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BACKGROUND: Immune checkpoint inhibitors (ICI) have profoundly impacted survival among patients with metastatic non-small cell lung cancer (NSCLC). However, population-based studies evaluating this impact on survival by race and socioeconomic factors are lacking. METHODS: We utilized the SEER-Medicare database to identify patients with metastatic NSCLC diagnosed between 2015 and 2019. The primary study outcomes were the receipt of an ICI and overall survival (OS). Chi-square tests and logistic regression were utilized to identify demographic factors associated with receipt of ICI. The Kaplan-Meier method was used to calculate 2-year OS rates, and log-rank tests were used to compared survival by race/ethnicity. RESULTS: Out of 17,134 patients, approximately 39% received an ICI. Those diagnosed with cancer recently (in 2019), who are relatively younger (<85 years old), non-Hispanic white, non-Hispanic Asian, or Hispanic, living in high socioeconomic status or metropolitan areas, not Medicaid eligible, and with adenocarcinoma histology were more likely to receive ICI. The 2-year OS rate from diagnosis was 21% for the overall population. The 2-year OS rate from ICI initiation was 30%, among those who received at least one cycle and 11% among those who did not receive ICI. The 2-year OS rates were higher among non-Hispanic whites (22%) and non-Hispanic Asians (23%) compared to non-Hispanic Blacks (15%) and Hispanics (17%). There was no significant racial differences in survival for those who received ICI. CONCLUSION: ICI utilization rates and the resulting outcomes were inferior for certain vulnerable groups, mandating the need for strategies to improve access to care.
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BACKGROUND: About 75% of medullary thyroid cancers (MTCs) are sporadic with 45% to 70% being driven by a RET mutation. Selpercatinib is an approved treatment for RET-mutated (mut RET ) MTC; however, treatments are needed for wild-type RET MTC (wt RET ). Genomic alterations and transcriptomic signatures of wt RET MTC may reveal new therapeutic insights. STUDY DESIGN: We did a retrospective analysis of MTC samples submitted for DNA/RNA sequencing and programmed cell death ligand 1 expression using immunohistochemistry at a Clinical Laboratory Improvement Amendments/College of American Pathologists-certified laboratory. Tumor microenvironment immune cell fractions were estimated using RNA deconvolution (quanTIseq). Transcriptomic signatures of inflammation and MAP kinase pathway activation scores were calculated. Mann-Whitney U, chi-square, and Fisher's exact tests were applied (p values adjusted for multiple comparisons). RESULTS: The 160-patient cohort included 108 mut RET and 52 wt RET MTC samples. wt RET tumors frequently harbored mitogen-activated protein kinase (MAPK) pathway mutations, including HRAS (42.31%), KRAS (15.7%), NF1 (6.7%), and BRAF (2%), whereas only 1 MAPK pathway mutation ( NF1 ) was identified among mut RET MTC. Recurrent mutations seen in wt RET MTC included MGA , VHL, APC , STK11 , and NFE2L2 . Increased transcriptional activation of the MAPK pathway was observed in patients with wt RET harboring mutations in MAPK genes. Although the frequency of programmed cell death ligand 1 expression was similar in wt RET and mut RET (10.2% vs 7%, p = 0.531), wt RET tumors were more often tumor mutational burden high (7.7% vs 0%, p = 0.011), and wt RET MTC exhibited higher expression of immune checkpoint genes. CONCLUSIONS: We identified molecular alterations and immune-related features that distinguish wt RET from mut RET MTC. Although RET mutation drives MTC in the absence of other alterations, we showed that wt RET MTC frequently harbors MAPK pathway mutations. These findings may indicate a potential basis for MAPK-targeted therapy, possibly in combination with immuno-oncology agents for selected patients with wt RET MTC.
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Carcinoma Neuroendocrino , Mutación , Proteínas Proto-Oncogénicas c-ret , Neoplasias de la Tiroides , Transcriptoma , Humanos , Neoplasias de la Tiroides/genética , Neoplasias de la Tiroides/tratamiento farmacológico , Estudios Retrospectivos , Proteínas Proto-Oncogénicas c-ret/genética , Femenino , Persona de Mediana Edad , Masculino , Carcinoma Neuroendocrino/genética , Carcinoma Neuroendocrino/tratamiento farmacológico , Adulto , Anciano , Terapia Molecular Dirigida , Proteínas Quinasas Activadas por Mitógenos/metabolismo , Proteínas Quinasas Activadas por Mitógenos/genética , Microambiente Tumoral , Anciano de 80 o más Años , Genómica , Adulto JovenRESUMEN
In this phase 2 multicenter study, we evaluated the efficacy and safety of lifileucel (LN-145), an autologous tumor-infiltrating lymphocyte cell therapy, in patients with metastatic non-small cell lung cancer (mNSCLC) who had received prior immunotherapy and progressed on their most recent therapy. The median number of prior systemic therapies was 2 (range, 1-6). Lifileucel was successfully manufactured using tumor tissue from different anatomic sites, predominantly lung. The objective response rate was 21.4% (6/28). Responses occurred in tumors with profiles typically resistant to immunotherapy, such as PD-L1-negative, low tumor mutational burden, and STK11 mutation. Two responses were ongoing at the time of data cutoff, including one complete metabolic response in a PD-L1-negative tumor. Adverse events were generally as expected and manageable. Two patients died of treatment-emergent adverse events: cardiac failure and multiple organ failure. Lifileucel is a potential treatment option for patients with mNSCLC refractory to prior therapy. Significance: Autologous tumor-infiltrating lymphocyte therapy lifileucel was administered to 28 patients with heavily pretreated metastatic non-small cell lung cancer (mNSCLC). Responses were observed in patients with driver mutations, and various tumor mutational burdens and PD-L1 expression, potentially addressing an unmet medical need in patients with mNSCLC refractory to prior therapy. See related commentary by Lotze et al., p. 1366.
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Carcinoma de Pulmón de Células no Pequeñas , Inhibidores de Puntos de Control Inmunológico , Neoplasias Pulmonares , Linfocitos Infiltrantes de Tumor , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Masculino , Persona de Mediana Edad , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/patología , Resistencia a Antineoplásicos , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/patología , Linfocitos Infiltrantes de Tumor/inmunología , Linfocitos Infiltrantes de Tumor/trasplanteRESUMEN
PURPOSE: Adenoid cystic carcinoma (ACC) is an uncommon salivary gland cancer with no approved therapies available to treat advanced, incurable disease. Recent molecular profiling efforts have identified two important subtypes: the more aggressive ACC-I is characterized by Notch pathway alterations and MYC amplification whereas ACC-II demonstrates a more indolent phenotype and TP63 overexpression. EXPERIMENTAL DESIGN: This retrospective observational cohort study involved de-identified samples from 438 patients with ACC with tumor samples sent for commercially-available molecular profiling (Caris Life Sciences). Next-generation whole-exome and whole-transcriptomic sequencing was performed on primary and metastatic samples. Immunostaining for PD-L1 and RNA deconvolution (quanTIseq) was used to explore the tumor immune microenvironment (TME). Real-world clinical and survival outcome metrics were extracted from insurance claims data. RESULTS: MYC expression was 1.61-fold higher (39.8 vs. 24.7; P < 0.0001) among NOTCH1-mutant ACC-I tumors, whereas MYB/L1 fusion rates were similar among ACC-I/II. The median B-cell fraction in the TME was higher among ACC-II (7.1% vs. 5.8%; P < 0.01), although infiltrating T cells subsets were low among either ACC subgroup (both <1%). When pooling systemic treatment categories, ACC-I patients had worse outcomes with available therapies (HR, 3.06; 95% confidence interval, 1.65-5.68; P < 0.01), with no significant difference in overall survival between ACC-I/II based on chemotherapy or VEGFR tyrosine kinase inhibitor exposure in smaller subsets. CONCLUSIONS: We confirmed the previously reported associations with MYC and TP63 in the prognostically relevant subgroups of ACC-I and -II, respectively, and report immunologic differences among these subtypes. Survival outcomes are comparatively worse in ACC-I regardless of treatment type.
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Biomarcadores de Tumor , Carcinoma Adenoide Quístico , Neoplasias de las Glándulas Salivales , Microambiente Tumoral , Humanos , Carcinoma Adenoide Quístico/genética , Carcinoma Adenoide Quístico/patología , Carcinoma Adenoide Quístico/mortalidad , Carcinoma Adenoide Quístico/tratamiento farmacológico , Carcinoma Adenoide Quístico/inmunología , Carcinoma Adenoide Quístico/terapia , Masculino , Femenino , Persona de Mediana Edad , Anciano , Microambiente Tumoral/inmunología , Microambiente Tumoral/genética , Neoplasias de las Glándulas Salivales/genética , Neoplasias de las Glándulas Salivales/patología , Neoplasias de las Glándulas Salivales/mortalidad , Neoplasias de las Glándulas Salivales/inmunología , Neoplasias de las Glándulas Salivales/terapia , Neoplasias de las Glándulas Salivales/tratamiento farmacológico , Biomarcadores de Tumor/genética , Estudios Retrospectivos , Adulto , Resultado del Tratamiento , Perfilación de la Expresión Génica , Proteínas Proto-Oncogénicas c-myc/genética , Pronóstico , Antígeno B7-H1/genética , Receptor Notch1/genética , Regulación Neoplásica de la Expresión Génica , Anciano de 80 o más Años , MutaciónRESUMEN
PURPOSE: Tumoral programmed cell death ligand-1 (PD-L1) expression is common in human papillomavirus (HPV)-associated head and neck squamous cell carcinoma (HNSCC). We assessed whether a DNA vaccine targeting HPV-16/18 E6/E7 with IL12 adjuvant (MEDI0457) combined with the PD-L1 inhibitor durvalumab could enhance HPV-specific T-cell response and improve outcomes in recurrent/metastatic HPV-16/18-associated HNSCC. PATIENTS AND METHODS: In this phase Ib/IIa study, immunotherapy-naïve patients with ≥1 previous platinum-containing regimen (neoadjuvant/adjuvant therapy or for recurrent/metastatic disease) received MEDI0457 7 mg intramuscularly with electroporation on weeks 1, 3, 7, and 12, then every 8 weeks, plus durvalumab 1,500 mg intravenously on weeks 4, 8, and 12, then every 4 weeks, until confirmed progression and/or unacceptable toxicity. Coprimary objectives were safety and objective response rate (ORR; H0: ORR ≤ 15%); secondary objectives included 16-week disease control rate (DCR-16), overall survival (OS), and progression-free survival (PFS). RESULTS: Of 35 treated patients, 29 were response evaluable (confirmed HPV-associated disease; received both agents). ORR was 27.6% [95% confidence interval (CI), 12.7-47.2; four complete responses, four partial responses]; responses were independent of PD-L1 tumor-cell expression (≥25% vs. <25%). DCR-16 was 44.8% (95% CI, 26.5-64.3). Median PFS was 3.5 months (95% CI, 1.9-9.0); median OS was 29.2 months (15.2-not calculable). Twenty-eight (80.0%) patients had treatment-related adverse events [grade 3: 5 (14.3%); no grade 4/5], resulting in discontinuation in 2 (5.7%) patients. HPV-16/18-specific T cells increased on treatment; 4 of 8 evaluable patients had a >2-fold increase in tumor-infiltrating CD8+ T cells. CONCLUSIONS: MEDI0457 plus durvalumab was well tolerated. While the primary efficacy endpoint was not reached, clinical benefit was encouraging.
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Neoplasias de Cabeza y Cuello , Infecciones por Papillomavirus , Humanos , Carcinoma de Células Escamosas de Cabeza y Cuello/tratamiento farmacológico , Virus del Papiloma Humano , Neoplasias de Cabeza y Cuello/tratamiento farmacológico , Infecciones por Papillomavirus/complicaciones , Papillomavirus Humano 16/genética , Antígeno B7-H1/genética , Papillomavirus Humano 18RESUMEN
BACKGROUND: We performed an integrated biomarker evaluation in pembrolizumab-treated patients with R/M HNSCC enrolled in KEYNOTE-012 or KEYNOTE-055. The relationship between biomarkers and HPV status was explored. METHODS: We evaluated PD-L1 (combined positive score [CPS]), TMB, T-cell-inflamed gene expression profile (Tcellinf GEP), and HPV status. Associations between biomarkers were evaluated by logistic regression (ORR) and Cox regression (PFS, OS). RESULTS: Two hundred and fifty-seven patients (KEYNOTE-012, n = 106; KEYNOTE-055, n = 151) had TMB data available; of these, 254 had PD-L1 and 236 had Tcellinf GEP. TMB, PD-L1, and Tcellinf GEP were each significantly associated with ORR (p < 0.01). Kaplan-Meier curves at prespecified cutoffs generally showed PFS and OS separation in the anticipated direction for these biomarkers, except for OS and TMB. TMB did not correlate with PD-L1 or Tcellinf GEP (Spearman ρ = -0.03 and ρ = -0.13, respectively); PD-L1 and Tcellinf GEP were moderately correlated (Spearman ρ = 0.47). In multivariate models, TMB, PD-L1, and Tcellinf GEP were each independently predictive for ORR (p < 0.001). ORR was higher in patients with high versus low levels of biomarkers when dichotomized using prespecified cutoffs; patients with higher versus lower levels of TMB and PD-L1 or TMB and Tcellinf GEP had the highest ORRs. Within HPV subgroups, higher versus lower distributions of biomarkers (PD-L1, TMB, and Tcellinf GEP) were associated with response. HPV detection by p16-immunohistochemistry and WES showed good concordance (81%); results were generally similar by HPV status, regardless of the detection method. CONCLUSIONS: TMB and the inflammatory biomarkers PD-L1 and Tcellinf GEP, assessed alone or together, may be useful for characterizing clinical response to pembrolizumab in R/M HNSCC.
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Antineoplásicos Inmunológicos , Neoplasias de Cabeza y Cuello , Infecciones por Papillomavirus , Humanos , Antígeno B7-H1 , Carcinoma de Células Escamosas de Cabeza y Cuello/tratamiento farmacológico , Carcinoma de Células Escamosas de Cabeza y Cuello/inducido químicamente , Infecciones por Papillomavirus/complicaciones , Antineoplásicos Inmunológicos/efectos adversos , Neoplasias de Cabeza y Cuello/tratamiento farmacológico , Biomarcadores de Tumor/genéticaRESUMEN
BACKGROUND: Immune checkpoint inhibitors (ICIs) are the newest class of anticancer drugs. Pneumonitis is increasingly being recognized as a potential complication of these agents. METHODS: We conducted a retrospective study of patients who received ICIs at a comprehensive cancer center. We collected data on demographics, type of malignancy, type of ICI agent, incidence of pneumonitis up to 6 weeks after receiving ICI agent, clinical characteristics, and risk factors for overall survival in patients who develop pneumonitis. RESULTS: A total of 654 patients received ICIs during the study period. The most common type of cancer for which ICI was given was adenocarcinoma of the lung (29%), followed by renal cell cancer (12%) and squamous cell lung cancer (12%). Among the study patients, 41% received nivolumab and 32% received pembrolizumab. Other patients in the study received combination of ICIs or ICI plus chemotherapeutic agent, or were part of clinical trial involving ICI. Overall 42 (6.4%) patients developed pneumonitis within 6 weeks after the last dose of treatment of any ICI agent. Of these, 81% of patients had Grade ≥ 2 pneumonitis and 45% of these required hospital admission for pneumonitis, with 10% of them requiring admission to intensive care unit. Overall, patients who received pembrolizumab-containing regimen, had prior chemotherapy, or who never had cancer-related surgery had increased risk of death. CONCLUSION: Our large retrospective study shows real-life data of incidence of pneumonitis in patients who are treated with ICIs for cancer treatment. Our data indicate that the incidence of pneumonitis is overall lower than that reported previously with relatively good outcomes.
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Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Neumonía , Humanos , Inhibidores de Puntos de Control Inmunológico/efectos adversos , Incidencia , Estudios Retrospectivos , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Neumonía/inducido químicamente , Neumonía/epidemiología , Neoplasias Pulmonares/tratamiento farmacológicoRESUMEN
Mammary analog secretory carcinoma (MASC) is a newly described carcinoma with a molecular hallmark of ETV6-NTRK3 fusion that promotes oncogenesis. While MASC histopathology was well-studied in the literature, clinical behavior remains unstudied. We present a 22-year-old man with painless parotid mass, which was diagnosed as salivary gland cancer, MASC subtype.
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Although treated appropriately, bladder cancer can recur and metastasize. We are reporting the case of a patient with a well-cured bladder cancer who presented after 14 months with femoral pain which turned out to be a bony metastasis. The patient underwent surgical excision followed by chemotherapy.
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PURPOSE: Locoregional relapse in patients with head and neck squamous cell carcinoma (HNSCC) is common, approaching 50% for some subsites despite multimodality therapy. Salvage surgery is the standard of care, but able to achieve durable control in only a minority of patients. While adjuvant radiotherapy or chemo-radiotherapy is offered to select patients, this approach can be prohibitively toxic. Given the activity and tolerability of programmed death-1 inhibitors in metastatic HNSCC, we investigated the safety and efficacy of adjuvant nivolumab after salvage surgical resection. PATIENTS AND METHODS: This was an open-label, multi-institutional phase II clinical trial (NCT03355560). Patients with recurrent, resectable HNSCC were enrolled within 6 weeks of salvage surgery. Six 28-day cycles of adjuvant nivolumab were planned. The primary endpoint was 2-year disease-free survival (DFS) more than 58%, based on an institutional historical control group of 71 patients with recurrent HNSCC who underwent salvage surgery. RESULTS: Between February 2018 and February 2020, 39 patients were enrolled. At a median follow-up of 22.1 months, 2-year DFS was 71.4% [95% confidence interval (CI), 57.8-88.1] and the 2-year overall survival (OS) was 73% (95% CI, 58-91.8). Three of 39 (8%) patients experienced grade 3 treatment-related adverse events and 3 of 39 (8%) discontinued treatment due to side effects. Ten of 39 had locoregional recurrence, while 2 of 10 also had synchronous metastatic disease. There was no difference in DFS between PD ligand-1 (PD-L1)-positive and PD-L1-negative patients. There was a nonsignificant trend toward improved DFS in patients with high tumor mutational burden (P = 0.083). CONCLUSIONS: Adjuvant nivolumab after salvage surgery in locally recurrent HNSCC is well tolerated and showed improved DFS compared with historical controls.
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Carcinoma de Células Escamosas , Neoplasias de Cabeza y Cuello , Antígeno B7-H1 , Carcinoma de Células Escamosas/tratamiento farmacológico , Carcinoma de Células Escamosas/cirugía , Neoplasias de Cabeza y Cuello/tratamiento farmacológico , Humanos , Recurrencia Local de Neoplasia/patología , Nivolumab/efectos adversos , Carcinoma de Células Escamosas de Cabeza y Cuello/terapiaRESUMEN
BACKGROUND: Initial primary head and neck cancer (IPHNC) is associated with second primary lung cancer (SPLC). We studied this association in a population with a high proportion of African American (AA) patients. METHODS: Patients with IPHNC and SPLC treated between 2000 and 2017 were reviewed for demographic, disease, and treatment-related characteristics and compared to age-and-stage-matched controls without SPLC. Logistic and Cox regression models were used to analyze the relationship of these characteristics with the development of SPLC and overall survival (OS). RESULTS: Eighty-seven patients and controls were compared respectively. AA race was associated with a significantly higher risk of developing SPLC (OR 2.92, 95% CI 1.35-6.66). After correcting for immortal time bias, patients with SPLC had a significantly lower OS when compared with controls (HR 0.248, 95% CI 0.170-0.362). CONCLUSIONS: We show that AA race is associated with an increased risk of SPLC after IPHNC; reasons of this increased risk warrant further investigation.
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Neoplasias de Cabeza y Cuello , Neoplasias Pulmonares , Neoplasias Primarias Secundarias , Negro o Afroamericano , Neoplasias de Cabeza y Cuello/complicaciones , Humanos , Neoplasias Primarias Secundarias/epidemiología , Estudios Retrospectivos , Factores de RiesgoRESUMEN
PURPOSE: Head and neck squamous cell carcinoma (HNSCC) is a frequently devastating cancer that affects more than a half million people annually worldwide. Although some cases arise from infection with human papillomavirus (HPV), HPV-negative HNSCC is more common, and associated with worse outcome. Advanced HPV-negative HNSCC may be treated with surgery, chemoradiation, targeted therapy, or immune checkpoint inhibition (ICI). There is considerable need for predictive biomarkers for these treatments. Defects in DNA repair capacity and loss of cell-cycle checkpoints sensitize tumors to cytotoxic therapies, and can contribute to phenotypes such as elevated tumor mutation burden (TMB), associated with response to ICI. Mutation of the tumor suppressors and checkpoint mediators TP53 and CDKN2A is common in HPV-negative HNSCC. EXPERIMENTAL DESIGN: To gain insight into the relation of the interaction of TP53 and CDKN2A mutations with TMB in HNSCC, we have analyzed genomic data from 1,669 HPV-negative HNSCC tumors with multiple criteria proposed for assessing the damaging effect of TP53 mutations. RESULTS: Data analysis established the TP53 and CDKN2A mutation profiles in specific anatomic subsites and suggested that specific categories of TP53 mutations are more likely to associate with CDKN2A mutation or high TMB based on tumor subsite. Intriguingly, the pattern of hotspot mutations in TP53 differed depending on the presence or absence of a cooccurring CDKN2A mutation. CONCLUSIONS: These data emphasize the role of tumor subsite in evaluation of mutational profiles in HNSCC, and link defects in TP53 and CDKN2A to elevated TMB levels in some tumor subgroups.
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Carcinoma de Células Escamosas , Neoplasias de Cabeza y Cuello , Infecciones por Papillomavirus , Biomarcadores de Tumor/genética , Carcinoma de Células Escamosas/patología , Inhibidor p16 de la Quinasa Dependiente de Ciclina/genética , Neoplasias de Cabeza y Cuello/genética , Humanos , Mutación , Infecciones por Papillomavirus/complicaciones , Infecciones por Papillomavirus/genética , Carcinoma de Células Escamosas de Cabeza y Cuello/genética , Proteína p53 Supresora de Tumor/genéticaRESUMEN
PURPOSE: ARRY-382 (PF-07265804) is a selective inhibitor of colony-stimulating factor-1 receptor. We evaluated the safety and preliminary efficacy of ARRY-382 plus pembrolizumab in patients with advanced solid tumors. PATIENTS AND METHODS: This was an open-label, multicenter, Phase 1b/2 study (NCT02880371) performed over September 1, 2016 to October 24, 2019. In the Phase 1b dose-escalation, patients with selected advanced solid tumors received ARRY-382 [starting dose 200 mg once daily (QD) orally] plus pembrolizumab [2 mg/kg intravenously (IV) every 3 weeks (Q3W)]. Phase 2 patients had: Pancreatic ductal adenocarcinoma (PDA); programmed cell death protein-1 (PD-1)/PD-ligand 1 (PD-L1) inhibitor-refractory (PD-1/PD-L1 IR) advanced solid tumors; or platinum-resistant ovarian cancer (prOVCA). Patients received ARRY-382 at the maximum tolerated dose (MTD) of 300 mg QD plus pembrolizumab 200 mg IV Q3W. RESULTS: Primary endpoints of dose-limiting toxicities (DLT; Phase 1b) and objective response rate (Phase 2) were met. In Phase 1b, 19 patients received ARRY-382 200-400 mg. Three patients reported DLTs. The MTD of ARRY-382 (plus pembrolizumab) was 300 mg QD. In Phase 1b, 2 patients (10.5%) had confirmed partial response (PR): 1 with PDA and 1 with ovarian cancer, lasting 29.2 and 3.1 months, respectively. In Phase 2, there were 27, 19, and 11 patients in the PDA, PD-1/PD-L1 IR, and prOVCA cohorts, respectively. One patient (3.7%) with PDA had a PR lasting 2.4 months. The most frequent ARRY-382-related adverse events were increased transaminases (10.5%-83.3%) and increased creatine phosphokinase (18.2%-50.0%). CONCLUSIONS: Although limited clinical benefit was observed, ARRY-382 plus pembrolizumab was well tolerated.
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Neoplasias Ováricas , Receptor de Muerte Celular Programada 1 , Anticuerpos Monoclonales Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Antígeno B7-H1 , Femenino , Humanos , Neoplasias Ováricas/tratamiento farmacológico , Inhibidores de Proteínas QuinasasRESUMEN
BACKGROUND: HER2 alteration (mutation and/or amplification) is associated with poor survival in NSCLC and can mediate resistance to EGFR tyrosine kinase inhibitors. METHODS: We retrospectively analyzed de-identified molecular information from 12,946 NSCLC samples that underwent next-generation sequencing (NGS) with Caris Life Sciences. The objectives were to determine the prevalence and type of HER2 alterations with and without EGFR as a co-mutation. Insurance claims were utilized to obtain outcomes data. RESULTS: Three hundred and twenty-one patients (2.5%) had HER2 alteration: mutation in 197 patients and amplification in 134. Median age was 65 years and 62% were female. A total of 84% were adenocarcinoma. HER2 exon 20 insertion was most common (69%). A total of 1551 (12%) patients had EGFR mutations. Among samples with EGFR mutations, 24 (1.5%) had concurrent HER2 alteration (8 with HER2 mutation and 16 with amplification). Among 8 patients who had both EGFR and HER2 mutations, 3 had EGFR exon 19 deletions and exon 8 HER2 mutation (S310F). One-third of the patients (7/21) with HER2 extracellular domain (ECD) mutation had co-occurring EGFR mutations. All 7 were S310. Patients with concurrent EGFR mutation and HER2 amplification had longer median time on treatment with EGFR TKI(s) than those with EGFR mutation without HER2 amplification (HR 2.284, P =.004). CONCLUSION: A minority of NSCLC samples with EGFR mutations had HER2 alterations. In patients with both mutations, exon 21 mutations for EGFR and exon 8 mutations for HER2 were common. It will be critical to continue to accumulate valuable clinical data for further real-world outcomes analysis.
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Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/genética , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Mutación , Receptor ErbB-2/genética , Anciano , Carcinoma de Pulmón de Células no Pequeñas/patología , Receptores ErbB/genética , Femenino , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Masculino , Persona de Mediana Edad , Pirazoles/uso terapéutico , Pirimidinas/uso terapéutico , Estudios RetrospectivosRESUMEN
Recurrent/metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) patients overall have a poor prognosis. However, human papillomavirus (HPV)-associated R/M oropharyngeal squamous cell carcinoma (OPSCC) is associated with a better prognosis compared to HPV-negative disease. Immune checkpoint blockade (ICB) is the standard of care for R/M HNSCC. However, whether HPV and its surrogate marker, p16, portend an improved response to ICB remains controversial. We queried the Caris Life Sciences CODEai database for p16+ and p16- HNSCC patients using p16 as a surrogate for HPV. A total of 2905 HNSCC (OPSCC, n = 948) cases were identified. Of those tested for both HPV directly and p16, 32% (251/791) were p16+ and 28% (91/326) were HPV+. The most common mutation in the OPSCC cohort was TP53 (33%), followed by PIK3CA (17%) and KMT2D (10.6%). TP53 mutations were more common in p16- (49%) versus the p16+ group (10%, p < 0.0005). Real-world overall survival (rwOS) was longer in p16+ compared to p16- OPSCC patients, 33.3 vs. 19.1 months (HR = 0.597, p = 0.001), as well as non-oropharyngeal (non-OP) HNSCC patients (34 vs. 17 months, HR 0.551, p = 0.0001). There was no difference in the time on treatment (TOT) (4.2 vs. 2.8 months, HR 0.796, p = 0.221) in ICB-treated p16+ vs. p16- OPSCC groups. However, p16+ non-OP HNSCC patients treated with ICB had higher TOT compared to the p16- group (4.3 vs. 3.3 months, HR 0.632, p = 0.016), suggesting that p16 may be used as a prognostic biomarker in non-OP HNSCC, and further investigation through prospective clinical trials is warranted.
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This is a case of a 60-year-old man living with HIV who presented with advanced cutaneous squamous cell carcinoma. After workup, medical and surgical treatment, and disease recurrence, he achieved a complete response with no unexpected toxicities after immunotherapy with cemiplimab.
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Importance: In head and neck cancer survivors, lung cancer screening may aid in detecting a second primary lung cancer or metastatic head and neck cancer earlier in the course of disease, which may improve treatment outcomes. However, no randomized data exist to assess the value of lung cancer screening in this population. Objective: To evaluate the incidence of second primary lung cancer in survivors of head and neck cancer survivors with screening low-dose computed tomography (CT) vs chest radiography (CXR). Design, Setting and Participants: For this ad hoc secondary analysis of a randomized clinical trial, head and neck cancer survivors were identified from the National Lung Screening Trial, which enrolled participants from August 2002 to April 2004. This randomized clinical trial compared screening using low-dose CT chest vs CXR in patients aged 55 to 74 years with at least a 30 pack-year history of cigarette smoking and who were current smokers or had quit within the past 15 years and who were at high risk for lung cancer. The incidences of second primary lung cancer and second primary head and neck cancer were compared with screening using low-dose CT vs CXR. Data were analyzed from December 1, 2020, to June 30, 2021. Interventions: Screening low-dose CT of the chest vs CXR. Main Outcomes and Measures: The primary outcome was the incidence of a second primary lung cancer. Results: Among 53â¯452 enrolled participants, we identified 171 survivors of head and neck cancer, of whom 82 were screened with low-dose CT of the chest and 89 with CXR. Participants' mean (SD) age was 61 (5) years, and 132 were men (77.2%). The incidence of lung cancer was higher among head and neck cancer survivors compared with participants without head and neck cancer (2080 per 100â¯000 person-years [2.1%] vs 609 per 100â¯000 person-years [0.6%]; adjusted rate ratio, 2.54; 95% CI, 1.63-3.95). In head and neck cancer survivors, the incidence of second primary lung cancer was 2610 cases per 100â¯000 person-years in the low-dose CT group vs 1594 cases per 100â¯000 person-years in the CXR group (rate ratio, 1.55; 95% CI, 0.59-3.63). In head and neck cancer survivors, overall survival was 7.07 years with low-dose CT vs 6.66 years with CXR (log-rank P = .48). Conclusions and Relevance: The results of this ad hoc secondary analysis of a randomized clinical trial suggest that head and neck cancer survivors are at especially high risk for a second primary lung cancer. These findings underscore the importance of low-dose CT screening in head and neck cancer survivors with significant cigarette smoking history who are fit to undergo treatment with curative intent.
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Carcinoma/diagnóstico por imagen , Detección Precoz del Cáncer/métodos , Neoplasias de Cabeza y Cuello/diagnóstico por imagen , Neoplasias Pulmonares/diagnóstico por imagen , Pulmón/diagnóstico por imagen , Neoplasias Primarias Secundarias/diagnóstico por imagen , Tomografía Computarizada por Rayos X , Adulto , Cuidados Posteriores/métodos , Anciano , Anciano de 80 o más Años , Carcinoma/epidemiología , Carcinoma/etiología , Fumar Cigarrillos/efectos adversos , Femenino , Estudios de Seguimiento , Neoplasias de Cabeza y Cuello/epidemiología , Humanos , Incidencia , Neoplasias Pulmonares/epidemiología , Neoplasias Pulmonares/etiología , Masculino , Persona de Mediana Edad , Neoplasias Primarias Secundarias/epidemiología , Neoplasias Primarias Secundarias/etiología , Factores de Riesgo , Tomografía Computarizada por Rayos X/métodosRESUMEN
Kirsten rat sarcoma viral oncogene homolog (KRAS) is a proto-oncogene of the RAS-MAPK pathway. KRAS mutations are present in a variety of malignancies including lung, colorectal, and pancreatic cancer. Until the recent approval of sotorasib, a KRAS G12C inhibitor, lack of targeted therapy for KRAS has resulted in poor prognosis of patients with tumors harboring KRAS mutations. While the conditional approval of sotorasib was a major breakthrough for those patients harboring KRAS G12C mutations, G12C only accounts for a fraction of those with KRAS mutations and eventual resistance to G12C inhibitors are unavoidable. This comprehensive review on KRAS inhibitors covers accumulating evidence on not only the G12C inhibitors but also other therapeutic attempts to tackle KRAS including combination therapy as well as direct inhibition with vaccines, adoptive T cell therapy, proteolysis-targeted chimeras (PROTACs) and CRISPR/Cas9.
Asunto(s)
Antineoplásicos , Vacunas contra el Cáncer/farmacología , Edición Génica/métodos , Inmunoterapia Adoptiva/métodos , Neoplasias , Proteínas Proto-Oncogénicas p21(ras) , Antineoplásicos/clasificación , Antineoplásicos/farmacología , Proteína 9 Asociada a CRISPR/metabolismo , Terapia Genética/métodos , Humanos , Terapia Molecular Dirigida/métodos , Neoplasias/tratamiento farmacológico , Neoplasias/genética , Neoplasias/patología , Proto-Oncogenes Mas , Proteínas Proto-Oncogénicas p21(ras)/antagonistas & inhibidores , Proteínas Proto-Oncogénicas p21(ras)/genéticaRESUMEN
Human epidermal growth factor receptor 2 (HER2) is a proto-oncogene that, when mutated or overexpressed, plays an important role in oncogenesis. The landscape of HER2-positive breast cancer has changed dramatically over the past 2 decades with the FDA approval of a growing number of agents (antibodies, tyrosine kinase inhibitors, and antibody-drug conjugates) targeting the HER2 receptor. HER2 inhibition has also been approved for HER2-positive gastric cancer. HER2 is amplified in 9% and mutated in 3% of lung cancer. Historically, HER2-targeted therapy for lung cancer with trastuzumab, pertuzumab, and trastuzumab emtansine has failed to demonstrate a survival benefit. Trastuzumab deruxtecan (T-DXd) is a novel antibody-drug conjugate with a tetrapeptide linker, which delivers a topoisomerase I inhibitor with a drug-to-antibody ratio of 7~8. The potency of the active payload, as well as its significant bystander effect, resulted in significant anti-tumor activity. The DESTINY-Lung01 trial evaluated T-DXd in HER2-positive non-squamous non-small cell lung cancer (NSCLC) and reported a progression-free survival of 14 months in HER2-mutated NSCLC, earning its breakthrough designation by the FDA. In this review, we will discuss the structural characteristics, pharmacodynamics, and pharmacokinetics of T-DXd. We will also shed light on the preclinical and ongoing clinical trials of T-DXd along with future directions in the management of HER2 positive lung cancer.
RESUMEN
BACKGROUND: Nuclear protein transport is essential in guiding the traffic of important proteins and RNAs between the nucleus and cytoplasm. Export of proteins from the nucleus is mostly regulated by Exportin 1 (XPO1). In cancer, XPO1 is almost universally hyperactive and can promote the export of important tumor suppressors to the cytoplasm. Currently, there are no studies evaluating XPO1 amplifications and mutations in NSCLC and the impact on outcomes. METHODS: Tumor samples were analyzed using next-generation sequencing (NGS) (NextSeq, 592 Genes), immunohistochemistry (IHC), and whole transcriptome sequencing (WTS, NovaSeq) (Caris Life Sciences, Phoenix, AZ). Survival was extracted from insurance claims data and calculated from time of tissue collection to last contact using Kaplan-Meier estimate. RESULTS: Among 18,218 NSCLC tumors sequenced, 26 harbored XPO1 mutations and 24 had amplifications. XPO1 mutant tumors were more likely to have high TMB (79% vs. 52%, p = 0.007) and less likely to have high PD-L1 (32% vs. 68%, p = 0.03). KRAS co-mutations were seen in 19% (n = 5) and EGFR co-mutations were rare (n = 2). Among the 17,449 NSCLC tumors with clinical data, there were 24 XPO1 mutant. Comparison of survival between XPO1 mutant and WT showed a negative association with a hazard ratio (HR) of 1.932 (95% CI: 1.144-3.264 p = 0.012). XPO1 amplification was not associated with survival. CONCLUSIONS: XPO1 pathogenic mutations were associated with a poor survival in NSCLC. Although XPO1 mutations are rare in NSCLC, further studies to assess its associations with treatment responses are warranted.