 3.49 to 55.75; P<0.001). Results for event-free survival and pathological complete response across most subgroups favored nivolumab plus chemotherapy over chemotherapy alone. At the first prespecified interim analysis, the hazard ratio for death was 0.57 (99.67% CI, 0.30 to 1.07) and did not meet the criterion for significance. Of the patients who underwent randomization, 83.2% of those in the nivolumab-plus-chemotherapy group and 75.4% of those in the chemotherapy-alone group underwent surgery. Grade 3 or 4 treatment-related adverse events occurred in 33.5% of the patients in the nivolumab-plus-chemotherapy group and in 36.9% of those in the chemotherapy-alone group.ConclusionsIn patients with resectable NSCLC, neoadjuvant nivolumab plus chemotherapy resulted in significantly longer event-free survival and a higher percentage of patients with a pathological complete response than chemotherapy alone. The addition of nivolumab to neoadjuvant chemotherapy did not increase the incidence of adverse events or impede the feasibility of surgery. (Funded by Bristol Myers Squibb; CheckMate 816 ClinicalTrials.gov number, NCT02998528.)