Metastatic Carcinoma Research Articles

Long-term outcomes of anlotinib and penpulimab combined with chemotherapy in the treatment of patients with metastatic nasopharyngeal carcinoma that failed definitive platinum-based chemoradiotherapy.

6040 Background: The median progression-free survival (mPFS) of anti-PD-1 monoclonal antibody (mAb) plus gemcitabine (G) and cisplatin (C) in the first-line treatment of metastatic nasopharyngeal carcinoma (M NPC) is still limited in about 10 ~12 months. The tolerance is also unfavorable, especially for patients (pts) who had undergone platinum-based chemoradiotherapy (CRT) previously. We performed a phase 2 study to explore the potency of replacing cisplatin with anloinib (A), a multi-kinase inhibitor in combined with penpulimab (P), a novel anti-PD-1 mAb as the first-line treatment of M NPC for pts with prior explosure of platinum-based CRT. Here we report the updated long term outcomes of this study. Methods: This is a prospective, three cohorts, single-arm study. Eligible pts were aged 18 ~ 75 years old, diagnosed with NPC and developed metastasis after platinum-based CRT. Pts who were diagnosed as having M NPC at the first visit or experienced treatment failure within 6 months after definitive CRT or adjuvant therapy were excluded. Pts were randomized to receive G + A + P (cohort GAP), G + C + A + P (cohort GCAP) or G+C+P (cohort GCP). Gemcitabine (1000mg/m2, d1, d8) and cisplatin (80mg/m2, d1) were given intravenously for 4 to 6 cycles, 3 weeks per cycle. Penpulimab (200mg, d1) and anlotinib (10mg, qd, d1-14) were given intravenously and orally respectively until disease progression, or unacceptable toxicities. The primary endpoint was objective response rate (ORR). Results: 21 pts were randomized to three cohorts in lead-in phase while only cohort GAP was selected into expansion phase to enrolled another 7 pts. Finally, totally 28 pts were enrolled and received study treatment. The data cutoff date was December 1, 2023. The median follow-up was 20.2 month (95% CI: 17.0, 23.4). The results were summered in the table below. In cohort GAP, the confirmed ORR was 92.3% (95% CI: 64.0%, 99.8%) and the mPFS was still not reached (95% CI: NE, NE). The most common Grade 3 treatment-related adverse event (TRAE) was neutrophil count decreased (3 pts). Only one patient occurred Grade 4 TRAE (neutrophil count decreased) and no treatment-related death was observed. Conclusions: The long term outcomes of this phase 2 study preliminarily disclosed the advantage of the treatment regimen including gemcitabine, anlotinib and penpulimab as the first-line treatment of M NPC, especially for pts who had exposed to platinum-based chemotherapy. The further study with more sample size is warranted. Clinical trial information: NCT04736810 . [Table: see text]

Real-world first-line treatment patterns and outcomes in patients with locally advanced or metastatic urothelial carcinoma in the United States.

e23287 Background: Historically, cisplatin-containing chemotherapy has been the recommended first-line (1L) treatment for locally advanced or metastatic urothelial carcinoma (la/mUC). For those ineligible for cisplatin due to poor performance status, impaired renal function, or comorbidities, alternative choices include carboplatin-based chemotherapy and PD-1/L1 inhibitors. This study aimed to describe real-world treatment patterns and overall survival (OS) among US Medicare patients with la/mUC receiving 1L therapy. Methods: This retrospective study used Medicare fee-for-service claims data from 2015 through 2022 to identify patients diagnosed with la/mUC who received systemic treatment. Initiation of 1L therapy was the index date for study inclusion; treatment patterns and OS were assessed until end of data availability, discontinuation of health plan enrollment, or death. OS was estimated using the Kaplan–Meier approach, and a log-rank test was used to compare OS across the following 1L treatment groups: platinum-based chemotherapy (PBC; cisplatin- and carboplatin-based), non-PBC monotherapy, and PD-1/L1 inhibitor monotherapy. Hazard ratios (HRs) were estimated across groups using Cox proportional hazards models adjusting for baseline characteristics. Results: Of 13,104 patients included in this analysis, 77.5% were male, and mean (SD) age was 76.2 (7.5) years. The most commonly observed 1L treatment categories were PBC (cisplatin-based, 19.7%; carboplatin-based, 28.4%), PD-1/L1 inhibitors (34.8%), non-PBC (13.7%), and other combination therapies (2.9%). Common comorbidities included renal disease (39.9%), chronic obstructive pulmonary disease (36.1%), and diabetes (32.2%). Compared with patients in the cisplatin cohort, patients in other cohorts had higher NCI Comorbidity Index scores. Median duration of 1L treatment was 3.5 months for PD-1/L1 inhibitors, 3.2 months for carboplatin, 3.0 months for cisplatin, and 2.0 months for non-PBC. Median OS was longest with cisplatin (17.0 months; IQR: 7.8–51.9), followed by non-PBC (14.7; 5.5–39.7), carboplatin (10.5; 4.9–25.1), and PD-1/L1 inhibitors (9.4; 2.8–27.9). In the adjusted Cox model, all treatment groups had statistically significantly higher hazards of death compared with cisplatin, with an HR (95% CI) of 1.50 (1.41, 1.59; P< 0.001) for PD-1/L1 inhibitors, 1.38 (1.30, 1.46; P< 0.001) for carboplatin, and 1.11 (1.03, 1.19; P= 0.007) for non-PBC. Conclusions: In this large retrospective study of US Medicare patients from 2015–2022 with la/mUC, PBC was the most common 1L treatment, followed by PD-1/L1 inhibitors and non-PBC. While cisplatin-treated patients had longer OS than patients in other groups, treatment durations were short, and OS was generally poor across regimens. These findings highlight an unmet need for more effective 1L therapies in la/mUC.

Treatment trends for metastatic urothelial carcinoma across eight Mexican centers: A global oncology perspective.

11171 Background: Urothelial carcinoma represents 3% of new cancer cases globally. Metastatic urothelial carcinoma (mUC) poses a notable challenge to healthcare systems, given its treatment complexity and high mortality. These challenges are magnified in resource-constrained settings. We aim to describe treatment trends for mUC across public and private Mexican centers. Methods: Retrospective study across 8 referral centers. Adults with mUC from 01/2001-12/2021 were included. We assessed clinical records, demographics and comorbidities. We recorded subject eligibility for first line platinum therapy, treatment lines received, and access to novel drugs. Descriptive statistics were used for demographics, treatment details and outcomes. Survival analysis was performed, including Kaplan Meier curves and Cox proportional hazards model. Results: We found 342 cases of mUC, 76% were male, with a median age of 67 years. Median follow-up was 8.4 months. Among those that received a first line (n=223, 65%), regimens used were cisplatin-based chemotherapy (n=100, 45%), carboplatin-based chemotherapy (n=87, 39%), gemcitabine (n=5, 2.2%), immunotherapy (n=4, 1.8%) or unspecified (n=27, 12%). Most causes of cisplatin ineligibility were ECOG ≥2 (41%) and glomerular filtration rate <60 ml/min (33%). Of those who received upfront platinum therapy (n=187), 65% received >3 cycles (n=121), 20% received 2 or 3 cycles (n=38) and 15% received 1 cycle (n=28). Progression as best response was found in 47% (n=88). Avelumab maintenance was only used in 14/99 eligible patients (14.1%). The proportion of individuals receiving a second, third or more lines was 24.6%, 8.8% and 3.5%, respectively. The most common second line treatment was chemotherapy (64.4%) followed by immunotherapy (28.6%). Median overall survival (mOS) was 11.8 months. Treatment notably impacted mOS, favoring those who received a first line(16.7 vs. 4.6 months, p<0.0001). Stratified analysis showed worse mOS for those with visceral disease (17.1 vs 10.3 months, p=0.0065) and ECOG ≥2 (17.6 vs 5.8 months, p<0.001).These features correlated with higher mortality, while first line treatment was associated with lower mortality. Conclusions: These data represent the first effort to delineate treatment trends of mUC in Mexico. First line treatment rates were higher than those described worldwide (35-60%1). Further, cisplatin-eligibility was higher compared to reports of high-income countries. Considerable rates of progression to platinum therapy were found, likely due to aggressive disease. This study highlights the limited access to novel treatments, showed by the infrequent use of avelumab maintenance, immunotherapy or targeted agents. [Table: see text]

Enrichment of somatic mosaic states involving DNA damage response and repair genes in patients treated with 177Lutetium.

3020 Background: Radioligand therapy (RLT) use has been increasing with the approval of 177Lu-Dotatate for metastatic neuroendocrine tumors (NET) & 177Lu-PSMA-617 for metastatic castration resistant prostate cancer (mCRPC). Therapy-related myeloid neoplasms [tMN, including myelodysplastic syndrome (MDS) & acute myeloid leukemia, (AML)] have been reported after 177Lutetium (177Lu) for NET with rates of 2-20% & median time from first 177Lu to tMN of 2.8yrs [4-12]. Clonal hematopoiesis (CH) is a risk factor for tMN, with the spectrum of CH depending on selection pressures. To describe the prevalence of therapy selected CH & tMN, we performed a retrospective analysis of patients (pts) who had a bone marrow biopsy (BMB) post-177Lu. Methods: After IRB approval, we queried the electronic health record for pts with BMB post-177Lu. Pt demographics, treatment history, labs & BMB results were collected. Results: Fifty-seven pts met criteria, 41 (72%) with NET & 16 (28%) with mCRPC. . Median age at BMB was 68yrs (range, 28-85). Of the 57pts, prior treatments included: radiation (RT) in 21 (37%), temozolomide in 14 (25%), taxane in 15 (26%), & platinum agents in 10 (18%). The median number of 177Lu cycles was 4 (range, 1-11).Cytogenetics were available in 84% (n = 48) & were normal in 60% (n = 29). Of those with abnormal cytogenetics (n = 18, 38%), the most common abnormalities involved chromosome (chr) 7 (n = 12, 26%), chr 5 (n = 7, 15%), chr 20 (n = 5, 11%) and complex karyotypes in 7 (15%), with 3 (17%) of these patients having no mutations. Diagnoses were assessable in 49 (86%) pts: 15 (31%) with undefined cytopeniasand 16 (33%) with tMDS. Metastatic carcinoma was identified in 17 Fifty-one percent (n = 29), at a median of 0.5yrs (range, 0.04-2.6) after hematologic diagnosis. Conclusions: The enrichment of CH involving the DDR pathway in recipients of 177Lu underscores the impact of RLT on bone marrow progenitors.

Sweet syndrome in the setting of breast cancer: A literature review.

e24044 Background: Sweet syndrome (SS) or acute febrile neutrophilic dermatosis typically present as patients with pyrexia, neutrophilia and rash with dermal neutrophilic dominance on biopsy. While the association of SS with malignancy is well-documented, the connection of sweet syndrome and solid tumors especially breast cancers is not explored enough. It is important to understand these associations better understand the disease course of SS in the setting of breast cancer. We aim to examine the different triggers, subtypes of breast cancer associated with SS, and differences in presentation and resolution time. Methods: A literature review from 1/1950-11/2023 was conducted for co-existing diagnoses of BC and SS in the PubMed Database. Search terms included Sweet Syndrome or Acute febrile neutrophilic dermatosis with Breast Cancer with subtypes. Key outcomes included: trigger identification, breast cancer subtypes, and treatment options. Findings were analyzed via a thematic lens. Results: A total of 34 cases of female BC patients with SS were identified with triggers divided into subtypes of surgery (47%), medication (20%), paraneoplastic (20%), and radiation therapy (11%). Depending on the trigger, average time to presentation varied with drug-triggered being the shortest (3.3 months) followed by radiation (8.5 months) while surgery (50 months) and paraneoplastic- associated (57 months) had similar presentation times. Although the time to presentation time for paraneoplastic-associated SS was the longest, 50% of these cases were associated with underlying progression of cancer. Regarding treatment and resolution time, 26 cases of SS resolved after treatment with treatment mainstay including oral (65%) and topical (12%) steroids. Analyzing triggers specific treatment outcomes, drug (2.7 days) and radiation-induced SS (7 days) had shorter average resolution times while paraneoplastic- associated (10.5 days) and surgery-associated SS (18.5 days) had longer resolution times. 5 cases that documented initial relapse or recurrence of SS after initial treatment were associated with paraneoplastic –induced sweet syndrome. On further analysis, among the 15 cases mentioned the BC type associated with SS- the most common breast cancer subtype was invasive ductal carcinoma of the breast (47%) followed by metastatic carcinoma (20%), adenocarcinoma (13%) and invasive lobular carcinoma (6%), canalicular breast carcinoma (6%) and unspecified malignant tumor of the breast (6%) regardless of the trigger mentioned. Conclusions: Oncologists should always consider SS on the differential for BC patients presenting with fever and rash given the varied presentation times depending on type of trigger. Treatment should be started promptly and continued for an adequate amount of time depending on the trigger to better mitigate complications in breast cancer patients.

A case report of renal cell carcinoma metastasis revealed through late‐onset thyroid nodules

AbstractBackgroundRenal cell carcinoma (RCC) is one of the most common and prevalent cancers all around the world with a prevalence of 3%. Approximately twenty percent of patients present with metastasis at the time of diagnosis, while late metastasis in renal cell carcinoma is a quite familiar phenomenon. Head and neck and particularly thyroid metastasis from RCC are rare events.CaseWe present a case of a 75‐year‐old woman who developed thyroid nodules 13 years after nephrectomy for RCC. Diagnosis confirmed metastatic RCC through clinical history, histomorphology, and immunohistochemistry. Imaging studies revealed thyroid lesions without metastasis in other organs. The patient underwent total thyroidectomy and remains symptom‐free after 2 years of follow‐up.ConclusionThis case highlights the importance of considering metastatic lesions is crucial in managing thyroid nodules in patients with a history of cancer, particularly RCC.

Corrigendum to: TMEM106A transcriptionally regulated by promoter methylation is involved in invasion and metastasis of hepatocellular carcinoma.

Corrigendum to: TMEM106A transcriptionally regulated by promoter methylation is involved in invasion and metastasis of hepatocellular carcinoma.

CDKN2A somatic copy number amplification in normal tissues surrounding gastric carcinoma reduces cancer metastasis risk in droplet digital PCR analysis.

The CDKN2A gene is frequently affected by somatic copy number variations (SCNVs, including deletions and amplifications [SCNdel and SCNamp]) in the cancer genome. Using surgical gastric margin tissue samples (SMs) as the diploid reference in SCNV analysis via CDKN2A/P16-specific real-time PCR (P16-Light), we previously reported that the CDKN2A SCNdel was associated with a high risk of metastasis of gastric carcinoma (GC). However, the status of CDKN2A SCNVs in SMs and their clinical significance have not been reported. Peripheral white blood cell (WBC) and frozen GC and SM tissue samples were collected from patients (n = 80). Droplet digital PCR (ddPCR) was used to determine the copy number (CN) of the CDKN2A gene in tissue samples using paired WBCs as the diploid reference. A novel P16-ddPCR system was initially established with a minimal proportion (or limit, 10%) of the detection of CDKN2A CN alterations. While CDKN2A SCNamp events were detected in both SMs and GCs, fewer CDKN2A SCNdel events were detected in SMs than in GCs (15.0% vs. 41.3%, P = 4.77E-04). Notably, significantly more SCNamp and fewer SCNdel of the CDKN2A gene were detected in SMs from GC patients without metastasis than in those from patients with lymph node metastasis by P16-ddPCR (P = 0.023). The status of CDKN2A SCNVs in SM samples was significantly associated with overall survival (P = 0.032). No cancer deaths were observed among the 11 patients with CDKN2A SCNamp. CDKN2A SCNVs in SMs identified by P16-ddPCR are prevalent and significantly associated with GC metastasis and overall survival.

Clinical analysis of patients with skin metastasis of cervical squamous cell carcinoma.

Cancers that metastasize to the skin are rare, especially cervical squamous cell carcinoma to the skin. Here, we have reported clinical analysis of patients with cervical squamous cell carcinoma metastasize to skin, to obtain a general understanding of this malignancy for clinicians. A retrospective analysis of patients with skin metastasis from cervical squamous cell carcinoma was conducted, focusing on clinical manifestations, histopathology, diagnosis, treatment, and prognosis. The average age of onset for the six patients with skin metastasis from cervical squamous cell carcinoma was 55.17±17.08 years, with four cases presenting as solitary lesions and two cases as multiple lesions. Treatment strategies included local excision for isolated lesions, chemotherapy, radiotherapy, or targeted therapy based on the extent of skin involvement, and immunotherapy was proved to have promising results in our cases. Among the six patients, three have passed away with a diagnosis-to-death time of approximately 5-6 months, while three patients are alive, with survival times ranging from 30 to 72 months. Skin metastasis from cervical squamous cell carcinoma is rare and often accompanies recurrent metastases to other visceral sites, necessitating early and accurate diagnosis. For isolated metastatic lesions, early detection followed by wide excision surgery and adjuvant radiotherapy can yield favorable outcomes. However, in cases of multiple skin metastases or concurrent metastases to multiple organs, treatment is challenging with a poor prognosis. Nevertheless, with advancements in medicine, combination chemotherapy, immunotherapy, and targeted therapy can effectively prolong survival, offering new hope for patients with skin metastasis from cervical cancer.

FAM188B promotes the growth, metastasis, and invasion of hepatocellular carcinoma by targeting the hnRNPA1/PKM2 axis

Hepatocellular carcinoma (HCC), the leading cause of cancer-related deaths worldwide, is characterised by rapid growth and marked invasiveness. Accumulating evidence suggests that deubiquitinases play a pivotal role in HCC growth and metastasis. However, the expression of the deubiquitinase FAM188B and its biological functions in HCC remain unknown. The aim of our study was to investigate the potential role of FAM188B in HCC. The expression of FAM188B was significantly upregulated in liver cancer cells compared to normal liver cells, both at the transcriptional and translational levels. Similarly, FAM188B expression was higher in liver cancer tissues than in normal liver tissues. Bioinformatic analysis revealed that high FAM188B expression was associated with poor prognosis in patients with HCC. We further demonstrated that FAM188B knockdown inhibited cell proliferation, epithelial-mesenchymal transition, migration and invasion both in vitro and in vivo. Mechanistically, FAM188B knockdown significantly inhibited the hnRNPA1/PKM2 pathway in HCC cells. FAM188B may inhibit ubiquitin-mediated degradation of hnRNPA1 through deubiquitination. Notably, we observed that the inhibitory effects of FAM188B knockdown on HCC cell proliferation, migration and invasion were reversed when hnRNPA1 expression was restored. In conclusion, FAM188B promotes HCC progression by enhancing the deubiquitination of hnRNPA1 and subsequently activating the hnRNPA1/PKM2 pathway. Therefore, targeting FAM188B is a potential strategy for HCC therapy.

High pre-treatment NLR and PLR predict poor prognosis of patients with recurrent/metastatic head and neck squamous cell carcinoma treated with immune checkpoint inhibitors.

e18001 Background: The treatment landscape of unresectable recurrent and/or metastatic (R/M) Head and Neck Squamous cell Carcinoma (HNSCC) has profoundly changed with the introduction of Immune checkpoint inhibitors (ICIs). High neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) have been associated with poor outcome in several tumor types. The aim of the present study was to investigate the role of pre-treatment NLR and PLR in predicting overall survival (OS) of patients treated with ICIs. Materials and Methods: We retrospectively reviewed the clinical records of 106 consecutive patients with R/M-HNSCC who received ICIs (single-agent or ICIs-based treatment) between January 2018 and June 2023 at the Istituto Oncologico Veneto of Padua. Patients were grouped into platinum-refractory (patients progressed within 6 months from the last platinum dose) and platinum-sensitive. The cut-off values of pre-treatment NLR and PLR were determined based on percentile distribution (75th percentile). OS was estimated using the Kaplan-Meier method. Univariate and multivariate Cox proportional hazards models were used to compare survival outcomes. Results: A total of 102 patients were analyzed. Four patients were excluded because of incomplete data. Primary tumor sites were oropharynx (37%), oral cavity (24%), hypopharynx (19%), larynx (15%), nasopharynx (5%) and nasal cavity (1%). 63 patients (62%) with platinum-refractory disease received nivolumab single-agent. All 39 patients (38%) with platinum-sensitive disease were PD-L1 positive (CPS≥1) and received pembrolizumab-based treatment. Median OS was 8.0 months (95% CI 5.8-10.1) in the platinum-refractory cohort and 13.3 months (95% CI 7.3-19.3) in the platinum-sensitive cohort. At the univariate analysis high NLR (≥7) and PLR (≥345) correlated with poor OS in the overall population and in both the platinum-refractory and the platinum-sensitive cohorts (Table1). At the multivariate analysis PLR was an independent predictor of OS. Conclusions: The efficacy results reported in this retrospective series were in line with the literature data. High PLR was an independent predictor of poor outcome regardless of the platinum sensitivity. Prospective studies are needed to better explore the predictive role of easily obtainable blood biomarkers in this poor prognostic population. Univariate analysis for OS [Table: see text]

A phase II multicenter study of enfortumab vedotin with or without pembrolizumab in rare genitourinary tumors (E-VIRTUE).

TPS4628 Background: Enfortumab vedotin (EV) is an antibody-drug conjugate (ADC) targeting nectin-4 with a monomethyl auristatin E (MMAE) payload, a potent microtubule inhibitor. It is standard of care (SOC) in metastatic urothelial carcinoma in combination with pembrolizumab in untreated patients and as monotherapy in post-chemotherapy, post-immune checkpoint blockade (ICB) patients. Nectin-4 expression has been retrospectively observed in 66.7-100% of urinary tract adenocarcinoma, 70-100% of urinary tract squamous cell carcinoma (SCC) (Case et al., 2022; Hoffman-Censits et al., 2021) and 36% of testicular germ cell tumors (GCTs) (The Human Protein Atlas). Metastatic urinary tract adenocarcinoma and SCC, and treatment refractory GCTs do not have an established SOC. Given the known nectin-4 expression, we hypothesize that EV with or without pembrolizumab will be active in these rare GU tumors. Methods: E-VIRTUE is an open-label, non-randomized, Phase 2 multicenter study. Eligible patients must have locally advanced or metastatic urinary tract pure adenocarcinoma, urinary tract pure SCC or refractory GCTs and have measurable disease by RECIST 1.1. Patients may have received any number of lines of prior systemic therapy except EV or other MMAE-based ADCs, and GCT patients must be refractory to all curative SOC treatments. Each histology will have an ICB-naïve and post anti-PD-1/PD-L1 ICB cohort: ICB-naïve patients will be given EV 1.25 mg/kg (maximum 125 mg) on Days 1 and 8 and pembrolizumab 200 mg on Day 1 of 21-day cycles, and post ICB patients will be given EV 1.25 mg/kg (maximum 125 mg) on Days 1, 8 and 15 of 28-day cycles. EV will be given for up to 5 years and pembrolizumab will be given for up to 2 years, or until progressive disease (PD) or unacceptable toxicity. Patients who stop pembrolizumab after achieving a complete response may resume it for 1 year after developing PD. The primary objective is to evaluate the objective response rate (ORR) in all cohorts. Secondary objectives include safety, progression-free survival (PFS) and overall survival (OS). The initial 6 cohorts will each be evaluated with exploratory intent. With 10 patients in each cohort, an exact binomial test with a 10% one-sided significance level will have 85.3% power to detect the difference between a very low (5%) ORR and a higher (30%) ORR. If there are ≥2/10 objective responses in any cohort, activity will be demonstrated. Additional histologies may be added after nectin-4 data emerges to justify their inclusion. Exploratory objectives include estimating the level of nectin-4 expression for each histology, performing DNA and RNA sequencing of tumor and blood samples, and observing changes in levels of circulating tumor cells (CTCs) and circulating tumor DNA (ctDNA) with treatment and disease status. Clinical trial registration NCT06041503. Clinical trial information: NCT06041503 .

An open-label, multicenter study investigating RP2 oncolytic immunotherapy in combination with second-line systemic atezolizumab combined with bevacizumab in patients with locally advanced unresectable or metastatic hepatocellular carcinoma.

TPS4191 Background: Despite advances in treatment for unresectable hepatocellular carcinoma (HCC), long-term survival rates remain poor. The combination of atezolizumab (Atezo) plus bevacizumab (Bev) is approved as frontline therapy for advanced HCC, but only a minority of patients (pts) respond and secondary resistance usually occurs within months. HCC has an immune-suppressed tumor microenvironment (TME), mediated by activated immune checkpoint signaling and angiogenesis pathways, which may contribute to therapeutic resistance. RP2 is an enhanced potency oncolytic herpes simplex virus type 1 (HSV-1) that expresses the fusogenic gibbon ape leukemia virus glycoprotein with the R sequence deleted (GALV-GP-R–), GM-CSF, and an anti–CTLA-4 antibody-like molecule. The direct oncolytic effect coupled with immune stimulation by RP2 in the TME is intended to provide systemic antitumor activity and synergize with anti–PD-1/PD-L1 agents, such as Atezo. Preclinical data have demonstrated improved distribution of oncolytic HSV within tumors in combination with Bev, supporting the clinical combination of RP2 with Bev. This study will evaluate the safety and efficacy of RP2 combined with Atezo plus Bev as second-line systemic therapy for unresectable and advanced HCC (NCT05733598). Methods: This is an open-label, single arm, phase 2 trial. Up to 30 pts will be enrolled and receive RP2 in combination with Atezo plus Bev. Key inclusion criteria include advanced unresectable HCC with ≥1 measurable tumor of ≥1 cm in longest diameter, Child-Pugh class A, an Eastern Cooperative Oncology Group performance status of 0 to 1, and progression on 1 prior systemic treatment, which must have included a PD-1/PD-L1–directed agent. Key exclusion criteria include untreated/incompletely treated esophageal and/or gastric varices with bleeding or at high risk for bleeding and macroscopic invasion of the tumor into any major blood vessel(s) and/or main bile ducts. Pts will receive intratumoral RP2 Q2W for 4 doses, then Q3W for up to 4 doses. Bev will be given at 10 mg/kg Q2W starting with the first dose of RP2 then at 15 mg/kg Q3W starting with cycle 4; Atezo will be given at 840 mg Q2W for cycles 2 and 3, then at 1200 mg Q3W starting with cycle 4. Pts will receive treatment until confirmed progressive disease, loss of clinical benefit, or unacceptable toxicity. The primary endpoint is overall response rate (ORR), defined as the proportion of pts achieving a best overall response of complete response or partial response per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 as modified for this study. Secondary endpoints are safety, ORR using HCC-modified RECIST, duration of response, complete response rate, and progression-free survival. Clinical trial information: NCT05733598 .

Enfortumab vedotin (EV) with pembrolizumab (P) versus chemotherapy (chemo) in previously untreated locally advanced or metastatic urothelial carcinoma (la/mUC): Analysis of cisplatin (cis)-eligible population from EV-302/KEYNOTE-A39.

4562 Background: EV-302/KEYNOTE-A39 (NCT04223856) is a phase 3, randomized, open-label, global study comparing EV+P with platinum-based chemo (PBC) for first-line (1L) treatment (tx) of patients (pts) with la/mUC regardless of cis eligibility. In EV-302, EV+P demonstrated a statistically significant and clinically meaningful benefit compared with PBC for the dual primary endpoints of progression-free survival (PFS) (hazard ratio [HR]: 0.45; P<0.00001) and overall survival (OS) (HR: 0.47; P<0.00001) in the overall pt population (Powles ESMO 2023), reducing the risk of progression and/or death by more than 50%. EV+P was FDA-approved in Dec 2023 for tx of adults with la/mUC. As cis eligibility status has long defined 1L tx, here we present results for pts who were eligible for cis at randomization. Methods: Pts with previously untreated la/mUC were randomized 1:1 to receive 3-week cycles of EV (1.25 mg/kg IV; Days 1 and 8) and P (200 mg IV; Day 1) or PBC (gemcitabine with cis or carboplatin). Select secondary endpoints included confirmed objective response rate (ORR), duration of response (DOR), and safety. Pts were deemed eligible/ineligible for cis by protocol-defined criteria and were stratified accordingly. Results: 478 pts (EV+P: 244, PBC: 234) were cis-eligible at randomization. 220 (94.0%) pts in the PBC arm received cis at Cycle 1. mPFS was 14.6 mo for EV+P; 6.5 mo for PBC (HR: 0.48, 95% CI, 0.38, 0.62). mOS was 31.5 mo for EV+P; 18.4 mo for PBC (HR: 0.53, 95% CI, 0.39, 0.72). ORR for EV+P was 70.8% with 32.5% complete response (CR) rate; mDOR (95% CI) was not reached (18.2 mo, NR). ORR for PBC was 53.0% with 15.5% CR rate; mDOR (95% CI) was 8.3 mo (5.9, 10.9). In EV+P arm, 82 pts (33.6%) remained on tx at data cutoff (DCO). 85 pts (34.8%) received subsequent therapy. 72 pts (29.5%) received any platinum-based therapy as first subsequent therapy; 43 pts (17.6%) received cis. In PBC arm, all pts were off study tx at DCO. 146 pts (62.4%) received any PD-1/L1 therapy following PBC. 83 pts received maintenance avelumab; 59 pts received PD-1/L1 therapy as 2L tx. Grade ≥3 TRAEs occurred in 53.9% of pts with EV+P and 62.7% of pts with PBC. Most common grade ≥3 TRAEs of special interest for EV were skin reactions (14.8%), hyperglycemia (7.8%), and peripheral neuropathy (5.8%). Most common grade ≥3 tx-emergent AEs of special interest for P were severe skin reactions (9.5%), pneumonitis (4.9%), and colitis (2.9%). Conclusions: EV+P improved clinical outcomes in pts who were eligible for cis with previously untreated la/mUC, reducing the risk of death by 47% compared with PBC. Results were consistent with the overall population. The AE profile of EV+P was generally manageable with no new safety signals. The results of EV-302 support EV+P as a new SOC for la/mUC, including pts who are eligible for cis. Clinical trial information: NCT04223856 .

Efficacy and safety of erdafitinib in pediatric patients with advanced solid tumors and FGFR alterations in the phase 2 RAGNAR trial.

10002 Background: Erdafitinib is an oral selective pan-fibroblast growth factor receptor (FGFR) tyrosine kinase inhibitor approved in the US for adult patients (pts) with locally advanced or metastatic urothelial carcinoma with susceptible FGFR3 genetic alterations, as determined by an FDA-approved companion diagnostic test, whose disease has progressed on or after ≥1 line of prior systemic therapy. Primary analysis of the RAGNAR study Broad Panel Cohort demonstrated tumor agnostic efficacy in pts with solid tumors harboring predefined FGFR mutations or fusions (Pant 2023). Here we report on Final Analysis of efficacy and safety results from the Pediatric Cohort of the RAGNAR study. Methods: Pediatric pts ≥6 years with advanced solid tumors and any FGFR mutation, fusion, or tandem duplication received oral erdafitinib. Starting doses were 8 mg, 5 mg, and 3 mg daily for ages > 15 years, 12 to < 15 years, and 6 to < 12 years, respectively, in 21-day cycles with possible individualized up-titration based on serum phosphate and adverse events (AEs). The primary endpoint was objective response rate (ORR) (Response Evaluation Criteria in Solid Tumors [RECIST] 1.1 or Response Assessment in Neuro-Oncology [RANO]) by independent review committee (IRC). Secondary endpoints included ORR by investigator, duration of response (DOR), disease control rate (DCR), clinical benefit rate (CBR), progression-free survival (PFS), and overall survival (OS). Results: 11 pts (median age 13 years; range, 6-16; 64% female) received erdafitinib. Median follow-up was 9.7 months at data cutoff. Histologies included low-grade glioma (LGG-6 pts); high-grade glioma (HGG-3 pts); soft tissue sarcoma (1 pt), and temporal neurocytoma (TNEURO-1 pt). 7, 1, and 3 pts had FGFR1, FGFR2, and FGFR3 alterations, respectively. 6, 4, and 1 pts had FGFR fusions, mutations, and tandem duplication, respectively. Pts had a median of 1 prior line of systemic treatment; 6 (55%) had prior radiotherapy. At data cutoff, 1 of 3 pts (33%) with HGG and an FGFR1-TACC1 fusion achieved a partial response based on investigator assessment with a response duration of 19.8 months. Investigator-assessed objective responses were not observed in the other tumor types. DCR and CBR were 100% in pts with LGG and 67% in pts with HGG. Most common treatment-emergent adverse events (TEAEs) included hyperphosphatemia (64%), diarrhea (64%), pain in extremity (45%), alanine transaminase increased (36%), nausea (36%), and onycholysis (27%). No central serous retinopathy events occurred; related serious adverse events (SAEs) occurred in 4 (36%) pts, including 1 SAE of epiphysiolysis; there were no related TEAEs leading to death. Conclusions: In this small pediatric population comprising primarily refractory HGG and LGG with any FGFR alteration, erdafitinib demonstrated limited objective responses but promising disease control with acceptable safety. Clinical trial information: NCT04083976 .

Case series: Outcomes of immunotherapy in locally advanced and metastatic cutaneous squamous cell carcinoma in Lakes and Waikato region.

e21529 Background: Cutaneous squamous cell carcinomas (CSCC) have an incidence of 425 per 100,000 in New Zealand (1). 5% progress to locally advanced or metastatic disease. Immunotherapy is unfunded for this indication despite excellent response and safety profile (2). The objective was to evaluate real world outcomes of patients who managed to access immunotherapy. Methods: Review of referrals to medical oncology in the Lakes & Waikato region between 1 August 2017 to 31 August 2022 with unresectable locally advanced or metastatic CSCC who had immunotherapy. Patients who were not referred to medical oncology, could not afford immunotherapy and/or unsuitable for a clinical trial were excluded from analysis. Results: 13/15 (86.7%) reviewed were male. Mean age was 71. 7 were locally advanced and 8 were metastatic. 14 self-funded pembrolizumab (11 first line, 3 second line). 1 accessed immunotherapy via a trial. 12 (80%) had significant responses; 3 achieved a complete response and 9 achieved a partial response. Median duration of response was not reached, with a median number of 18 cycles delivered. Median follow up was 23.8 months. 9 (60%) remain alive with ongoing response. 6 died on treatment; 3 from non-malignancy and non-treatment related causes. No Grade IV toxicities were observed. Grade III transaminitis was seen in one patient. Grade I-II toxicities seen in 11 (73.3%), including arthralgia (26.7%), fatigue (20%), transaminitis (13.3%), rash (20%), hypothyroidism (6.7%), diarrhoea (6.7%) and dyspnoea (6.7%). Conclusions: Despite an elderly & comorbid cohort, immunotherapy resulted in durable responses and excellent safety profile, highlighting the unmet need for immunotherapy funding in New Zealand. More understanding is required around the different responses to anti-PD1 therapies for the same malignancy type. (1) Pondicherry A, et al. The burden of non-melanoma skin cancers in Auckland, New Zealand. Australas J Dermatol. 2018 Aug; 59(3):210-213 (2) Hughes B, et al. Pembrolizumab for locally advanced and recurrent/metastatic cutaneous squamous cell carcinoma (KEYNOTE-629 study): an open-label, nonrandomized, multicentre, phase II trial. Ann Oncol. 2021;32(10):1276-1285.

Interaction between VEGF-A and immune checkpoint targets in triple-negative breast cancer and mechanisms of immune evasion and tumor progression.

1096 Background: Immune checkpoint inhibitors (ICIs) have revolutionized the treatment triple negative breast cancer (TNBC). However, not all patients with TNBC benefit from the addition of ICIs due to factors such as intrinsic and acquired resistance to ICIs, and complex interplay between tumor and immune cells in the tumor microenvironment (TME). Vascular endothelial growth factor (VEGF) promotes angiogenesis and potentially modulates tumor immune evasion. A phase I clinical trial has shown that a bispecific antibody to VEGF-A and PD-L1 produces encouraging tumor responses in advanced TNBC. In this study, we investigated the interaction between VEGF and various immune gene expression signatures including PD-L1 in a real-world breast cancer patient population. Methods: Comprehensive immune profiling, including the RNA-seq based gene expression assessment of 395 immune-associated genes, was performed on 120 formalin-fixed paraffin-embedded breast cancer samples. PD-L1 expression (Combined Positive Score, CPS ≥ 10%) was measured by immunohistochemistry (IHC; 22C3). Clinicopathologic variables were collected. Statistical associations between quantitative biomarkers, including 28 immune checkpoint genes, were calculated using Pearson correlations (r), and comparisons of quantitative biomarkers between groups were performed using the proportions test. For statistical significance, p<0.05 was required. Results: The study cohort included 29 patients (24.2%) with TNBC and 91 (75.2%) with non-TNBC (including ER+/HER2- and HER2+). Most patients had metastatic tumors (n=92, 76.7%) and invasive ductal carcinoma (n=83, 69.2%). Among the TNBC group, 21 patients had PD-L1 positive tumors (72.4%), defined by CPS ≥ 10.In non-TNBC, VEGF has significant, though weak (r<0.35) correlations with the expression of three checkpoint genes: AKT1 (r=0.35, p=0.00063), ICOS (r=0.34, p=0.00099), and TIM3 (r=0.29, p=0.0061). In TNBC, VEGF has significant, strong (r>0.47) correlations with the expression of three other checkpoint genes: PD-1 (r=0.47, p=0.0094), PD-L1 (r=0.57, p=0.0012), and PIK3CA (r=0.6, p=0.00051) However, in TNBC, VEGF gene expression does not have a statistical association with PD-L1 IHC (CPS ≥/< 10 (p=0.9)). Conclusions: Our findings suggest that there is an interplay between angiogenesis and an immunosuppressive tumor immune microenvironment in TNBC to a greater degree than in non-TNBCs. This supports the notion that angiogenesis mediators such as VEGF-A may enhance the expression of immunosuppressive checkpoint molecules, leading to immune evasion and tumor progression. Combination treatments of ICIs, especially anti-PD-1 therapy, with VEGF antibodies may be promising approaches to enhance the immune responses in TNBC, especially in tumors with CPS<10, where the current frontline treatment is cytotoxic chemotherapy.

Frequency of HER2-Low in breast cancer biopsies in Chile.

e13163 Background: In breast cancer (BC), human epidermal growth factor receptor 2 (HER2) is a prognostic and predictive biomarker. Traditionally, the use of HER2-targeted therapies is reserved for BC that overexpress HER2, defined as immunohistochemical (IHC) expression of 3+ or 2+ with amplification of the gene encoding HER2, detected by in situ hybridization (ISH). Recently, the term HER2-Low, defined as the IHC expression of 1+ or 2+ with negative ISH, has gained relevance as a new predictive biomarker for the use of trastuzumab-deruxtecan. The frequency of HER2-Low BC in the Chilean population is unknown. The objective of this study is to show the frequency of HER2-Low BC in a Chilean center. Methods: Descriptive cross-sectional analysis of clinical records and biopsies of localized or metastatic invasive breast carcinoma performed at Clínica Santa María between January 2020 and December 2023. The IHC expression of the estrogen receptor (ER), progesterone receptor (PR), Ki-67, HER2, histological grade (G) and HER2 in situ hybridization (ISH) when appropriate. The frequency and characteristics of HER2-Low cases are described and compared with the surrogate clinicopathological subtypes luminal A, luminal B (HER2-Positive and Negative), HER2-Positive and Triple Negative (TN), according to the St Gallen Consensus Conference 2013. Results: Between January 2020 and December 2023, a total of 339 biopsies with invasive BC were identified, from which 104 (36.0%) met the definition of HER2-Low. The frequency of luminal B and luminal A that met the definition of HER2-Low was 54 (51.9%) and 40 (38.5%), respectively. Of the 253 biopsies classified as luminal, 94 (37.2%) met the definition of HER2-Low, while of the 36 biopsies classified as TN, 10 (27.8%) did. Luminal B HER2-Negative and TN surrogate subtypes that met the definition of HER2-Low had a higher frequency of G3 than their non-HER2-Low counterpart. Conclusions: In the population analyzed, a considerable percentage of cases meet the definition of HER2-Low. This has relevant therapeutic implications. Distribution of biopsies that meet HER2-Low criteria according to surrogate clinicopathological subtype of breast cancer. [Table: see text]

Phase II study of the combination of lenvatinib (L) and eribulin (E) in advanced solid tumors.

3158 Background: Tumor angiogenesis remains a focal point in cancer therapeutics, necessitating innovative strategies to counter resistance mechanisms. Lenvatinib, a multitargeted tyrosine kinase inhibitor, and eribulin, a microtubule inhibitor, exhibit promise in disrupting tumor vasculature. Understanding their efficacy and safety in combination therapy is crucial, especially in heavily pretreated patients with advanced solid tumors. Methods: A single-center phase II study (NCT02640508) enrolled patients with stage IV breast carcinoma, lung carcinoma, and sarcoma, evaluating the safety and efficacy of lenvatinib and eribulin combination therapy. Eribulin was given on day 1 and day 8 at 1.4 mg/m2 and lenvatinib at a dose of 20 mg starting on day 2 of a 21-day cycle. Immunohistochemistry assessed biomarkers CD31, e-cadherin, CA-9, and vimentin. Statistical analyses included multivariate modeling and Kaplan-Meier curves. The primary endpoint of the study was the overall response rate (ORR), defined per RECIST 1.1 as assessed by investigator imaging review. Secondary endpoints included safety, progression free survival (PFS) and overall survival (OS). Results: Among 29 patients enrolled, median age was 58 years, majority were female and had at least ≥3 prior lines of chemotherapy. Treatment with lenvatinib and eribulin resulted in an ORR of 24%, as seen in the table. Median PFS was 7.4 months and OS was 8.2 months. Toxicities were manageable with grade ≥3 neutropenia seen in 34.5%, febrile neutropenia in 17.2%, and hypertension in 13.8% of patients. Treatment-related adverse events leading to study-drug discontinuation occurred in 6.8% of patients. Vimentin-negative patients exhibited significantly increased OS (fold change 4.374, p<0.001) and PFS (fold change 3.395, p<0.001) after adjusting for age, CD31, and CA9. Conclusions: Lenvatinib combined with eribulin showcased promising anti-tumor activity in heavily pretreated patients with metastatic breast carcinoma, lung carcinoma, and sarcoma. Although manageable, neutropenia emerged as a notable adverse effect. These findings underscore the potential of this combination as a therapeutic strategy for advanced solid tumors, warranting further clinical investigation. The observed significant survival benefits in Vimentin-negative patients align with the biological role of Vimentin in tumor invasiveness and metastatic potential, supporting the plausibility of these results biologically. Acknowledgement: This clinical trial was supported by Eisai. Clinical trial information: NCT02640508 . [Table: see text]

Clinical and molecular features and survival in thyroid cancer with brain metastases.

2023 Background: Brain metastases (BM) in advanced thyroid cancer are rare; however, they may be underreported as staging brain imaging is not routine. Prognostic features and molecular alterations for this group are poorly described. We characterized the clinical and molecular features of thyroid cancer with BM and evaluated differences in survival. Methods: In this single-center retrospective analysis, patients with metastatic radioactive iodine refractory well-differentiated, poorly-differentiated, or medullary thyroid carcinoma seen at the Princess Margaret Cancer Center from 2007-2022 were included. Electronic medical records were reviewed to collect clinicopathologic and treatment data. All patients had tumor next-generation sequencing (NGS) by a targeted gene panel. Overall survival (OS) from initial medical oncology consultation was analyzed using the Kaplan-Meier method and univariate and multivariate Cox proportional hazards models. Results: Of 248 patients with advanced thyroid cancer, 41(17%) were diagnosed with BM. The median interval from thyroid cancer diagnosis to BM development was 6.49 years (y) (IQR 3.51- 14.35 y). The median age at the time of BM diagnosis was 63.6 y and 23 (56%) were male. Most (76%) were asymptomatic at the diagnosis of BM and 80% had an ECOG of 0-1. Among patients with well-differentiated histology, 27 (18%) developed BM, while 7 (12%) with poorly-differentiated and 7 (19%) with medullary thyroid cancer developed BM. The most common molecular alterations included BRAFV600E (n=19), TERT (n=11), RAS (n=9), RET (n=8), and FANCA (n=3). Patients were treated with surgery (n=5), stereotactic radiation (n=21), whole brain radiation therapy (n=12), or a combination of both (n=2). OS was similar in patients with BM compared to those without (6.05 vs 6.45 y). There were no differences in histology or molecular alterations between patients that developed BM compared to those who did not. The median survival from the time of BM was 3.23 y. Patients with BM with ≥4 lesions had worse survival (0.52 vs 5.09 y, p=0.01). There were no differences in survival based on histology, symptoms, treatment or molecular alterations among those with BM. Conclusions: This is one of the largest reported thyroid BM cohorts and the first with complete NGS. The prevalence of BM in our cohort was higher than previously described, often diagnosed incidentally. Screening for BM in advanced thyroid cancer may detect higher rates, offering prognostic insights. While the number of BM was predictive of survival, molecular alterations did not predict BM development or survival and larger studies are needed.