6031 Background: Anti-PD-1 therapy alone or in combination with chemotherapy has improved outcomes as first line treatment for patients with recurrent or metastatic (R/M) head and neck squamous cell ...carcinoma (HNSCC), but therapy options are limited in the second line and beyond. The phosphatidylinositol 3-kinase (PI3K) signaling cascade is frequently dysregulated in HNSCC, and blocking this pathway may lead to modifications in the tumor immune microenvironment and enhanced taxane microtubule inhibitor sensitivity. BERIL-1 investigated buparlisib with paclitaxel in platinum-pretreated R/M HNSCC, but here we conducted a phase 2 trial (NCT05057247) evaluating the dual PI3K (δ/γ isoforms) inhibitor duvelisib in combination with docetaxel in patients with R/M HNSCC who previously received anti-PD-1 therapy. Methods: Patients (pts) with R/M HNSCC who had received anti-PD-1 blockade as part of 1-2 prior lines of R/M therapy were eligible regardless of HPV or PI3K tumor mutational status. Pts received duvelisib (25 mg orally twice daily) with docetaxel (75 mg/m 2 IV) every 21-days until progression. The primary endpoint was overall response rate (ORR) (RECIST v1.1), employing a Simon two-stage design (stage 1: enroll 13, <2 in response yields futility; stage 2: enroll 13, >4/26 in response rules out 10% ORR 89% power, α=0.09 warranting further investigation). Secondary endpoints included safety, progression-free survival (PFS), overall survival (OS), and correlating pre-treatment PD-L1 status and genomics with outcomes. Results: Twenty-six pts enrolled from 11/1/21 to 10/10/23. Median age of the cohort was 64 (34-74), comprised of 96% (25/26) men, 69% (18/26) former/current smokers, and 50% (13/26) with HPV+ disease (primary site: 12 oropharynx, 11 oral cavity, 3 larynx/hypopharynx). Best ORR was 19% (5/26) (95%CI: 6.8-40.7%), all 5 were partial responses (median duration: 6.9 months 0.7-15.5); with 46% (12/26) exhibiting stable disease and 32% (8/26) progression (1 unevaluable). Two pts remain on-treatment at data cutoff; 25% (6/24) came off for toxicity. Grade 3+ treatment-related adverse events were observed in 13/26 (50%), most often elevated liver function tests (6, 23%). No deaths were treatment related. At median follow-up of 7.1 months (0.7-22+), median PFS was 2.8 months (95%CI: 1.9-7.0); 10/26 pts had died. Median OS was 10.2 months (95%CI: 6.7-NA) and 1-year OS was 48%. Median baseline tumor PD-L1 score was 18 (0-100), which did not differ statistically by response (p=1.00; Wilcoxon rank-sum test). Disease in response was observed in 3/8 pts with somatic alterations in PIK3CA. Conclusions: We report a favorable response rate when combining a PI3K pathway inhibitor with taxane chemotherapy in patients with anti-PD-1 refractory HNSCC. Further evaluation of this strategy is ongoing in the phase 3 BURAN trial which is investigating buparlisib with paclitaxel. Clinical trial information: NCT05057247 .
6109 Background: Multi-kinase inhibitors show activity in both MTC & RAIR DTC. However, therapeutic options are limited after disease becomes refractory to one or two lines of standard of care ...therapies. We report here results of an investigator-initiated phase II clinical trial evaluating regorafenib in this population (NCT02657551). Methods: Patients with MTC (disease progression within 6-12 months, mo, prior to study registration) and RAIR DTC (progression within 12 mo) were enrolled regardless of prior lines of therapy. Regorafenib (each cycle 3 weeks ON/1 week OFF) was started at 80 mg daily, with planned escalation after 1 & 2 weeks to 120 mg daily & 160 mg daily, respectively, in absence of significant treatment-related adverse events (TRAEs). The highest tolerated dose was continued from cycle 2 onwards until progression. The primary endpoints were proportion progression-free at 10 months in MTC & overall response rate (ORR) by RECIST v1.1 in RAIR DTC. Simon two-stage design was utilized; MTC: <2 in 8 progression-free in first stage stops for futility, stage 2: enroll 13, >6/21 provides 81% power for proportion >20%; DTC: <3 in 9 in response in first stage stops for futility; stage 2: enroll 11, >7/20 provides 81% power for ORR >25%. Results: 17 patients (8 MTC, 9 DTC) were enrolled between April 2016 and October 2022. Among MTC, median (range) age was 54.7y (48.1, 62.8), 25% female. Among DTC, median age (range) was 62.8y (44.3, 75.8), 55.6% female. In MTC group, the proportion progression-free at 10 months was 12.5% (95% CI 0.3%, 52.7%) & did not meet the criteria to continue into 2 nd stage. ORR in MTC group was 12.5% (95% CI 0.3%, 52.7%). In DTC group, ORR was 11.1% (95% CI 0.3%, 48.2%), & did not meet the criteria to continue into 2 nd stage. No patients were receiving treatment at cutoff. Patients with MTC and DTC with objective responses (1 each) had received one (vandetanib) & no prior systemic therapy, respectively. The most common reason for discontinuation was disease progression in MTC (4, 50%) & DTC (5, 55.6%). Grade 3-4 TRAEs were observed in 8/17 (47.1%), most frequent were diarrhea, hypophosphatemia, & hypertension (each grade 3: 2, 11.7%). There were no treatment-related deaths. Median progression-free survival (PFS) in MTC & DTC were 5.3 (95% CI 3.6, 20.1) & 11.0 (95% CI 1.2, 24.0) mo, respectively. Median overall survival (OS) in MTC & DTC were 16.1 (95% CI 5.2, NA) and 20.1 (95% CI 1.6, NA) mo, respectively. Conclusions: Regorafenib clinical trial did not reach its primary endpoints in MTC and DTC. Analyses are planned to investigate impact of prior VEGFR inhibitor exposure, biomarkers and resistance mechanisms. Clinical trial information: NCT02657551 . Table: see text
Background: Fetal growth restriction (FGR) affects 5–10% term gestational age pregnancies. When accompanied by prematurity, FGR infants have significantly greater risk of perinatal morbidity and/or ...mortality compared to non-growth restricted preterm infants. Aim: Current study aimed to ascertain the incidence FGR among premature infants and its association with respiratory morbidity. Methods: Institution database for preterm infants of 23–31+6 weeks of gestation was accessed. FGR infants were compared with gestation/sex matched appropriately grown infants. Results: During the period 2016–2018, 973 infants between 23 and 31+6 weeks gestation were admitted amongst whom, 206 (27%) were FGR. Between 28 and 31+6 weeks gestation, approximately 1/3rd were FGR. Gestation and birth weight of the FGR and appropriately grown cohorts were 30.2±0.2 versus 30.1±0.2 weeks (p=0.8) and 1132±43 versus 1499±54 g (p<0.0001), respectively. While antenatal steroids, surfactant, mechanical ventilation, sepsis, and ductal therapy were comparable, respiratory outcomes were significantly worse in the FGR cohort (duration of respiratory support: 37±10 vs. 23±5 days p=0.016, home oxygen: 24 11.6% vs. 8 3.8%; p=0.005 and chronic lung disease CLD: 53 25.7% vs. 28 13.6%, p=0.002, respectively). The odds ratio (95% confidence intervals) for developing CLD and for home oxygen when born FGR were 2.2 (1.3–3.6) and 3.2 (1.4–7.4), respectively. Conclusions: In spite of comparable postnatal variables, FGR infants had significantly greater respiratory morbidity.
The optimal management of advanced non‐small cell lung cancer (NSCLC) with noncanonical epidermal growth factor receptor (EGFR) mutations (i.e., exon 19 deletion and exon 21 L858R) is constrained by ...the heterogeneous behavior of individual uncommon mutations and limited prospective clinical data in this setting. Despite encouraging results with osimertinib from a recently published phase II trial from South Korea, afatinib remains the only currently approved drug for patients with tumors harboring uncommon EGFR mutations (i.e., S768I, L861Q, and/or G719X). When used at the standard dose of 40 mg daily, afatinib is associated with significant rates of treatment‐related adverse events, leading to frequent dose reductions and treatment discontinuations. We report a case of a woman with advanced NSCLC harboring EGFR‐G719A mutation treated with afatinib (at an off‐label pulse dose strategy that merits further evaluation in prospective studies) with sustained partial response for 20 months with manageable expected toxicities. Subsequent disease progression was mediated by off‐target pan‐EGFR inhibitor (including osimertinib)–resistant KRAS mutation and not by acquisition of EGFR‐T790M. We further present the current state of evidence in the literature behind use of first‐, second‐, and third‐generation tyrosine kinase inhibitors and summarize the evolving spectrum of activity ascribed to osimertinib (and newer EGFR inhibitors with a more favorable therapeutic window and intracranial penetration) in this population of patients with advanced NSCLC and uncommon EGFR mutations.
Key Points
Uncommon EGFR mutations characterize a heterogeneous group of patients with advanced non‐small cell lung cancer (NSCLC).
Afatinib is the only currently U.S. Food and Drug Administration–approved drug for management of advanced NSCLC with uncommon EGFR mutations (S768I, L861Q, and/or G719X).
Afatinib treatment at 40 mg daily is associated with high rates of adverse events and dose reductions; alternative strategies including pulse intermittent dosing should be evaluated prospectively.
Osimertinib (with favorable safety profile and intracranial penetration) has shown promising results in this population in a phase II trial from South Korea; additional trials are ongoing.
This article presents the case of patient with advanced non‐small cell lung cancer harboring an EGFR‐G719A mutation treated with afatinib and reviews the literature regarding the use of first‐, second‐, and third‐generation tyrosine kinase inhibitors in this patient population.
Abstract Purpose: Many patients with locoregionally advanced human papillomavirus–negative head and neck squamous cell carcinoma (HNSCC) relapse. ctDNA has the potential to identify minimal residual ...disease, but its clinical utility for virus-negative HNSCC is not well understood. Experimental Design: We retrospectively evaluated a personalized, commercial ctDNA assay (Signatera, Natera) during clinical care of patients treated for predominantly newly diagnosed human papillomavirus–negative HNSCC. Signatera utilizes 16-plex PCR from matched tumor and blood. Objectives were to understand ctDNA detectability and correlate changes posttreatment with disease outcomes. Results: Testing was successful in 100/116 (86%) patients (median age: 65 years, 68% male, 65% smokers); testing failed in 16 (14%) because of insufficient tissue. Oral cavity (55, 47%) tumors were most common; most had stage III to IV disease (82, 71%), whereas 17 (15%) had distant metastases. Pretreatment, 75/100 patients with successful testing (75%) had detectable ctDNA (range: 0.03–4049.69 mean tumor molecules/mL). No clinical features predicted ctDNA detectability or levels (multivariate analysis). At a median follow-up of 5.1 months (range: 0.2–15.1), 55 (55%) had >1 test result (range: 1–7; 194 samples). Of 55 patients, 17 (31%) remained ctDNA positive after starting treatment. Progression-free survival was significantly worse for patients who were ctDNA positive versus ctDNA negative posttreatment (HR, 7.33; 95% confidence interval, 3.12–17.2; P < 0.001); 1-year overall survival was 89.1% versus 100%, respectively (HR, 7.46; 95% confidence interval, 0.46–119.5; P = 0.155). Conclusions: Tumor-informed ctDNA testing is feasible in nonviral HNSCC. ctDNA positivity is an indicator of disease progression and associated with inferior survival. Further research is warranted to understand whether ctDNA may be leveraged to guide therapy in HNSCC.
8521 Background: Integrin beta-6 (IB6), a tumor-associated membrane protein, plays an important role in pathogenesis and invasiveness and its expression correlates with poor outcomes. Sigvotatug ...vedotin (SV), formerly called SGN-B6A, is an IB6-directed ADC with encouraging activity in NSCLC in the Ph 1 study SGNB6A-001 (NCT04389632) (Hollebecque 2023). Here, we report updated efficacy and safety of SV in NSCLC. Methods: SGNB6A-001 is an open-label, multicenter, Ph 1 study evaluating the safety, pharmacokinetics (PK), and antitumor activity (cORR, DOR, and PFS per RECIST v1.1, and OS) of SV in patients (pts) with advanced solid tumors. Multiple dose regimens were explored during dose escalation (Part A). Dose expansion (Part B) is ongoing with selected regimens in various tumors including NSCLC. Parts C and D will evaluate SV in combination with pembrolizumab in NSCLC and HNSCC. Eligible pts had no therapeutic options (Part A) or had received platinum-based and anti-PD-(L)1 therapy unless contraindicated (Part B) and were dosed with the SV expansion regimens on D1 and D8 in a 21-day cycle (2Q3W; 1.2/1.25 mg/kg total body weight TBW) or D1 and D15 in a 28-day cycle (2Q4W; 1.5 mg/kg TBW, 1.8 mg/kg adjusted ideal body weight AiBW). Results: As of 01-Dec-2023, 306 pts had received SV; 113 pts with NSCLC received expansion regimens in Parts A and B. Prior lines of therapy and efficacy data for all pts with NSCLC and select subgroups are summarized in the table; cORR was 19.5% (95% CI, 12.6-28.0) in all pts with NSCLC and 32.5% (95% CI, 18.6-49.1) in pts with non-squamous (non-Sq)/taxane-naive NSCLC. Additional time-to-event data will be presented. Rates of TEAEs, ≥G3 TEAEs, SAEs, and TEAEs leading to discontinuation were 98.2%, 46.0%, 33.6%, and 13.3% in pts with NSCLC, and were consistent in all treated pts. The most common ≥G3 TEAEs in pts with NSCLC were dyspnea (9.7%), fatigue (7.1%), and neutropenia (5.3%). One pt with NSCLC had a treatment-related death (pneumonitis). PK variability across weight groups was lowest with 1.8 mg/kg AiBW 2Q4W. Conclusions: SV continues to demonstrate encouraging antitumor activity and a manageable safety profile in pts with NSCLC. Data at 1.8 mg/kg AiBW 2Q4W support initiation of the Ph 3 SGNB6A-002 study in 2/3L NSCLC (NCT06012435) and combination with pembrolizumab in earlier settings. Clinical trial information: NCT04389632 . Table: see text
6056 Background: Highly sensitive minimal residual disease (MRD) assays using circulating tumor (ct)DNA have broad clinical potential and are impacting cancer care. Circulating human papillomavirus ...(HPV) DNA has emerged as a biomarker of occult MRD among patients (pts) with HPV+ oropharyngeal cancers, but most head and neck squamous cell carcinomas (HNSCC) are not virally driven. Despite multimodality therapy, nearly half of pts with locoregionally advanced HPV-negative HNSCC relapse. As ctDNA has the potential to identify MRD, predict outcomes, and guide treatment for these pts, we performed a retrospective cohort study to evaluate the performance of a custom-built, clinically and commercially available ctDNA assay for this population. Methods: Pts with newly diagnosed HPV-negative HNSCC (all mucosal sites) treated at a single academic institution with pre-treatment ctDNA testing (Signatera, Natera) performed during clinical care were identified. Signatera utilizes up to 16-plex PCR from matched tumor and blood to develop a personalized ctDNA assay. A subset of patients had additional ctDNA testing during follow-up. Study objectives were to understand baseline ctDNA detection in relation to disease characteristics, and to correlate ctDNA changes on- and post-treatment with disease status and survival. Results: Testing was performed in 92 of 115 (80%) pts with HPV-negative HNSCC (median age: 66, 69% male, 64% smokers); ctDNA testing could not be performed in 23 (20%) pts due to insufficient tumor tissue. Oral cavity (43%) and larynx (22%) were the most common subsites; with most having clinical T2-3 (54%) and N1-2 (51%) disease (AJCC 2017 8 th edition) treated with definitive surgery (46, 40%) and/or chemoradiation (59, 51%). Pre-treatment, 69/92 (75%) pts had detectable ctDNA (range: 0.03-4049.69 mean tumor molecules/mL). No baseline independent clinical features predicted pre-treatment ctDNA detectability or levels (multiple logistic/linear regression modeling), but levels varied by T and N stage in univariate analysis (both p<0.05; Kruskal-Wallis test). At a median follow-up of 5.2 months (range: 0.2-15.1), 47 pts (51%) had >1 test result (range: 1-7; 170 total samples). Of 47 pts, 17 (36%) had ctDNA detected after treatment. Disease-free survival was significantly worse for pts who were ctDNA positive vs. negative after treatment (HR 4.35, 95%CI: 1.68-11.21, p<0.01); 1-year overall survival was 83.7% vs. 100% for pts who were ctDNA positive vs. negative. Conclusions: Tumor-informed, personalized ctDNA testing is feasible among pts with non-virally mediated HNSCC. ctDNA positivity as an early indicator of MRD positivity post-treatment was associated with inferior survival, identifying a high-risk subgroup. Further research is warranted to understand whether ctDNA may be leveraged to guide therapy and improve outcomes for HNSCC.
3024
Background: The receptor ITGB6 plays a role in tumor pathogenesis and invasiveness, and its overexpression is correlated with poor outcomes. Non-small cell lung cancer (NSCLC), head and neck ...(HNSCC), and esophageal cancer (EC) are among tumors with high ITGB6 expression (Lyon 2021). SGN-B6A is an ITGB6-directed vedotin ADC with a monomethyl auristatin E (MMAE) payload. SGN-B6A elicits antitumor activity via MMAE-mediated cytotoxicity, bystander effect, and immunogenic cell death. Here, we present updated results of an ongoing phase 1 study with a focus on NSCLC, HNSCC, and EC (Hollebecque SITC 2022). Methods: SGNB6A-001 (NCT04389632) is an open-label, multicenter, dose-escalation/expansion study evaluating the safety, pharmacokinetics, and antitumor activity of SGN-B6A (per RECIST v1.1) in patients (pts) with advanced solid tumors. Dose escalation (Part A) explored continuous weekly and intermittent dosing regimens. Dose was calculated using total body weight (TBW) or adjusted ideal body weight. Dose expansion (Part B) is enrolling pts with NSCLC, HNSCC, and EC. Results: As of 14 December 2022, 148 pts received SGN-B6A, 88 pts in Part A and 60 pts in Part B; enrollment for Part A is complete. In all cohorts (N=148), treatment-emergent adverse events (TEAEs) were observed in 88.5% of pts: 50.7% were Grade ≥ 3 (21.6% related), and 37.2% were serious (8.1% related); 6.1% of pts discontinued treatment due to TEAEs. 3 pts (2.0%) died due to TEAEs; none of the deaths were considered treatment-related. The most common TEAE was fatigue (35.1%); the most common Grade ≥ 3 TEAE was neutropenia (8.1%); the most common TEAEs leading to treatment discontinuation were peripheral sensory neuropathy and pneumonia (1.4% each). Prior lines of therapy and efficacy data for Part A (NSCLC, EC, and HNSCC) and Part B (HNSCC) subsets are summarized. Conclusions: SGN-B6A demonstrated a manageable safety profile, and showed encouraging preliminary antitumor activity and response durability in dose escalation in a heavily pretreated population. Part B dose expansion cohorts in NSCLC, esophageal squamous cell carcinoma (ESCC), and HNSCC are ongoing. Clinical trial information: NCT04389632 . Table: see text
6062
Background: Most patients with R/M SCCHN do not derive durable benefit from standard-of-care anti-PD-1-based therapy. The currently utilized biomarker, PD-ligand-1 combined proportion score is ...limited by the availability and heterogeneity of tumor samples. There is an unmet need to develop easily accessible peripheral blood-based biomarkers for response to immunotherapy. Methods: We are conducting a prospective multi-center study to identify peripheral blood derived DNA-based methylation biomarkers measured in patients with R/M SCCHN on treatment with FDA-approved anti-PD-1 based therapy. DNA isolated from these samples undergo bisulfite conversion, methylation profiling using Illumina EPIC microarray, and cellular deconvolution to generate peripheral blood immune profiles (PMID 35140201), including granulocytic (g) and monocytic (m) myeloid derived suppressor cell (MDSC) scores. Associations between baseline peripheral blood immune profiles before the start of treatment with progression-free survival (PFS) and overall survival (OS) were evaluated using Kaplan Meier curves and Cox proportional hazards models adjusted for age and sex. Additionally, logistic regression models adjusted for age and sex were utilized to investigate the baseline immune profiles between subgroups of patients who received anti-PD-1 monotherapy with durable clinical benefit for at least 1 year (Group A) versus progression or death within 100 days (Group B) from start of therapy. Results: 61 patients with R/M SCCHN who received anti-PD-1 based therapy as of Oct 31, 2022, were eligible for this preliminary analysis. Mean (SD) age of the entire population was 66.4 (11.8) years, 82% were male. gMDSC score was the only immune parameter with a statistically significant association with PFS (HR 2.6 (1.40 – 4.87) independent of age and sex, with higher scores stratified by median value associated with shorter PFS (Median PFS: 75 days vs. 145 days). Memory CD4 T cells, total CD4 T cells, percentage of T regulatory /CD4 cells, and absolute memory B cells were significantly associated with OS in this population, independent of age and sex (Table). Among the subgroup treated with anti-PD-1 monotherapy, Group A with durable benefit (n = 7, 86% male, mean age: 64.7 years) had significantly higher proportion of CD4 naïve/total CD4 cells (p = 0.03), and significantly lower gMDSC (p = 0.015) & mMDSC (p = 0.000049) scores, compared with Group B (n = 27, 78% male, mean age: 66.4 years). Conclusions: Peripheral blood DNA-based epigenetic immune profiling can recognize clinically relevant methylation biomarkers of benefit from anti-PD-1 therapy before the start of treatment. Table: see text
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Background: In the ~1% of patients with SCCHN who experience CNS metastases, median overall survival (mOS) is <1 year. We investigated whether molecular/immunologic features distinguish SCCHN ...cases that metastasize to the CNS. Methods: We performed a case-control study on a convenience sample of individuals with SCCHN treated at two academic institutions. Next generation targeted sequencing and/or immunoprofiling of primary and metastatic tumor sites were performed. Results: We identified 39 patients with SCCHN (21 with CNS metastases (cases), 18 without (controls)). Median age at diagnosis 60, 79% male, 46% current/former smokers, 51% oropharyngeal primary, 51% HPV+/31% HPV-/18% not tested (NT) across all cases, and 69% stage III or IV disease at diagnosis. HPV+ frequency trended higher among cases (52%+, 14%-, 33% NT) vs. controls (50%+, 50%-, 0% NT) (p=0.08). mOS from diagnosis was 34.4 months (95% CI 14.5-41.0) in cases and 44.4 months (95% CI 19.0-82.3) in controls. Genomic data was available for 18 (86%) cases and 12 (67%) controls. Most common mutations in cases were KMT2D (39%) and NOTCH1 (39%). There were no genes for which alteration frequency differed significantly between groups. Tumors of 18 (86%) cases and 18 (100%) controls underwent immunoprofiling. Mean PD-1 density at the tumor-stroma interface (TSI), CPS, and TPS were higher in controls (Table). In cases, TSI PD-1 density tended to be higher at primary sites than at sites of CNS metastases. No significant difference was seen in CD8 or FOXP3 staining. Conclusions: SCCHN with CNS metastases shows markers of lower immunogenicity at both the primary site and site of CNS metastasis vs. other SCCHN tumors, regardless of HPV status. This suggests that localized tumors with low immune infiltration and poor responsiveness to immunotherapy may be at higher risk of CNS metastasis and could imply reduced benefit from immunotherapy for patients with CNS metastases. Table: see text
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