The impact of myelosuppression on quality of life of patients treated with chemotherapy.

Side effects from chemotherapy-induced myelosuppression can negatively affect patients' quality of life (QoL). Neutropenia increases infection risk, and anemia frequently results in debilitating fatigue. Additionally, the bleeding risk associated with thrombocytopenia can lead to fear and anxiety. However, traditional interventions for myelosuppression fall short of the ideal. Granulocyte colony-stimulating factors reduce the risk of severe neutropenia but commonly lead to bone pain. Erythropoiesis-stimulating agents are not always effective and may cause thromboembolic events, while transfusions to correct anemia/thrombocytopenia are associated with transfusion reactions and volume overload. Trilaciclib, which is approved for reducing myelosuppression in patients with extensive-stage small cell lung cancer, together with several investigational agents in development for managing myelosuppression have the potential to improve QoL for patients on chemotherapy.

Chemotherapy can cause side effects by killing blood-forming cells in the bone marrow. This is known as myelosuppression and leads to neutropenia (decreased neutrophils [white blood cells]), anemia (decreased red blood cells) and thrombocytopenia (decreased platelets). Neutropenia can increase the risk of getting an infection, and severe cases might result in patients being hospitalized. Both neutropenia and anemia can cause fatigue, which is often reported by patients as being the most draining symptom of chemotherapy. Thrombocytopenia increases the risk of bleeding and can cause patients with cancer to become even more scared and anxious. Myelosuppression due to chemotherapy is usually managed with delays or reductions in the amount of chemotherapy that patients receive, but this may worsen the disease. Other treatments, known as supportive care interventions, include growth factors, which stimulate the production of blood cells and red blood cell or platelet transfusions. However, having these treatments in addition to chemotherapy can be a burden to patients, and they can cause side effects such as bone pain and blood clots. A treatment called trilaciclib is approved by the US Food and Drug Administration for patients receiving certain types of chemotherapy for advanced small-cell lung cancer. Trilaciclib has been shown to reduce neutropenia, anemia and thrombocytopenia in these patients and improve their quality of life. Other drugs are also being assessed in clinical trials for preventing or treating myelosuppression in patients with different cancer types. In the future, these drugs may improve quality of life for patients on chemotherapy.

Outcomes in biomarker-selected subgroups from the KESTREL study of durvalumab and tremelimumab in recurrent or metastatic head and neck squamous cell carcinoma.

BACKGROUND: Selective biomarkers may improve outcomes in patients with recurrent or metastatic head and neck squamous cell carcinoma (R/M HNSCC) treated with immune checkpoint inhibitor therapy. We investigated three independent biomarkers for association with efficacy in the randomized, phase III KESTREL study (NCT02551159) of first-line durvalumab monotherapy or durvalumab plus tremelimumab versus the EXTREME regimen: programmed cell death ligand-1 (PD-L1) immunohistochemistry, blood tumor mutational burden (bTMB) via circulating tumor DNA, and neutrophil-to-lymphocyte ratio (NLR). METHODS: Tumor or blood samples from patients enrolled in the KESTREL study were analyzed for PD-L1, bTMB, and NLR. Associations with overall survival (OS) or objective response rates (ORRs) were evaluated based on prespecified cut-offs for PD-L1 (tumor cell [TC] ≥ 50%/immune cell ≥ 25% or TC ≥ 25%), bTMB (≥ 16 mutations [mut] per megabase [Mb]), and NLR (≤ 7). Ad hoc analyses of exploratory cut-offs were performed. RESULTS: Prespecified or exploratory cut-offs for PD-L1 did not enrich for ORR or OS for durvalumab monotherapy or durvalumab plus tremelimumab versus EXTREME. In the bTMB ≥ 16 mut/Mb subgroup, OS hazard ratios (95% confidence interval) for durvalumab monotherapy and durvalumab plus tremelimumab versus EXTREME were 0.90 (0.48-1.72) and 0.69 (0.39-1.25), respectively. Complete response rates were 8.6% with durvalumab plus tremelimumab and 4.3% with EXTREME (≥ 16 mut/Mb subgroup). No improvement in OS was observed for durvalumab monotherapy or durvalumab plus tremelimumab versus EXTREME at prespecified or exploratory NLR cut-offs. CONCLUSIONS: bTMB demonstrated potential utility for selecting patients with R/M HNSCC who benefited from durvalumab with or without tremelimumab versus EXTREME. Trial registration ClinicalTrials.gov identifier NCT02551159.

A phase 2 study of neoadjuvant chemotherapy plus durvalumab in resectable locally advanced head and neck squamous cell carcinoma.

BACKGROUND: Patients with locally advanced head and neck squamous cell cancer (HNSCC) are treated with surgery followed by adjuvant (chemo) radiotherapy or definitive chemoradiation, but recurrence rates are high. Immune checkpoint blockade improves survival in patients with recurrent/metastatic HNSCC; however, the role of chemo-immunotherapy in the curative setting is not established. METHODS: This phase 2, single-arm, multicenter study evaluated neoadjuvant chemo-immunotherapy with carboplatin, nab-paclitaxel, and durvalumab in patients with resectable locally advanced HNSCC. The primary end point was a hypothesized pathologic complete response rate of 50%. After chemo-immunotherapy and surgical resection, patients received study-defined, pathologic risk adapted adjuvant therapy consisting of either durvalumab alone (low risk), involved field radiation plus weekly cisplatin and durvalumab (intermediate risk), or standard chemoradiation plus durvalumab (high risk). RESULTS: Between December 2017 and November 2021, 39 subjects were enrolled at three centers. Oral cavity was the most common primary site (69%). A total of 35 of 39 subjects underwent planned surgical resection; one subject had a delay in surgery due to treatment-related toxicity. The most common treatment-related adverse events were cytopenias, fatigue, and nausea. Post treatment imaging demonstrated an objective response rate of 57%. Pathologic complete response and major pathologic response were achieved in 29% and 49% of subjects who underwent planned surgery, respectively. The 1-year progression-free survival was 83.8% (95% confidence interval, 67.4%-92.4%). CONCLUSIONS: Neoadjuvant carboplatin, nab-paclitaxel, and durvalumab before surgical resection of HNSCC were safe and feasible. Although the primary end point was not met, encouraging rates of pathologic complete response and clinical to pathologic downstaging were observed.

Intracranial Efficacy of Adagrasib in Patients From the KRYSTAL-1 Trial With KRASG12C-Mutated Non-Small-Cell Lung Cancer Who Have Untreated CNS Metastases.

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.Patients with Kirsten rat sarcoma viral oncogene homolog (KRAS)-mutated non-small-cell lung cancer (NSCLC) and untreated CNS metastases have a worse prognosis than similar patients without KRAS mutations. Adagrasib has previously demonstrated CNS penetration preclinically and cerebral spinal fluid penetration clinically. We evaluated adagrasib in patients with KRASG12C-mutated NSCLC and untreated CNS metastases from the KRYSTAL-1 trial (ClinicalTrials.gov identifier: NCT03785249; phase Ib cohort), in which adagrasib 600 mg was administered orally, twice daily. Study outcomes included the safety and clinical activity (intracranial [IC] and systemic) by blinded independent central review. Twenty-five patients with KRASG12C-mutated NSCLC and untreated CNS metastases were enrolled and evaluated (median follow-up, 13.7 months); 19 patients were radiographically evaluable for IC activity. Safety was consistent with previous reports of adagrasib, with grade 3 treatment-related adverse events (TRAEs) in 10 patients (40%) and one grade 4 (4%) and no grade 5 TRAEs. The most common CNS-specific TRAEs included dysgeusia (24%) and dizziness (20%). Adagrasib demonstrated an IC objective response rate of 42%, disease control rate of 90%, progression-free survival of 5.4 months, and median overall survival of 11.4 months. Adagrasib is the first KRASG12C inhibitor to prospectively demonstrate IC activity in patients with KRASG12C-mutated NSCLC and untreated CNS metastases, supporting further investigation in this population.

Guidance for clinicians and patients with non-small cell lung cancer in the time of precision medicine.

Major advances in the diagnosis and treatment of non-small cell lung cancer (NSCLC) have resulted in a sharp decline in associated mortality rates, thereby propelling NSCLC to the forefront of precision medicine. Current guidelines recommend upfront comprehensive molecular testing for all known and actionable driver alterations/biomarkers (EGFR, ALK, ROS1, BRAF, KRAS, NTRK, MET, RET, HER2 [ERBB2], and PD-L1), especially in advanced disease stages, as they significantly influence response to therapy. In particular, hybrid capture-based next-generation sequencing (HC-NGS) with an RNA fusion panel to detect gene fusions is a veritable requirement at both diagnosis and progression (resistance) of any-stage non-squamous adenocarcinoma NSCLCs. This testing modality ensures selection of the most timely, appropriate, and personalized treatment, maximization of therapeutic efficacy, and prevention of use of suboptimal/contraindicated therapy. As a complement to clinical testing and treatment, patient, family, and caregiver education is also key to early screening and diagnosis, access to care, coping strategies, positive outcomes, and survival. The advent of social media and increased internet access has amplified the volume of educational and support resources, consequently changing the dynamics of patient care. This review provides guidance on integration of comprehensive genomic testing with an RNA fusion panel as a global diagnostic standard for all adenocarcinoma NSCLC disease stages and provides key information on patient and caregiver education and resources.

Biomarkers predictive of response to pembrolizumab in head and neck cancer.

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.

Adagrasib with or without Cetuximab in Colorectal Cancer with Mutated KRAS G12C.

BACKGROUND: Adagrasib, an oral small-molecule inhibitor of mutant KRAS G12C protein, has shown clinical activity in pretreated patients with several tumor types, including colorectal cancer. Preclinical studies suggest that combining a KRAS G12C inhibitor with an epidermal growth factor receptor antibody could be an effective clinical strategy. METHODS: In this phase 1-2, open-label, nonrandomized clinical trial, we assigned heavily pretreated patients with metastatic colorectal cancer with mutant KRAS G12C to receive adagrasib monotherapy (600 mg orally twice daily) or adagrasib (at the same dose) in combination with intravenous cetuximab once a week (with an initial loading dose of 400 mg per square meter of body-surface area, followed by a dose of 250 mg per square meter) or every 2 weeks (with a dose of 500 mg per square meter). The primary end points were objective response (complete or partial response) and safety. RESULTS: As of June 16, 2022, a total of 44 patients had received adagrasib, and 32 had received combination therapy with adagrasib and cetuximab, with a median follow-up of 20.1 months and 17.5 months, respectively. In the monotherapy group (43 evaluable patients), a response was reported in 19% of the patients (95% confidence interval [CI], 8 to 33). The median response duration was 4.3 months (95% CI, 2.3 to 8.3), and the median progression-free survival was 5.6 months (95% CI, 4.1 to 8.3). In the combination-therapy group (28 evaluable patients), the response was 46% (95% CI, 28 to 66). The median response duration was 7.6 months (95% CI, 5.7 to not estimable), and the median progression-free survival was 6.9 months (95% CI, 5.4 to 8.1). The percentage of grade 3 or 4 treatment-related adverse events was 34% in the monotherapy group and 16% in the combination-therapy group. No grade 5 adverse events were observed. CONCLUSIONS: Adagrasib had antitumor activity in heavily pretreated patients with metastatic colorectal cancer with mutant KRAS G12C, both as oral monotherapy and in combination with cetuximab. The median response duration was more than 6 months in the combination-therapy group. Reversible adverse events were common in the two groups. (Funded by Mirati Therapeutics; KRYSTAL-1 ClinicalTrials.gov number, NCT03785249.).

Tumour-agnostic efficacy and safety of selpercatinib in patients with RET fusion-positive solid tumours other than lung or thyroid tumours (LIBRETTO-001): a phase 1/2, open-label, basket trial.

BACKGROUND: Selpercatinib is a first-in-class, highly selective RET kinase inhibitor with CNS activity that has shown efficacy in RET fusion-positive lung and thyroid cancers. RET fusions occur rarely in other tumour types. We aimed to investigate the efficacy and safety of selpercatinib in a diverse group of patients with RET fusion-positive non-lung or thyroid advanced solid tumours (ie, a tumour-agnostic population). METHODS: LIBRETTO-001 is an ongoing phase 1/2, single-group, open-label, basket trial of selpercatinib in patients aged 18 years and older (or ≥12 years, where permitted by regulatory authorities) with RET-altered cancers. The trial is being conducted at 89 sites in 16 countries; the tumour-agnostic population was enrolled at 30 sites (outpatient and inpatient medical facilities) across eight countries. A prespecified interim analysis of LIBRETTO-001 was planned to investigate the efficacy and safety of selpercatinib in a tumour-agnostic population of patients with RET fusion-positive advanced solid tumours; the data cutoff date was Sept 24, 2021. Eligible patients had disease progression on or after previous systemic therapies or no satisfactory therapeutic options and an Eastern Cooperative Oncology Group performance status of 0-2. Selpercatinib was orally administered in a continuous 28-day cycle. Patients enrolled in the phase 1 dose-escalation portion received between 20 mg once daily or 20-240 mg twice daily; the phase 2 recommended dose was 160 mg twice daily. The primary endpoint was the objective response rate as determined by the independent review committee. The efficacy-evaluable tumour-agnostic population was defined as patients with RET fusion-positive cancer, other than non-small-cell lung cancer and thyroid cancer, who had at least 6 months of follow-up from the first study dose at the time of data cutoff (all responders at the time of data cutoff were followed up for at least 6 months from the onset of response unless they progressed or died earlier). Safety was analysed in the tumour-agnostic population of patients who had been enrolled and received selpercatinib on or before the data cutoff date. This study is registered with ClinicalTrials.gov (NCT03157128) and is still recruiting participants. FINDINGS: Between Dec 4, 2017, and Aug 4, 2021, 45 patients with RET fusion-positive tumour-agnostic cancers were enrolled from the phase 1 dose-escalation and phase 2 dose-expansion cohorts of the trial. 43 (96%) of 45 patients received a starting dose of selpercatinib at the recommended dose of 160 mg twice daily. Of the two patients who did not, one received a dose of 160 mg twice daily via intra-patient dose escalation (as allowed per protocol for patients enrolled in the phase 1 portion of the study at lower doses) and the other patient's starting dose of 120 mg twice daily was never escalated. Of the 41 efficacy-evaluable patients, the objective response rate as per the independent review committee was 43·9% (95% CI 28·5-60·3; 18 of 41 patients). The most common grade 3 or worse treatment-emergent adverse events were hypertension (ten [22%] of 45 patients), increased alanine aminotransferase (seven [16%]), and increased aspartate aminotransferase (six [13%]). Treatment-emergent serious adverse events occurred in 18 (40%) of 45 patients. No treatment-related deaths occurred. INTERPRETATION: Selpercatinib showed clinically meaningful activity in the RET fusion-positive tumour-agnostic population, with a safety profile consistent with that observed in other indications. Comprehensive genomic testing that includes RET fusions will be crucial for identifying patients who might benefit from selpercatinib. FUNDING: Loxo Oncology.

Targeting brain lesions of non-small cell lung cancer by enhancing CCL2-mediated CAR-T cell migration.

Metastatic non-small cell lung cancer (NSCLC) remains largely incurable and the prognosis is extremely poor once it spreads to the brain. In particular, in patients with brain metastases, the blood brain barrier (BBB) remains a significant obstacle for the biodistribution of antitumor drugs and immune cells. Here we report that chimeric antigen receptor (CAR) T cells targeting B7-H3 (B7-H3.CAR) exhibit antitumor activity in vitro against tumor cell lines and lung cancer organoids, and in vivo in xenotransplant models of orthotopic and metastatic NSCLC. The co-expression of the CCL2 receptor CCR2b in B7-H3.CAR-T cells, significantly improves their capability of passing the BBB, providing enhanced antitumor activity against brain tumor lesions. These findings indicate that leveraging T-cell chemotaxis through CCR2b co-expression represents a strategy to improve the efficacy of adoptive T-cell therapies in patients with solid tumors presenting with brain metastases.

Sinonasal Squamous Cell Carcinoma Survival Outcomes Following Induction Chemotherapy vs Standard of Care Therapy.

OBJECTIVE: To compare oncologic outcomes in sinonasal squamous cell carcinoma (SNSCC) treated with standard of care (SOC) definitive therapy, consisting of surgery or chemoradiotherapy, vs induction therapy followed by definitive therapy. STUDY DESIGN: Retrospective review. SETTING: Academic tertiary care hospital. METHODS: The medical records of patients with biopsy-proven SNSCC treated between 2000 and 2020 were reviewed for demographics, tumor characteristics, staging, treatment details, and oncologic outcomes. Patients were matched 1-to-1 by age, sex, and cancer stage according to treatment received. Time-to-event analyses were conducted. RESULTS: The analysis included 26 patients with locally advanced SNSCC who received either induction therapy (n = 13) or SOC (n = 13). Baseline demographics, Charlson Comorbidity Index, and median follow-up time were well balanced. Weekly cetuximab, carboplatin, and paclitaxel were the most common induction regimen utilized. Tolerance and safety to induction were excellent. Objective responses were observed in 11 of 13 patients receiving induction. No difference in disease-free survival was found between the induction and SOC groups at 1 or 3 years. However, when compared with SOC, induction therapy resulted in significant improvement in overall survival at 2 years (100% vs 65.3%, P = .043) and 3 years (100% vs 48.4%, P = .016) following completion of definitive therapy. Two patients in the SOC group developed metastatic disease, as compared with none in the induction group. CONCLUSIONS: Induction therapy was safe and effective. When compared with SOC, induction therapy improved 3-year overall survival.

Real-World Treatment Patterns and Outcomes Among Patients With Metastatic NSCLC Previously Treated With Programmed Cell Death Protein-1/Programmed Death-Ligand 1 Inhibitors.

INTRODUCTION: Programmed cell death protein-1 (PD-1)/programmed death-ligand 1 (PD-L1) inhibitors are standard-of-care treatment for metastatic NSCLC (mNSCLC). Intolerance to treatment/disease progression warrants additional lines of therapy. Real-world treatment patterns and efficacy outcomes after PD-1/PD-L1 use are insufficiently characterized to inform treatment decisions. METHODS: Electronic health records of adults with stage IV NSCLC initiating PD-1/PD-L1 inhibitors as first-line monotherapy (cohort 1), first-line combination therapy (cohort 2), or second-line monotherapy (cohort 3) who received a subsequent line of therapy (i.e., index therapy) in the Flatiron NSCLC Core Registry Dataset were identified. Patient characteristics, types of index treatments/therapies, and associated index treatment outcomes were extracted. RESULTS: A total of 1061 patients with mNSCLC were included in this analysis. In cohort 1 (n = 242), median real-world overall survival (mrwOS) with index therapies for the overall population was 9.18 months (95% confidence interval: 7.54-12.13); platinum-based chemotherapy was the most common index therapy (39.3%) with mrwOS of 12.52 months (8.39-not applicable). In cohort 2 (n = 145), mrwOS for the overall population was 6.43 months (5.34-7.61); vascular endothelial growth factor inhibitor plus chemotherapy was the most common index therapy (32.4%) with mrwOS of 5.97 months (4.95-7.34). In cohort 3 (n = 647), mrwOS for the overall population was 7.21 months (6.39-7.80); single-agent chemotherapy was the most common index therapy (45.4%) with mrwOS of 6.59 months (5.64-7.61). CONCLUSIONS: Real-world treatment patterns and survival outcomes of index therapies in mNSCLC after PD-1/PD-L1 use are variable. These analyses provide insights to optimize post-PD-1/PD-L1 treatments and inform standards of care.

Influence of tumor mutational burden, inflammatory gene expression profile, and PD-L1 expression on response to pembrolizumab in head and neck squamous cell carcinoma.

BACKGROUND: To characterize genomic determinants of response to pembrolizumab in recurrent/metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) in the KEYNOTE-012 study. METHODS: Associations between biomarkers (tumor mutational burden (TMB), neoantigen load (NL), 18-gene T-cell-inflamed gene expression profile (TcellinfGEP), and PD-L1 combined positive score (CPS)) and clinical outcomes with pembrolizumab were assessed in patients with R/M HNSCC (n=192). Tumor human papillomavirus (HPV) status was also evaluated with the use of p16 immunohistochemistry and whole exome sequencing (WES; HPV+, mapping >20 HPV reads) in pretreatment tumor samples (n=106). RESULTS: TMB, clonality-weighted TMB, and TcellinfGEP were significantly associated with objective response (p=0.0276, p=0.0201, and p=0.006, respectively), and a positive trend was observed between NL and PD-L1 CPS and clinical response (p=0.0550 and p=0.0682, respectively). No correlation was observed between TMB and TcellinfGEP (Spearman ρ=-0.026) or TMB and PD-L1 (Spearman ρ=0.009); a correlation was observed between TcellinfGEP and PD-L1 (Spearman ρ=0.511). HPV status by WES and p16 immunohistochemistry showed concordance (84% Ò¡=0.573) among patients whose HPV results were available using both methods. CONCLUSIONS: TMB and inflammatory biomarkers (TcellinfGEP and PD-L1) may represent distinct and complementary biomarkers predicting response to anti-programmed death 1 therapies in HNSCC; further study of these relationships in randomized clinical trials is needed. TRIAL REGISTRATION NUMBER: NCT01848834.

Targeting disialoganglioside GD2 with chimeric antigen receptor-redirected T cells in lung cancer.

BACKGROUND: We explored whether the disialoganglioside GD2 (GD2) is expressed in small cell lung cancer (SCLC) and non-SCLC (NSCLC) and can be targeted by GD2-specific chimeric antigen receptor (CAR) T cells. METHODS: GD2 expression was evaluated in tumor cell lines and tumor biopsies by flow cytometry and immunohistochemistry. We used a GD2.CAR that coexpress the IL-15 to promote T-cell proliferation and persistence, and the inducible caspase 9 gene safety switch to ablate GD2.CAR-T cells in case of unforeseen toxicity. The antitumor activity of GD2.CAR-T cells was evaluated using in vitro cocultures and in xenograft models of orthotopic and metastatic tumors. The modulation of the GD2 expression in tumor cell lines in response to an epigenetic drug was also evaluated. RESULTS: GD2 was expressed on the cell surface of four of fifteen SCLC and NSCLC cell lines (26.7%) tested by flow cytometry, and in 39% of SCLC, 72% of lung adenocarcinoma and 56% of squamous cell carcinoma analyzed by immunohistochemistry. GD2 expression by flow cytometry was also found on the cell surface of tumor cells freshly isolated from tumor biopsies. GD2.CAR-T cells exhibited antigen-dependent cytotoxicity in vitro and in vivo in xenograft models of GD2-expressing lung tumors. Finally, to explore the applicability of this approach to antigen low expressing tumors, we showed that pretreatment of GD2low/neg lung cancer cell lines with the Enhancer of zeste homolog 2 inhibitor tazemetostat upregulated GD2 expression at sufficient levels to trigger GD2.CAR-T cell cytotoxic activity. CONCLUSIONS: GD2 is a promising target for CAR-T cell therapy in lung cancer. Tazemetostat treatment could be used to upregulate GD2 expression in tumor cells, enhancing their susceptibility to CAR-T cell targeting.

Advances in Treatment of Recurrent Small Cell Lung Cancer (SCLC): Insights for Optimizing Patient Outcomes from an Expert Roundtable Discussion.

Second-line treatment options for patients with relapsed, extensive-stage small cell lung cancer (ES-SCLC) are limited, and even with currently available treatments, prognosis remains poor. Until recently, topotecan (a topoisomerase I inhibitor) was the only drug approved by the United States (US) Food and Drug Administration (FDA) for the management of ES-SCLC following progression after first-line treatment with etoposide plus a platinum derivative (EP; carboplatin preferred). With the most recent approval of EP plus a programmed death ligand 1 (PD-L1) inhibitor, there are now more therapeutic options for managing ES-SCLC. A number of novel agents have emerging data for activity in relapsed ES-SCLC, and single-agent lurbinectedin (an alkylating drug and selective inhibitor of oncogenic transcription and DNA repair machinery in tumor cells) has conditional FDA approval for use in this patient population. Trilaciclib, a short-acting cyclin-dependent kinase 4/6 (CDK 4/6) inhibitor, has also been recently approved as a supportive intervention for use prior to an EP or a topotecan-containing regimen to diminish the incidence of chemotherapy-induced myelosuppression. The current review is based on a recent expert roundtable discussion and summarizes current therapeutic agents and emerging data on newer agents and biomarkers. It also provides evidence-based clinical considerations and a treatment decision tool for oncologists treating patients with relapsed ES-SCLC. This paper discusses the importance of various factors to consider when selecting a second-line treatment option, including prior first-line treatment, available second-line treatment options, tumor platinum sensitivity, and patient characteristics (such as performance status, comorbidities, and patient-expressed and perceived values).

A case of metastatic NUT carcinoma with prolonged response on gemcitabine and nab-paclitaxel.

BACKGROUND: NUT carcinoma is an aggressive malignancy characterized by translocations in the NUTM1 gene. There are currently no consensus treatment recommendations for NUT carcinomas. METHODS: Here, we describe the case of a previously healthy male diagnosed with NUT carcinoma after presenting with sinus pressure, found to have a sinonasal mass and distant metastatic disease in the lungs. While pathologic evaluation and immunohistochemistry were consistent with NUT carcinoma, initial genomic profiling did not demonstrate a NUTM1 translocation. RESULTS: Whole transcriptomic RNA sequencing of the tumor revealed a YAP1-NUTM1 fusion. Based on an in vitro drug sensitivity screen, the patient was treated with gemcitabine and nab-paclitaxel, achieving a partial response that persisted for 9 months. CONCLUSIONS: Unbiased transcriptomic sequencing may identify previously uncharacterized NUTM1 fusion partners. Gemcitabine and nab-paclitaxel is a well-tolerated combination chemotherapy regimen and could offer a novel treatment approach for NUT carcinoma.

Phase 1 trial of adavosertib (AZD1775) in combination with concurrent radiation and cisplatin for intermediate-risk and high-risk head and neck squamous cell carcinoma.

BACKGROUND: Adavosertib (AZD1775) is an inhibitor of the Wee1 kinase. The authors conducted a phase 1b trial to evaluate the safety of adavosertib in combination with definitive chemoradiotherapy for patients with newly diagnosed, intermediate-risk/high-risk, locally advanced head and neck squamous cell carcinoma (HNSCC). METHODS: Twelve patients with intermediate-risk/high-risk HNSCC were enrolled, including those with p16-negative tumors of the oropharynx, p16-positive tumors of the oropharynx with ≥10 tobacco pack-years, and tumors of the larynx/hypopharynx regardless of p16 status. All patients were treated with an 8-week course of concurrent intensity-modulated radiotherapy at 70 grays (Gy) (2 Gy daily in weeks 1-7), cisplatin 30 mg/m2 weekly (in weeks 1-7), and adavosertib (twice daily on Monday, Tuesday, and Wednesday of weeks 1, 2, 4, 5, 7, and 8). The primary objective was to determine the maximum tolerated dose and the recommended phase 2 dose of adavosertib given concurrently with radiation and cisplatin. Secondary objectives were to determine the 12-week objective response rate and progression-free and overall survival. RESULTS: Three patients (25%) experienced a dose-limiting toxicity, including febrile neutropenia (n = 2) and grade 4 thromboembolism (n = 1). Two dose-limiting toxicities occurred with adavosertib at 150 mg. The median follow-up was 14.7 months. The 12-week posttreatment objective response rate determined by positron emission tomography/computed tomography was 100%. The 1-year progression-free and overall survival rates were both 90%. The maximum tolerated dose of adavosertib was 100 mg. CONCLUSIONS: Adavosertib 100 mg (twice daily on Monday, Tuesday, and Wednesday of weeks 1, 2, 4, 5, 7, and 8), in combination with 70 Gy of intensity-modulated radiotherapy and cisplatin 30 mg/m2 , is the recommended phase 2 dose for patients with HNSCC.

Veliparib in combination with carboplatin/paclitaxel-based chemoradiotherapy in patients with stage III non-small cell lung cancer.

OBJECTIVES: Veliparib is a potent poly(ADP)-ribose polymerase (PARP) 1 and 2 inhibitor that impedes repair of DNA damage induced by cytotoxic and radiation therapies. This phase 1 study evaluated veliparib in combination with chemoradiotherapy in patients with unresectable stage III non-small cell lung cancer (NSCLC). MATERIALS AND METHODS: Patients received veliparib orally twice daily (BID) in escalating doses (60-240 mg, Day -3 to 1 day after last dose of radiation) combined with weekly carboplatin (area under the curve [AUC] 2 mg/mL/min), paclitaxel (45 mg/m2), and daily radiation therapy (60 Gy in 30 fractions), followed by two cycles of veliparib (120-240 mg BID, Days -2 through 5 of each 21-day cycle), carboplatin (AUC 6 mg/mL/min, Day 1 of each cycle), and paclitaxel (200 mg/m2, Day 1 of each cycle) consolidation. Endpoints included veliparib maximum tolerated dose (MTD), recommended phase 2 dose (RP2D), pharmacokinetics, safety, and efficacy. RESULTS: Forty-eight patients were enrolled. The MTD/RP2D of veliparib was 240 mg BID with chemoradiotherapy followed by 120 mg BID with consolidation. The most common any-grade adverse events (AEs) in this cohort for the whole treatment period were nausea (83%), esophagitis (75%), neutropenia (75%), and thrombocytopenia (75%). Dose-proportional pharmacokinetics of veliparib were observed. Median progression-free survival (mPFS) was 19.6 months (95% CI: 9.7-32.6). Median overall survival was estimated to be 32.6 months (95% CI: 15.0-not reached). In patients treated with the RP2D, mPFS was 19.6 months (95% CI: 3.0-not reached). CONCLUSIONS: When combined with standard concurrent chemoradiotherapy and consolidation chemotherapy in patients with stage III NSCLC, veliparib demonstrated an acceptable safety profile and antitumor activity with an mPFS of 19.6 months.

Landscape and selection of vaccine epitopes in SARS-CoV-2.

BACKGROUND: Early in the pandemic, we designed a SARS-CoV-2 peptide vaccine containing epitope regions optimized for concurrent B cell, CD4+ T cell, and CD8+ T cell stimulation. The rationale for this design was to drive both humoral and cellular immunity with high specificity while avoiding undesired effects such as antibody-dependent enhancement (ADE). METHODS: We explored the set of computationally predicted SARS-CoV-2 HLA-I and HLA-II ligands, examining protein source, concurrent human/murine coverage, and population coverage. Beyond MHC affinity, T cell vaccine candidates were further refined by predicted immunogenicity, sequence conservation, source protein abundance, and coverage of high frequency HLA alleles. B cell epitope regions were chosen from linear epitope mapping studies of convalescent patient serum, followed by filtering for surface accessibility, sequence conservation, spatial localization near functional domains of the spike glycoprotein, and avoidance of glycosylation sites. RESULTS: From 58 initial candidates, three B cell epitope regions were identified. From 3730 (MHC-I) and 5045 (MHC-II) candidate ligands, 292 CD8+ and 284 CD4+ T cell epitopes were identified. By combining these B cell and T cell analyses, as well as a manufacturability heuristic, we proposed a set of 22 SARS-CoV-2 vaccine peptides for use in subsequent murine studies. We curated a dataset of ~ 1000 observed T cell epitopes from convalescent COVID-19 patients across eight studies, showing 8/15 recurrent epitope regions to overlap with at least one of our candidate peptides. Of the 22 candidate vaccine peptides, 16 (n = 10 T cell epitope optimized; n = 6 B cell epitope optimized) were manually selected to decrease their degree of sequence overlap and then synthesized. The immunogenicity of the synthesized vaccine peptides was validated using ELISpot and ELISA following murine vaccination. Strong T cell responses were observed in 7/10 T cell epitope optimized peptides following vaccination. Humoral responses were deficient, likely due to the unrestricted conformational space inhabited by linear vaccine peptides. CONCLUSIONS: Overall, we find our selection process and vaccine formulation to be appropriate for identifying T cell epitopes and eliciting T cell responses against those epitopes. Further studies are needed to optimize prediction and induction of B cell responses, as well as study the protective capacity of predicted T and B cell epitopes.

Intracranial Efficacy of Selpercatinib in RET Fusion-Positive Non-Small Cell Lung Cancers on the LIBRETTO-001 Trial.

PURPOSE: We report the intracranial efficacy of selpercatinib, a highly potent and selective RET inhibitor, approved in the United States for RET fusion-positive non-small cell lung cancers (NSCLC). PATIENTS AND METHODS: In the global phase 1/2 LIBRETTO-001 trial (NCT03157128) in advanced RET-altered solid tumors, selpercatinib was dosed orally (160 mg twice every day) in 28-day cycles. Patients with baseline intracranial metastases had MRI/CT scans every 8 weeks for 1 year (12 weeks thereafter). In this pre-planned analysis of patients with RET fusion-positive NSCLC with baseline intracranial metastases, the primary endpoint was independently assessed intracranial objective response rate (ORR) per RECIST 1.1. Secondary endpoints included intracranial disease control rate, intracranial duration of response, and intracranial progression-free survival (PFS) independently reviewed. RESULTS: Eighty patients with NSCLC had brain metastases at baseline. Patients were heavily pretreated (median = 2 systemic therapies, range = 0-10); 56% of patients received ≥1 course of intracranial radiation (14% whole brain radiotherapy, 45% stereotactic radiosurgery). Among 22 patients with measurable intracranial disease at baseline, intracranial ORR was 82% [95% confidence interval (CI), 60-95], including 23% with complete responses. Among all intracranial responders (measurable and nonmeasurable, n = 38), median duration of intracranial response was not reached (95% CI, 9.3-NE) at a median duration of follow-up of 9.5 months (IQR = 5.7, 12.0). At 12 months, 55% of intracranial responses were ongoing. In all 80 patients, median intracranial PFS was 13.7 months (95% CI, 10.9-NE) at a median duration of follow-up of 11.0 months (IQR = 7.4, 16.5). No new safety signals were revealed in patients with brain metastases compared with the full NSCLC trial population. CONCLUSIONS: Selpercatinib has robust and durable intracranial efficacy in patients with RET fusion-positive NSCLC.