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To address ongoing concerns about the implementation of the FDA’s Accelerated Approval pathway in oncology, a comprehensive strategy is needed — one that equally emphasizes “on-ramp” and “off-ramp” considerations.

Somatic gene mutations can alter the vulnerability of cancer cells to T-cell-based immunotherapies. Here we perturbed genes in human melanoma cells to mimic loss-of-function mutations involved in resistance to these therapies, by using a genome-scale CRISPR–Cas9 library that consisted of around 123,000 single-guide RNAs, and profiled genes whose loss in tumour cells impaired the effector function of CD8 + T cells. The genes that were most enriched in the screen have key roles in antigen presentation and interferon-γ signalling, and correlate with cytolytic activity in patient tumours from The Cancer Genome Atlas. Among the genes validated using different cancer cell lines and antigens, we identified multiple loss-of-function mutations in APLNR , encoding the apelin receptor, in patient tumours that were refractory to immunotherapy. We show that APLNR interacts with JAK1, modulating interferon-γ responses in tumours, and that its functional loss reduces the efficacy of adoptive cell transfer and checkpoint blockade immunotherapies in mouse models. Our results link the loss of essential genes for the effector function of CD8 + T cells with the resistance or non-responsiveness of cancer to immunotherapies. The authors describe a two-cell-type CRISPR screen to identify tumour-intrinsic genes that regulate the sensitivity of cancer cells to effector T cell function. CRISPR screen identifies genes driving resistance to cancer immunotherapy Some mutations in cancer cells make them resistant to immunotherapy. Nicholas Restifo and colleagues designed a 'two-cell-type' CRISPR–Cas9 screen to identify tumour-intrinsic genetic mutations associated with the sensitivity of melanoma cells to effector T cell function. The candidate genes identified included mediators of MHC class I antigen presentation and genes unknown to be involved in these immunity processes. The authors highlight the interaction between T-cell-secreted apelin and its receptor APLNR on tumour cells as a node for potent T-cell-mediated killing of cancer cells.

The Nepal Geodetic Array was funded by internal funding to JPA from Caltech and DASE and by the Gordon and Betty Moore Foundation, through Grant GBMF 423.01 to the Caltech Tectonics Observatory and was maintained thanks to NSF Grant EAR 13-5136. Andrew Miner and the PAcific Northwest Geodetic Array (PANGA) at Central Washington University are thanked for technical assistance with the construction and operation of the Tribhuvan University-CWU network. Additional funding for the TU-CWU network came from United Nations Development Programme and Nepal Academy for Science and Technology. The high rate data were recovered thanks to a rapid intervention funded by NASA (US) and the Department of Foreign International Development (UK). We thank Trimble Navigation Ltd and the Vaidya family for supporting the rapid response as well. The accelerometer record at KATNP was provided by USGS. Research at UC Berkeley was funded by the Gordon and Betty Moore Foundation through grant GBMF 3024. A portion of this work was carried out at the Jet Propulsion Laboratory, California Institute of Technology, under a contract with the National Aeronautics and Space Administration. The GPS data were processed by ARIA (JPL) and the Scripps Orbit and Permanent Array Center. The effort at the Scripps Institution of Oceanography was funded by NASA grants NNX14AQ53G and NNX14AT33G. ALOS-2 data were provided under JAXA (Japan) PI Investigations 1148 and 1413. JPA thanks the Royal Society for support. We thank Susan Hough, Doug Given, Irving Flores and Jim Luetgert for contribution to the installation of this station.

When Diversity Goals Meet Multiregional TrialsTo achieve goals focused on diversity in clinical research, trials may need to enroll large numbers of U.S. participants. But diversity initiatives and multiregional strategies can be complementary.

ContextCushing disease (CD) due to adrenocorticotropic hormone–secreting pituitary tumors can be a management challenge.ObjectiveTo better understand the outcomes of stereotactic radiosurgery (SRS) for CD and define its role in management.DesignInternational, multicenter, retrospective cohort analysis.SettingTen medical centers participating in the International Gamma Knife Research Foundation.PatientsPatients with CD with >6 months endocrine follow-up.InterventionSRS using Gamma Knife radiosurgery.Main Outcome MeasuresThe primary outcome was control of hypercortisolism (defined as normalization of free urinary cortisol). Radiologic response and adverse radiation effects (AREs) were recorded.ResultsIn total, 278 patients met inclusion criteria, with a mean follow-up of 5.6 years (0.5 to 20.5 years). Twenty-two patients received SRS as a primary treatment of CD. Mean margin dose was 23.7 Gy. Cumulative initial control of hypercortisolism was 80% at 10 years. Mean time to cortisol normalization was 14.5 months. Recurrences occurred in 18% with initial cortisol normalization. Overall, the rate of durable control of hypercortisolism was 64% at 10 years and 68% among patients who received SRS as a primary treatment. AREs included hypopituitarism (25%) and cranial neuropathy (3%). Visual deficits were related to treatment of tumor within the suprasellar cistern (P = 0.01), whereas both visual (P < 0.0001) and nonvisual cranial neuropathy (P = 0.02) were related to prior pituitary irradiation.ConclusionsSRS for CD is well tolerated and frequently results in control of hypercortisolism. However, recurrences can occur. SRS should be considered for patients with persistent hypercortisolism after pituitary surgery and as a primary treatment in those unfit for surgery. Long-term endocrine follow-up is essential after SRS.We studied the outcomes of stereotactic radiosurgery for Cushing disease in 278 patients and found that this treatment can result in durable endocrine remission in appropriately selected patients.

IntroductionSinonasal tumors that harbor neuroendocrine histologic features include olfactory neuroblastoma (previously known as esthesioneuroblastoma), sinonasal neuroendocrine carcinoma, and sinonasal undifferentiated carcinoma. These tumors represent a diverse spectrum of clinical behavior and as such require histology-specific management. Herein, we review the management of these sinonasal tumors with neuroendocrine features and discuss fundamentals of multi-modality care for each histology. An emphasis is placed on olfactory neuroblastomas, given their relative frequency and skullbase origin.MethodsA comprehensive literature review on contemporary management of olfactory neuroblastoma, sinonasal neuroendocrine carcinoma, and sinonasal undifferentiated carcinoma was performed.ResultsManagement of sinonasal tumors with neuroendocrine features can include surgical resection, radiation therapy, and/or chemotherapy. Due to their site of origin, these tumors can frequently involve the skullbase, which can require site-specific care. The optimal treatment modalities and the sequence in which they are performed are largely dependent on histology. In most cases, olfactory neuroblastoma is best managed with surgical resection followed by radiation therapy. Sinonasal neuroendocrine carcinomas represent a variety of histologic phenotypes (carcinoid, atypical carcinoid, small cell, and large cell), which determine the optimal treatment modality. Finally, sinonasal undifferentiated carcinoma is likely best managed by induction chemotherapy with subsequent therapy dictated by the initial response.ConclusionsA team approach to multi-modality care is essential in the treatment of olfactory neuroblastoma, sinonasal neuroendocrine carcinoma, and sinonasal undifferentiated carcinoma. Early biopsy, histologic diagnosis, and comprehensive imaging are critical to determining the appropriate management paradigm.

BackgroundThe role of immunotherapy for metastatic melanoma has expanded over the past decade triggering questions regarding the combination and timing of immunotherapy and radiation for brain metastases. We used the National Cancer Database (NCDB) to see if the time from radiation to immunotherapy in patients with melanoma brain metastases had an impact on survival.MethodsWe queried the NCDB from 2010 to 2015 for patients with melanoma brain metastases treated with immunotherapy and stereotactic radiosurgery (SRS). Receiver operator characteristic (ROC) curve analysis was done to determine a timepoint associated with outcome. Cox regression was used to identify predictors of survival. Propensity matching was done to account for indication bias.ResultsWe identified 247 patients meeting the above criteria. The median patient age was 62 years (27–90) and the vast majority were Caucasian (99%). The median SRS dose was 22 Gy (18–24 Gy).The median time to SRS was 39 days (0–344) and the median time to immunotherapy was 56 days (6–454). The ROC analysis revealed 8 days from SRS to immunotherapy as associated with outcome. Fifty-six patients had immunotherapy prior to SRS, 30 patients had immunotherapy within 0–7 days of SRS, and the remaining 161 had immunotherapy greater than 7 days from SRS. Three year survival rates were 21%, 55%, and 35% for those timeframes, respectively (p = 0.0153). Propensity matching of the 0–7 day and > 7 day groups yielded 28 pairs and Kaplan Meier analysis showed 3 year overall survival of 55% and 35%, in favor of immunotherapy within 7 days of SRS (p = 0.0357). Multivariable Cox regression identified lack of extracranial disease, more recent year of treatment, and time from SRS to immunotherapy of 0–7 days as predictors of improved survival.ConclusionsImmunotherapy within 7 days of SRS shows a possible association with improve outcomes in patients with brain metastases from melanoma.

ObjectiveContemporary management of patients with neuro-oncologic disease requires an understanding of approvals by the US Food and Drug Administration (FDA) related to nervous system tumors. To summarize FDA updates applicable to neuro-oncology practitioners, we sought to review oncology product approvals and Guidances that were pertinent to the field in the past year.MethodsOncology product approvals between January 1, 2020, and December 31, 2020, were reviewed for clinical trial outcomes involving tumors of the nervous system. FDA Guidances relevant to neuro-oncology were also reviewed.ResultsFive oncology product approvals described outcomes for nervous system tumors in the year 2020. These included the first regulatory approval for neurofibromatosis type 1: selumetinib for children with symptomatic, inoperable plexiform neurofibromas. Additionally, there were 4 regulatory approvals for non-central nervous system (CNS) cancers that described clinical outcomes for patients with brain metastases. These included the approval of tucatinib for metastatic human epidermal growth factor receptor 2 (HER2)-positive breast cancer including patients with brain metastases, brigatinib for anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer (NSCLC), and pralsetinib and selpercatinib for RET fusion-positive NSCLC. Finally, two FDA Guidances for Industry, “Cancer Clinical Trial Eligibility Criteria: Brain Metastases” and “Evaluating Cancer Drugs in Patients with Central Nervous System Metastases” were published to facilitate drug development for and inclusion of patients with CNS metastases in clinical trials.ConclusionsDespite the challenges of the past year brought on by the COVID-19 pandemic, progress continues to be made in neuro-oncology. These include first-of-their-kind FDA approvals and Guidances that are relevant to the management of patients with nervous system tumors.

Abstract On August 11, 2022, FDA granted accelerated approval to fam-trastuzumab deruxtecan-nxki (DS-8201a, T-DXd, ENHERTU, Daiichi Sankyo) for adult patients with unresectable or metastatic non-small cell lung cancer (NSCLC) whose tumors have activating human epidermal growth factor receptor 2 (HER2) mutations, as detected by an FDA-approved test, and who have received a prior systemic therapy. The approval was based on a prespecified interim analysis of DESTINY-Lung02 (Study U206), a multi-center, randomized, dose-optimization trial in patients with NSCLC harboring activating HER2-mutations. At the approved dose of 5.4 mg/kg given intravenously every 3 weeks, the overall response rate (ORR) was 58% (95% confidence interval [CI]: 43, 71). The median duration of response was 8.7 months (95% CI: 7.1, not estimable). These results were consistent with response rates observed at the 6.4 mg/kg dose level. The most common (≥ 20%) adverse reactions were nausea, constipation, decreased appetite, vomiting, fatigue, and alopecia. The rate of interstitial lung disease (ILD) or pneumonitis was 6% at the 5.4 mg/kg dose level and 14% at the 6.4 mg/kg dose level. In the setting of similar efficacy and reduced toxicity, approval was granted for the 5.4 mg/kg dose level. The applicant conducted a randomized, dose-optimization study with guidance from the FDA Oncology Center of Excellence’s Project Optimus. This is the first approval of a targeted therapy for HER2-mutated NSCLC. The FDA granted accelerated approval to fam-trastuzumab deruxtecan-nxki for adult patients with unresectable or metastatic non-small cell lung cancer whose tumors have activating HER2 mutations. This article reports the review process that led to this approval.