Resistance to oncogene-targeted therapies involves discrete drug-tolerant persister cells, originally discovered through in vitro assays. Whether a similar phenomenon limits efficacy of programmed ...cell death 1 (PD-1) blockade is poorly understood. Here, we performed dynamic single-cell RNA-Seq of murine organotypic tumor spheroids undergoing PD-1 blockade, identifying a discrete subpopulation of immunotherapy persister cells (IPCs) that resisted CD8+ T cell-mediated killing. These cells expressed Snai1 and stem cell antigen 1 (Sca-1) and exhibited hybrid epithelial-mesenchymal features characteristic of a stem cell-like state. IPCs were expanded by IL-6 but were vulnerable to TNF-α-induced cytotoxicity, relying on baculoviral IAP repeat-containing protein 2 (Birc2) and Birc3 as survival factors. Combining PD-1 blockade with Birc2/3 antagonism in mice reduced IPCs and enhanced tumor cell killing in vivo, resulting in durable responsiveness that matched TNF cytotoxicity thresholds in vitro. Together, these data demonstrate the power of high-resolution functional ex vivo profiling to uncover fundamental mechanisms of immune escape from durable anti-PD-1 responses, while identifying IPCs as a cancer cell subpopulation targetable by specific therapeutic combinations.
Despite widespread administration of programmed death receptor 1 (PD-1) pathway inhibitors among individuals with NSCLC, little is known about the safety and activity of these agents among human ...immunodeficiency virus (HIV) – infected patients since this population has largely been excluded from immunotherapy clinical trials.
Here, we describe seven patients with metastatic NSCLC and HIV infection who were treated with PD-1 inhibitors nivolumab (two cases) or pembrolizumab (five cases with three in the first-line setting).
Partial responses to immune checkpoint inhibitors were observed in three of seven cases. Among four patients with a programmed death ligand-1 tumor proportion score ≥50%, three partial responses were observed. All patients received antiretroviral therapy while on anti–PD-1 treatment. None of the patients experienced grade 3 or 4 immune-related adverse events or immune reconstitution inflammatory syndrome, and none required PD-1 inhibitor dose interruption or discontinuation due to toxicity.
Nivolumab and pembrolizumab can be safe and effective among patients with NSCLC and HIV. Larger studies will be needed to determine the overall safety and efficacy of immune checkpoint inhibitors among cancer patients with HIV.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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Background: Pembrolizumab (P) is now widely used as standard of care (SOC) in advanced NSCLC. We sought to identify prognostic factors influencing survival with it in a real-world ...setting. Methods: We conducted a retrospective cohort study of with advanced NSCLC patients who initiated treatment with SOC P monotherapy at our center from 2/11/16 to 10/15/19 (data cutoff 1/15/20). Patient demographic, clinicopathologic, therapeutic and outcomes data were extracted. Survival time was defined from start of P. Cox proportional hazards and logistic regression were utilized. Results: Of 74 patients with median follow up of 83.9 weeks, 30 (40.5%) were alive at cutoff. Patient characteristics at start of therapy were: 36 (48.6%) female, median age 68.5 yr (range 33-87), 10 (13.5%) with symptomatic brain metastases; 54 (72.9%) treatment-naïve, 29 (39.2%) with ECOG performance status (PS) ≥2. Tumor characteristics were: 53 (71.6%) with PD-L1 tumor proportion score (TPS) ≥50%, median PD-L1 TPS 75% (range 1-100), tumor mutational burden (TMB) tested in only 37 (50%) patients, median TMB 8 mut/mB (range 1-62). Any grade immune-related adverse events (irAE) occurred in 33 (44.6%) patients, while 16 (21.6%) received systemic steroids. Median survival was 43.3 wks (95% CI 29-104.1). Multivariable regression showed ECOG PS of ≥2 as the strongest risk factor for death (Table). We next evaluated differences in characteristics of patients who were alive vs dead within 12 wks of starting P, by which initial response assessments are completed in routine practice. ECOG PS was the only significantly different baseline variable, even after multivariable adjustment (p = 0.002). Conclusions: ECOG PS of ≥2 is a poor prognostic risk factor associated with P monotherapy in advanced NSCLC. Though comprising a clinically significant subset of patients in real-world, they were not included in landmark trials (KEYNOTE-024 & 042). Prospective evaluation is warranted. Table: see text
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Background: P and P+C are standard-of-care (SOC) treatment options for advanced NSCLC. However, they have not yet been directly compared in clinical trials. Methods: We conducted ...a retrospective cohort study of patients with advanced NSCLC who initiated treatment with SOC P±C at our center from 2/11/16 to 10/15/19 (data cutoff 1/15/20). Patient demographic, clinicopathologic, therapeutic and outcomes data were extracted. All radiographic scans were independently evaluated by a thoracic radiologist using iRECIST. Survival time was defined from the start of P±C. Kaplan-Meier and Cox proportional hazards model were utilized. Results: Of 103 patients with median follow up of 17.7 months, 74 (71.8%) had received P, while 29 (28.2%) had received P+C. In PD-L1 tumor proportion score (TPS) unselected population, there were no significant differences in age, sex, smoking status, driver mutation, tumor mutational burden (TMB), line of therapy, ECOG performance status (PS) or immune-related adverse events (irAE) between P and P+C groups. 71.6% in P vs 13.8% in P+C had PD-L1 TPS ≥50% (p < 0.001). There were no significant differences between the two groups in objective response rate (ORR), disease control rate (DCR), unadjusted progression-free survival (PFS) or unadjusted overall survival (OS) (Table). Multivariable adjustment for confounding factors between P+C vs P revealed no differences in OS hazard ratio (HR) for death, 1.53, 95% CI 0.55 – 4.25 or PFS HR for progression/death, 1.75, 95% CI 0.63 – 4.91. Further stratification into PD-L1 TPS ≥50% and < 50% showed no significant differences between P+C vs. P in adjusted OS HR for death, TPS < 50%- 1.54 (95% CI 0.59 – 4.03); TPS ≥50%- 0.71 (95% CI 0.11 – 4.52) or PFS HR for progression/death, TPS < 50%- 1.58 (95% CI 0.72 – 3.48); TPS ≥50%- 0.64 (95% CI 0.06 – 6.93). ECOG PS and development of irAE influenced OS in all groups, while TMB was relevant in PD-L1 ≥50% only. Conclusions: Our study shows no significant differences in outcomes with P vs P+C in advanced NSCLC in a real-world setting, albeit with limitations of single-center design, limited sample size, different line settings and lack of disease burden stratification. Ongoing phase III trials comparing front line P vs P+C will definitively address the long-term clinical benefits -if any- of combining cytotoxic chemotherapy with anti-PD-1 drugs. Table: see text
RAS mutations occur across the spectrum of thyroid neoplasms, and more tools are needed for better prognostication. The objective of this study was to evaluate how additional genetic events affecting ...key genes modify prognosis in patients with RAS-mutant thyroid cancers, and specifically differentiated thyroid cancers (DTC).
We performed a clinical-genomic analysis of consecutive patients with DTC, poorly differentiated (PDTC), or anaplastic thyroid cancer (ATC) between January 2014 and December 2021, in whom a custom-targeted next-generation sequencing assay was performed. Patients harboring RAS mutations were included, and we compared their clinical features and outcomes based upon the presence of additional oncogenic alterations.
Seventy-eight patients were identified, with 22% (17/78) harboring a driver RAS mutation plus an additional oncogenic alteration. All six (100%) ATCs had an additional mutation. Compared with DTCs harboring a solitary RAS mutation, patients with DTC with RAS and additional mutation(s) were more likely to be classified as American Thyroid Association high-risk of recurrence (77% vs. 12%; P < 0.001) and to have larger primary tumors (4.7 vs. 2.5 cm; P = 0.002) and advanced stage (III or IV) at presentation (67% vs. 3%; P < 0.001). Importantly, over an average 65-month follow-up, DTC-specific-mortality was more than 10-fold higher (20% vs. 1.8%; P = 0.011) when additional mutations were identified.
Identification of key additional mutations in patients with RAS-mutant thyroid cancers confers a more aggressive phenotype, increases mortality risk in DTC, and can explain the diversity of RAS-mutated thyroid neoplasia. These data support genomic profiling of DTCs to inform prognosis and clinical decision-making.
Despite approximately 40% of patients having Eastern Cooperative Oncology Group (ECOG) performance status (PS) scores of at least 2 in the real world, most landmark clinical trials that led to the ...use of pembrolizumab as standard of care in advanced non-small cell lung cancer (NSCLC) excluded this group.
To evaluate whether an ECOG PS score of at least 2 at the start of therapy is associated with progression-free survival (PFS) and overall survival (OS) in advanced NSCLC treated with pembrolizumab monotherapy.
This cohort study included all consecutive patients with advanced NSCLC who underwent treatment with palliative pembrolizumab monotherapy from February 2016 to October 2019 at a single academic cancer center, with data censoring on January 15, 2020.
ECOG PS score at start of therapy, with 0 and 1 indicating fully active or restricted in strenuous activity and scores of 2 and higher indicating increasing disability.
PFS and OS, measured from initiation of pembrolizumab monotherapy.
Of 74 patients (median range age, 68.5 33-87 years; 36 48.7% women; 53 71.6% White individuals) with median follow-up of 19.5 (95% CI, 13.4-27.8) months, 45 (60.8%) had an ECOG PS of 0 or 1, while 29 (39.2%) had an ECOG PS of at least 2. There were no significant differences in the baseline characteristics, except in age. Compared with patients with PS scores of 0 or 1, those with PS scores of at least 2 had significantly lower disease control rates (38 88.4% vs 15 53.6%; P = .002), shorter median PFS (7.9 95% CI, 4.6-15.4 months vs 2.3 95% CI, 1.8-4.8 months; P = .004), and shorter median OS (23.2 14.0 vs 35.7 months vs 4.1 95% CI, 2.1-6.9 months; P < .001). Among those potentially eligible for subsequent cancer-directed therapy beyond pembrolizumab monotherapy, patients in the group with PS scores of at least 2 were less likely to receive it than those with PS scores of 0 or 1 (2 8.3% vs 14 45.2%; P = .003). Multivariable adjustment for baseline characteristics confirmed ECOG PS of at least 2 as an independent risk factor for worse PFS (HR, 2.02; 95% CI, 1.09-3.74; P = .03) and worse OS (HR, 2.87; 95% CI, 1.40-5.89; P = .004).
In this cohort study, having an ECOG PS score of at least 2 was associated with poorer prognosis for treatment of advanced NSCLC with palliative pembrolizumab monotherapy. Further prospective studies are needed to evaluate more objective and consistent measures of functional status to facilitate identification of patients with borderline performance status who may achieve durable clinical benefit from treatment with pembrolizumab monotherapy.
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Background: Improved awareness and management of immune checkpoint inhibitor (ICI) related adverse events (IRAEs) is a mandate for best practice given widespread use of ICIs in ...clinic. IRAE grading is standardized by the Common Terminology Criteria for Adverse Events (CTCAE); management has been standardized in recently published consensus guidelines. In the thoracic oncology clinic at the Beth Israel Deaconess Medical Center grading and management of IRAEs has been inconsistent. Methods: A retrospective review of 98 patients receiving ICIs in the thoracic oncology clinic from March 2015-April 2018 was conducted with a focus on IRAE grading and management. Oncologists were surveyed regarding barriers to grading, management, and subspecialty referral for IRAEs. We aimed to improve documentation of IRAE grading to 75% as well as the rate of specialist referral for grade 3-4 IRAEs. As an intervention we implemented a macro to document IRAE CTCAE grade and management. Additionally, our team created a pathway for specialist referral for patients with grade 3-4 IRAEs. Results: Upon review of 98 patient charts, 38 patients developed 58 IRAEs of which 36% were grade 1-2, 17% were grade 3, 0% were grade 4 and 47% were ungraded. The most commonly affected organs were skin (25%), thyroid (25%) and lung (11%). 53% of active IRAEs were formally graded in the oncologist’s assessment, only 6% of resolved IRAEs were documented in the subsequent oncologic history. A total of 11 patients were hospitalized for IRAEs, 7 of which had undocumented severity; 40% of grade 3 IRAEs were hospitalized. 14 specialist referrals were made, most with undocumented severity; 30% of patients with grade 3 IRAEs were referred. Overall, 18 patients required steroids, of these 40% were ungraded, and 19 had immunotherapy stopped or held, of these 45% were ungraded. Conclusions: While the presence of IRAEs is consistently documented, documentation of severity and subsequent management are inconsistent- including amongst those patients requiring hospitalization, specialty referral and/or treatment modification. Further data will be reported regarding utilization of the macro, documentation of IRAE grading and management as well as specialist referral rate.
6036 Background: BM is a rare complication of HNSCC that carries a high rate of morbidity and poor prognosis. Clinical risk factors, molecular characteristics, and the immunogenicity of HNSCC BM are ...not well defined, leaving a critical knowledge gap in this field. We performed one of the largest multi-institutional analyses summarizing the clinical, molecular, and immunologic profile of 61 cases of BM-HNSCC. Methods: We conducted a pooled analysis of the clinical characteristics pertaining to BM-HNSCC from 3 academic institutions (n=24). Next-generation sequencing (NGS) and immune profiling (IP) of primary and BM specimens was conducted on a subset of cases (n=19 and n=16, respectively); there were 3 paired samples for NGS and 0 for IP. Four samples (2 BM and 2 non-BM) were submitted to Phase Genomics, Inc for evaluation of structural variants in BM genomes by proximity ligation sequencing (PLS). These results were complimented by a comparative analysis of genomic alterations in an additional cohort of BM (n=37) and local samples (n=4082) submitted for NGS at Foundation Medicine, Inc (FMI). Statistical comparisons were done using Fisher’s exact testing of 2x2 contingency tables with p-values controlled for FDR by the Benjamini-Hochberg procedure. Results: Clinical features were as follows: median age at diagnosis 59 years, 75% male, 55% current/former smokers, 75% oropharyngeal primary, and 84% HPV+ or p16+. The most frequently altered genes in BM specimens (62% HPV/p16+) were ATM (54%), KMT2A (54%), PTEN (46%), RB1 (46%), and TP53 (46%). BM and non-BM samples demonstrated significant levels of structural rearrangement ranging from 9 to 90 variants by PLS. IP identified lower densities of CD8+, PD1+, PDL1+, and FOXP3+ cells in BMs compared to primary tumors. PDL1 combined positive scores were <1% in 12/13 unpaired samples (92%; 10 BM and 2 primary). The FMI BM-HNSCC cohort (51% HPV+) identified CDKN2A (40.5%), TP53 (37.8%), and PIK3CA (27.0%) as the most frequently altered genes. Enrichment analysis of the FMI cohort showed MAP2K2 alterations significantly enriched in BM (11.8% vs 6.4%, P=0.005) and TSC1 alterations significantly enriched in the local site (67.3% vs 37.8%, P=0.008). HPV+ was also significantly enriched in the BM cohort (51.25% vs 26.11%, P=0.001). Overall survival from BM diagnosis was 6m (range 0-27m). Conclusions: HNSCC patients with BM have higher-than-expected proportions of oropharyngeal primary site and HPV/p16-positivity. The most frequent molecular alterations in BM samples are also commonly found in non-BM HNSCC, including targetable PIK3CA alterations. MAP2K2 alterations were significantly enriched in BM compared to non-BM samples, which warrants further investigation. BM samples also tended to have lower markers of immunogenicity. This latter finding could have important clinical implications when considering immunotherapy or immune-modulating drugs.
2582 Background: The Phase 1/2, dose escalation/expansion study evaluates NGM707, a dual anti-ILT2/ILT4 humanized monoclonal antibody, as monotherapy or in combination with pembrolizumab in patients ...(pt) with advanced solid tumors. Methods: We enrolled pt with locally advanced or metastatic solid tumors into dose-escalating cohorts of 6-1800 mg NGM707 monotherapy and 200-1800 mg NGM707 combined with 200 mg pembrolizumab, administered Q3W IV. Primary aim was to assess safety/tolerability and dosing of expansion cohorts. Secondary/exploratory objectives included pharmacokinetics, biomarkers, and preliminary antitumor activity per RECIST v1.1. Results: As of November 6, 2023, we treated 82 pt with NGM707 monotherapy or combination at dose levels up to 1800 mg; five pt crossed over from monotherapy to combination. Primary tumor types included colorectal, NSCLC, gastric, pancreatic, and melanoma. Median age 59 yrs 28-85; ECOG PS 0 (18.3%), 1 (81.7%). Pt received a median of 4 prior therapies (range 1-16) and 91.5% had metastatic disease. Fifty percent of the pt were pre-treated with anti-PD(L)1. Peripheral RO was dose-dependent, with NGM707 doses ≥200 mg maintaining full ILT2 and ILT4 RO. PK was typical for monoclonal antibodies, with a half-life of 12.8 days. Paired tumor biopsies showed evidence of myeloid and T cell activation. Treatment(tx)-related adverse events (TEAEs) any grade/grade ≥3 occurred in 46.3%/4.8% of pt in the monotherapy and 41.3%/4.4% of pt in the combination. Fatigue (12.2%), arthralgia (9.8%), nausea (9.8%) were reported in monotherapy; fatigue (17.4%), diarrhea (6.5%) were reported in combination. One dose-limiting toxicity (DLT; pneumonitis) occurred in monotherapy and no DLTs in combination. MTD was not reached for both tx; MAD was 1800 mg NGM707. Of 35 response-evaluable monotherapy pt, best overall responses (BOR) were one confirmed PR in pt with melanoma, SD (n=9) and non-CR/non-PD (n=1), leading to DCR ~31%. Eight pt had reduced target lesion (TL) size with maximum reduction of 71%. Of 37 response-evaluable pt in combination, the BOR to date are PR (confirmed; n=4), and SD (n=12), representing DCR ~43%. Nine pt had reduced TL size with a maximum reduction of 100%. Of the 4 pt who had PR, 3 pt were pre-treated with anti-PD(L)1. Two pt with MSS CRC achieved PR, one of them with liver/adrenal TL reduction allowing surgical resection of all residual disease with pCR; ctDNA was not detected. Durable response in this pt led to PFS of 11 months prior to the surgery and ongoing DFS post-surgery. Conclusions: NGM707 as monotherapy and in combination with pembrolizumab was safe and well tolerated at all dose levels. In heavily pretreated advanced and metastatic solid tumor malignancies, we observed early efficacy and biomarker signals, including in tumors considered unresponsive to anti-PD(L)1. These results support further evaluation of NGM707. Clinical trial information: NCT04913337 .
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