A vertebrobasilar junction aneurysm successfully treated with a combination of surgical clipping and flow diverter placement based on the results of computational fluid dynamics analysis: illustrative case.

BACKGROUND: The treatment of vertebrobasilar junction (VBJ) aneurysms is challenging. Although flow diverters (FDs) are a possible treatment option, geometrical conditions hinder intervention. VBJ aneurysms possess dual inflow vessels from the bilateral vertebral arteries (VAs), one of which is ideally occluded prior to FD treatment. However, it remains unclear which VA should be occluded. OBSERVATIONS: A 75-year-old male with a growing VBJ complex aneurysm exhibiting invagination toward the brainstem and causing perifocal edema required intervention. Preoperative computational fluid dynamics (CFD) analysis demonstrated that left VA occlusion would result in more stagnant flow and less impingement of flow than right VA occlusion. According to the simulated strategy, surgical clipping of the left VA just proximal to the aneurysm was performed, followed by FD placement from the basilar artery trunk to the right VA. The patient demonstrated tolerance of the VA occlusion, and follow-up computed tomography angiography at 18 months after FD treatment confirmed the disappearance of the aneurysm. LESSONS: Preoperative flow dynamics simulations using CFD analysis can reveal an optimal treatment strategy involving a hybrid surgery that combines FD placement and direct surgical occlusion for a VBJ complex aneurysm.

Serum CYFRA 21-1 Level as a Prognostic Marker for Extensive Disease Small Cell Lung Cancer.

BACKGROUND/AIM: Pretreatment serum cytokeratin 19 fragment (CYFRA21-1) level predicts outcomes in patients with non-small cell lung cancer; however, little is known about the clinical value of serum CYFRA21-1 level in patients with small cell lung cancer (SCLC). The aim of this study was to evaluate the prognostic value of pretreatment serum CYFRA21-1 level in patients with extensive disease (ED)-SCLC treated using platinum-doublet chemotherapy. PATIENTS AND METHODS: We retrospectively analyzed the pretreatment serum CYFRA21-1 levels of patients with ED-SCLC who were treated using first-line platinum-doublet chemotherapy. RESULTS: A total of 98 patients were analyzed. The patients with a high CYFRA21-1 level (≥7.0 ng/ml) (n=29) had significantly shorter progression-free survival (PFS) and overall survival (OS) than the patients with low CYFRA21-1 levels (n=67) [median PFS=118 days vs. 125 days, respectively (p=0.018); median OS=213 days vs. 295 days, respectively (p=0.046)]. In addition, high CYFRA21-1 level was associated with a high refractory relapse rate. CONCLUSION: Serum CYFRA21-1 level may be a prognostic marker for patients with ED-SCLC treated with platinum-doublet chemotherapy.

Trastuzumab deruxtecan in patients with human epidermal growth factor receptor 2-expressing salivary gland carcinoma: a pooled analysis of two phase I studies.

BACKGROUND: HER2-expressing salivary gland carcinoma (SGC) is associated with poor prognosis. Trastuzumab deruxtecan (T-DXd, DS-8201) has shown evidence of antitumor activity for several HER2-expressing solid tumors in multiple studies. This study aimed to present the efficacy and safety of T-DXd in patients with HER2-expressing SGC from a pooled analysis. METHODS: Patients with HER2-expressing SGC were pooled from two phase I, open-label studies of T-DXd: a two-phase, multiple-dose, first-in-human study (NCT02564900) and a single-sequence crossover drug-drug interaction study (NCT03383692). Endpoints included efficacy (objective response rate [ORR], duration of response [DoR] and progression-free survival [PFS]) and safety. RESULTS: This pooled analysis included 17 patients with SGC (median age: 57 years; male: 88.2%); median (range) follow-up duration was 12.0 (2.3-|34.8) months. Among these patients, 14 had received prior HER2-targeted agents and 13 had undergone prior radiotherapy. The investigator-assessed confirmed ORR was 58.8% (95% confidence interval [CI], 32.9-|81.6). The median (95% CI) DoR and PFS were 17.6 months (4.0 to not evaluable [NE]) and 20.5 months (11.1-NE), respectively. All 17 patients reported treatment-emergent adverse events (TEAEs); 76.5% reported TEAEs of grade ≥3. The most common TEAEs were decreased appetite (94.1%), nausea (88.2%) and neutrophil count decreased (76.5%). Of the 17 patients, five (29.4%) reported adjudicated drug-related interstitial lung disease (grade 1, n = 3; grade 2, n =1; grade 3, n = 1). CONCLUSION: The results of this pooled analysis provide evidence that clinical benefit is achievable with T-DXd in patients with HER2-expressing SGC. CLINICAL TRIAL INFORMATION: FIH study, NCT02564900; DDI study, NCT03383692.

Stereotactic radiotherapy of radiation-induced meningioma previously irradiated retrobulbar for Graves' ophthalmopathy: A case report.

A 69-year-old woman was diagnosed with an asymptomatic intracranial tumor nine years ago and has been followed with annual MR imaging studies. Two years ago, the tumor had grown in size, requiring treatment. She experienced ophthalmopathy due to hyperthyroidism 27 years ago and was treated with 20 Gy in 10 fractions using parallel opposed beams to her bilateral posterior eyeballs, supplemented with steroid pulse therapy. The tumor originated in the medial aspect of the right sphenoid border and compressed the temporal lobe, while bone infiltration was observed, partially extending to the soft tissue outside the maxillary sinus. The tumor was removed by craniotomy. The pathological diagnosis was atypical meningioma (WHO grade II). Four months postsurgery, the resection cavity's tumor exhibited growth inclination, necessitating Gamma Knife radiosurgery. Radiation planning was executed at a marginal tumor dose of 30 Gy in 5 fractions. Since the optic nerve had been previously exposed to radiation, a plan was devised to minimize radiation exposure. The dose on the optic nerve was limited to 6.9 Gy in 5 fractions. She did not experience any visual or visual field disruptions postradiation. This is a case of radiation-induced meningioma resulting from radiation therapy for Graves' ophthalmopathy and is the first reported case of a grade II meningioma. The patient's condition calls for adjuvant radiation therapy following surgical removal. Accordingly, a radiation treatment plan that safeguards the optic nerve, which was previously exposed to radiation, was deemed indispensable.

Trastuzumab deruxtecan in patients with locally advanced or metastatic HER2-positive gastric cancer: a multicenter, open-label, expanded-access study.

BACKGROUND: Trastuzumab deruxtecan (T-DXd) is an antibody-drug conjugate that consists of an anti-human epidermal growth factor receptor 2 (HER2) antibody bound by a cleavable tetrapeptide-based linker to a cytotoxic topoisomerase I inhibitor. Prior to marketing approval in Japan in September 2020, this expanded-access study was conducted to provide T-DXd to previously treated patients with locally advanced or metastatic HER2-positive gastric or gastroesophageal junction adenocarcinomas. METHODS: This multicenter, open-label, expanded-access study was conducted between March 25 and September 25, 2020 at 17 Japanese sites. Previously treated patients with locally advanced or metastatic HER2-positive gastric or gastroesophageal junction adenocarcinomas received T-DXd 6.4 mg/kg via intravenous infusions at 3-week intervals. Serious adverse events (SAEs), all potential cases of interstitial lung disease (ILD)/pneumonitis, all liver-related events potentially meeting Hy's Law criteria, and all cases of overdose were reported on the case report forms. RESULTS: A total of 64 patients were treated with T-DXd. Among the 17 (26.6%) patients with reported SAEs, 10 (15.6%) had SAEs related to T-DXd treatment. Febrile neutropenia was the most common SAE (n = 6). SAEs led to death in six patients; drug-related SAEs (sepsis and febrile neutropenia) led to death in one patient. Drug-related ILD, as determined by the external Adjudication Committee, occurred in three patients (Grade 1, Grade 2, and Grade 3: all n = 1). CONCLUSION: This expanded-access study provided T-DXd to a broader population of Japanese patients prior to marketing approval in Japan, bridging the gap between clinical trials and drug approval. No new safety concerns were identified.

Clinical activity of crizotinib in lung adenocarcinoma harboring a HLA_A­ROS1 rearrangement: A case report.

The benefits of crizotinib therapy in patients with tyrosine receptor kinase ROS proto-oncogene 1 (ROS1)-rearranged non-small cell lung cancer (NSCLC) have been demonstrated. The present study reports a 47-year-old woman with lung adenocarcinoma harboring a rare HLA_A-ROS1 rearrangement with clinical response to crizotinib. To the best of our knowledge there have been no reports of HLA_A-ROS1-rearranged lung cancer regarding clinical course and the efficacy of treatment with crizotinib. A good response to crizotinib therapy in the present case could be a reference for the treatment and prognosis of ROS1-rearranged NSCLC with the same fusion partner. The current report will remind oncologists and pulmonologists to consider the importance of accurate multigene panel assays for detecting driver oncogenes in treating patients with NSCLC.

Combined transarterial and transvenous embolization of anterior cranial fossa dural arteriovenous fistula.

Background: Excessive glue injection into the drainage vein in patients with dural arteriovenous fistula (dAVF) can result in venous obstruction. We performed transarterial embolization (TAE) combined with transvenous embolization (TVE) with coils to prevent the glue from migrating into the normal cortical veins. Case Description: A 57-year-old man was pointed out to have a Borden Type III anterior cranial fossa dAVF during a check-up for putaminal hemorrhage. Because a left frontal normal cortical vein drained into the pathological drainage vein, excessive glue injection into the drainage vein may have caused venous obstruction. We performed TVE with coils at the foot of the draining vein to prevent excessive migration of glue into the drainer, followed by TAE with glue. With this technique, complete obliteration of the shunt without venous ischemia was obtained. Conclusion: The combined treatment of TAE and TVE is effective in preventing venous ischemia caused by unintended migration of glue cast into the drainage vein.

Lung Cancer Complicated by Relapsing Polychondritis.

A 77-year-old man presented with a 1-month history of cough, pharyngeal discomfort, and weight loss. Chest radiography revealed a mass shadow in the right upper lung field. Bronchoscopy showed multiple white nodules along the tracheal cartilage ring. Although adenocarcinoma cells were detected in the mass, several biopsy specimens of the tracheal lesions exhibited no malignancy. 18F-fluorodeoxyglucose positron emission tomography revealed an intense accumulation in the mass, nasal septum, and tracheal cartilage. Furthermore, anti-type II collagen antibody levels were elevated. We finally diagnosed him with lung cancer complicated by relapsing polychondritis. Treatment with oral prednisolone was initiated, followed by sequential chemoradiotherapy for lung cancer.

Trastuzumab Deruxtecan in Anti-Human Epidermal Growth Factor Receptor 2 Treatment-Naive Patients With Human Epidermal Growth Factor Receptor 2-Low Gastric or Gastroesophageal Junction Adenocarcinoma: Exploratory Cohort Results in a Phase II Trial.

PURPOSE: To investigate efficacy and safety of trastuzumab deruxtecan (T-DXd) in human epidermal growth factor receptor 2 (HER2)-low gastric or gastroesophageal junction (GEJ) adenocarcinoma. METHODS: Patients with locally advanced or metastatic HER2-low (cohort 1, immunohistochemistry 2+/in situ hybridization-negative; cohort 2, immunohistochemistry 1+) gastric/GEJ adenocarcinoma treated with at least two prior regimens, including fluoropyrimidine and platinum, but anti-HER2 therapy naive, received T-DXd 6.4 mg/kg intravenously once every 3 weeks. The primary end point was confirmed objective response rate by independent central review. RESULTS: Among 21 patients enrolled in cohort 1 and 24 enrolled in cohort 2, 19 and 21 patients, respectively, had central HER2 confirmation, received T-DXd, and had measurable tumors at baseline. The confirmed objective response rate was 26.3% (95% CI, 9.1 to 51.2) from five partial responses in cohort 1 and 9.5% (95% CI, 1.2 to 30.4) from two partial responses in cohort 2. Thirteen patients (68.4%) in cohort 1 and 12 (60.0%) in cohort 2 experienced reduced tumor size. The median overall survival was 7.8 months (95% CI, 4.7 to nonevaluable) in cohort 1 and 8.5 months (95% CI, 4.3 to 10.9) in cohort 2; the median progression-free survival was 4.4 months (95% CI, 2.7 to 7.1) and 2.8 months (95% CI, 1.5 to 4.3), respectively. The most common grade ≥ 3 treatment-emergent adverse events in cohorts 1 and 2 were anemia (30.0% and 29.2%), decreased neutrophil count (25.0% and 29.2%), and decreased appetite (20.0% and 20.8%). Drug-related interstitial lung disease/pneumonitis occurred in one patient in each cohort (grade 1 or 2). No drug-related deaths occurred. CONCLUSION: This study provides preliminary evidence that T-DXd has clinical activity in patients with heavily pretreated HER2-low gastric/GEJ adenocarcinoma.

[A Case of Second Primary Small Cell Lung Carcinoma after Radiotherapy for Breast Cancer].

We report the case of a 72-year-old woman who underwent partial mastectomy due to left breast cancer(invasive ductal carcinoma)in March 20XX-4. This was followed by radiotherapy(50 Gy/25 Fr)and hormone therapy. In July 20XX, she was referred to our department because a chest computed tomography(CT)scan performed at the postoperative follow-up revealed a band-like consolidation adjacent to the pleura in the lingular segment, with enlarged ipsilateral hilar and mediastinal lymph nodes. CT-guided lung tumor biopsy was performed, and she was diagnosed with limited-stage small cell lung cancer. Chemotherapy with carboplatin, etoposide, and atezolizumab was initiated. Radiotherapy was not performed due to the overlap between the distribution of the lung tumor and the postoperative irradiation field of breast cancer. Due to the difference in the histopathological findings of the first and second primary tumors, and the location of the tumor in the postoperative irradiation field, the second cancer was considered to be radiation-induced cancer despite the short latency period.

Prospective analysis of the expression status of FGFR2 and HER2 in colorectal and gastric cancer populations: DS-Screen Study.

PURPOSE: Fibroblast growth factor receptor 2 (FGFR2) and human epidermal growth factor receptor 2 (HER2) proteins are both molecular targets for cancer therapy. The objective of this study was to evaluate the expression status of FGFR2 and HER2 in patients with gastric cancer (GC) or colorectal cancer (CRC). METHODS: Archived tumor tissue samples from patients with histologically-confirmed GC or CRC suitable for chemotherapy were analyzed for FGFR2 and HER2 expression using immunohistochemistry and fluorescence in situ hybridization (HER2 in CRC only). RESULTS: A total of 176 GC patients and 389 CRC patients were enrolled. Among patients with GC, 25.6% were FGFR2-positive and 26.1% were HER2-positive. Among patients with CRC, 2.9% were FGFR2-positive and 16.2% were HER2-positive. No clear relationship was found between FGFR2 and HER2 status in either GC or CRC. In GC, FGFR2 and HER2 statuses did not differ between different primary cancer locations, whereas there were some differences between histological types. Based on FGFR2- and/or HER2-positive status, 117 patients were identified as potentially suitable for inclusion in clinical trials of therapeutic agents targeting the relevant protein (GC = 45, CRC = 72; FGFR = 56, HER2 = 62), of whom 7 were eventually enrolled into such clinical trials. CONCLUSIONS: This study indicated the prevalence of FGFR2 and HER2 in GC and CRC in the Japanese population. The screening performed in this study could be useful for identifying eligible patients for future clinical trials of agents targeting these proteins. TRIAL REGISTRATION: Clinical trial registration Japic CTI No.: JapicCTI-163380.  https://www. CLINICALTRIALS: jp/cti-user/trial/ShowDirect.jsp?directLink=RNlzx1PPCuT.PrVNPxPRwA .

Management of Groin Pain Using an Iliohypogastric Nerve Block in a Patient with Inguinal Hernia due to Persistent Müllerian Duct Syndrome.

Persistent Müllerian duct syndrome can cause an inguinal hernia, although this is a rare occurrence; recurrent inguinal hernias can, in turn, cause ongoing groin pain. Management of groin pain plays an important role in patients' quality of life. We present our experience with a 43-year-old man who had a 2-week history of left-sided groin pain. The patient underwent laparoscopic surgery for a left inguinal hernia via the transabdominal preperitoneal approach. Right-sided cryptorchidism was noted during surgery, with a solid structure-thought to be a uterus-extending into the left inguinal canal. The diagnosis was persistent Müllerian duct syndrome, and the groin pain was relieved after a laparoscopic right orchiectomy with a bilateral preperitoneal hernia repair using a mesh. Four years later, magnetic resonance imaging performed for new-onset left groin pain showed a left inguinal hernia caused by the uterine structure. We diagnosed the recurrent hernia as the cause of his pain. Prior to performing any invasive surgical procedures, an iliohypogastric nerve block was performed using 1% lidocaine. Short-term analgesia was provided by the block, improving his quality of life. He has been followed since then and has declined surgical neurectomy. An iliohypogastric nerve block can be an effective method of controlling groin pain caused by an inguinal hernia resulting from persistent Müllerian duct syndrome; the effectiveness of the nerve block will help determine whether surgical neurectomy is indicated for permanent pain control.

[Pharmacological and clinical study results of trastuzumab deruxtecan (T-DXd, ENHERTU®)].

Antibody-drug conjugates (ADCs) combine the specific antibody and cytotoxic agent by a linker and represent a promising drug class with a wider therapeutic window than conventional chemotherapeutic agents by substantiating efficient and specific drug delivery to antigen-expressing tumor cells. However, there are rooms for improvement in terms of efficacy, safety, physicochemical property; therefore, the development of promising ADC drugs across multiple indications are eagerly awaited. In 2015, Daiichi Sankyo initiated the first-in-human study of HER2 ADC, trastuzumab deruxtecan (T-DXd, ENHERTU®) which possesses DNA topoisomerase I inhibitor, exatecan derivative and proprietary linker, in Japan. Based on the provocative results in phase 1 study, the global development program has been accelerated to show the high and durable efficacy in patients with HER2 positive breast cancer pretreated with trastuzumab emtansine. As a result, T-DXd was approved based on single arm phase 2 study in the US (Dec 2019) and Japan (March 2020) by leveraging the breakthrough designation and conditional early approval system, respectively, at the first time for the HER2 positive breast cancer. In addition, T-DXd was recently approved in gastric cancer through Sakigake designation in Japan based on a randomized phase 2 study. T-DXd is also being developed in the earlier lines or other indications where no anti-HER2 therapies were approved to date. Combination studies with other agents, such as immune checkpoint inhibitors are underway. In the near future, we hope that more patients worldwide can enjoy the therapeutic benefits of T-DXd through our continuous efforts to expand its indications.

An Aneurysm at the Origin of a Duplicated Middle Cerebral Artery Treated by Stent-Assisted Coiling Using the "Wrapped-Candy" Low-Profile Visualized Intraluminal Support (LVIS) Technique: A Technical Case Report and Review of the Literature.

BACKGROUND: Aneurysms at the origin of a duplicated middle cerebral artery (DMCA) are quite rare. Here, we report a patient with such an aneurysm successfully treated endovascularly using our novel "wrapped-candy" low-profile visualized intraluminal support (LVIS) technique. CASE DESCRIPTION: A 44-year-old woman underwent endovascular treatment for an unruptured wide-necked aneurysm at the origin of a DMCA that incorporated the origin of the DMCA into its neck. Stent-assisted coiling was performed using our newly developed "wrapped-candy" LVIS technique. To protect the origin of the DMCA and increase the stent metal density at the neck, an LVIS blue 3.5-mm × 22-mm stent was deployed by pushing the delivery wire aggressively to transform the visible wire components of the LVIS into a shape like "wrapped candy," maximizing the strut compaction at the neck of the aneurysm. Subsequently, the aneurysm component was coiled using a jailed microcatheter. The final procedural angiography demonstrated almost complete aneurysm occlusion with DMCA preservation. CONCLUSIONS: Stent-assisted coiling can be a feasible treatment for an unruptured, usually wide-necked, aneurysm at the origin of a DMCA. The wrapped-candy LVIS technique may be useful in more challenging morphologies such as wide-necked aneurysms that incorporate the branch origin into the aneurysm neck.

Double Stent Retriever (SR) Technique: A Novel Mechanical Thrombectomy Technique to Facilitate the Device-Clot Interaction for Refractory Acute Cerebral Large Vessel Occlusions.

BACKGROUND: Mechanical thrombectomy has become the standard treatment for acute ischemic stroke caused by large vessel occlusion; however, refractory occlusions still occur despite various thrombectomy procedures. The double stent retriever (SR) technique, which employs 2 SRs simultaneously at the occlusion, can be useful for such refractory occlusions. METHODS: We described 2 cases of refractory acute cerebral occlusion despite the use of conventional thrombectomy procedures that were both treated with the double SR technique. To discuss the technical aspects of how this easy-to-perform technique facilitates the device-clot interaction, we also evaluated radiographic findings of the SR strut during the procedure. RESULTS: In both cases, conventional thrombectomy procedures, including an SR alone, an aspiration catheter alone, and combined use of the SR and aspiration catheter, failed to recanalize the occlusion. The double SR technique was then performed with the stent-in-stent method in 1 patient and the parallel stent method in 1 patient. One pass of this technique retrieved hard clots and successfully recanalized the refractory occlusion in both cases. Intraprocedural radiographic images of these cases showed that the degree of stent expansion improved after deployment of the second SR compared with the first SR. CONCLUSIONS: Our radiographic findings suggested that adding a second SR facilitates the device-clot interaction at the occlusion site. The double SR technique may be an easy-to-perform thrombectomy technique to improve clot-capturing ability for the management of refractory acute cerebral artery occlusions.

Trastuzumab Deruxtecan in Previously Treated HER2-Positive Gastric Cancer.

BACKGROUND: Trastuzumab deruxtecan (DS-8201) is an antibody-drug conjugate consisting of an anti-HER2 (human epidermal growth factor receptor 2) antibody, a cleavable tetrapeptide-based linker, and a cytotoxic topoisomerase I inhibitor. The drug may have efficacy in patients with HER2-positive advanced gastric cancer. METHODS: In an open-label, randomized, phase 2 trial, we evaluated trastuzumab deruxtecan as compared with chemotherapy in patients with HER2-positive advanced gastric cancer. Patients with centrally confirmed HER2-positive gastric or gastroesophageal junction adenocarcinoma that had progressed while they were receiving at least two previous therapies, including trastuzumab, were randomly assigned in a 2:1 ratio to receive trastuzumab deruxtecan (6.4 mg per kilogram of body weight every 3 weeks) or physician's choice of chemotherapy. The primary end point was the objective response, according to independent central review. Secondary end points included overall survival, response duration, progression-free survival, confirmed response (response persisting ≥4 weeks), and safety. RESULTS: Of 187 treated patients, 125 received trastuzumab deruxtecan and 62 chemotherapy (55 received irinotecan and 7 paclitaxel). An objective response was reported in 51% of the patients in the trastuzumab deruxtecan group, as compared with 14% of those in the physician's choice group (P<0.001). Overall survival was longer with trastuzumab deruxtecan than with chemotherapy (median, 12.5 vs. 8.4 months; hazard ratio for death, 0.59; 95% confidence interval, 0.39 to 0.88; P = 0.01, which crossed the prespecified O'Brien-Fleming boundary [0.0202 on the basis of number of deaths]). The most common adverse events of grade 3 or higher were a decreased neutrophil count (in 51% of the trastuzumab deruxtecan group and 24% of the physician's choice group), anemia (38% and 23%, respectively), and decreased white-cell count (21% and 11%). A total of 12 patients had trastuzumab deruxtecan-related interstitial lung disease or pneumonitis (grade 1 or 2 in 9 patients and grade 3 or 4 in 3), as adjudicated by an independent committee. One drug-related death (due to pneumonia) was noted in the trastuzumab deruxtecan group; no drug-related deaths occurred in the physician's choice group. CONCLUSIONS: Therapy with trastuzumab deruxtecan led to significant improvements in response and overall survival, as compared with standard therapies, among patients with HER2-positive gastric cancer. Myelosuppression and interstitial lung disease were the notable toxic effects. (Funded by Daiichi Sankyo; DESTINY-Gastric01 ClinicalTrials.gov number, NCT03329690.).

Targeting HER2 with Trastuzumab Deruxtecan: A Dose-Expansion, Phase I Study in Multiple Advanced Solid Tumors.

HER2-targeted therapies are approved only for HER2-positive breast and gastric cancers. We assessed the safety/tolerability and activity of the novel HER2-targeted antibody-drug conjugate trastuzumab deruxtecan (T-DXd) in 60 patients with pretreated, HER2-expressing (IHC ≥ 1+), non-breast/non-gastric or HER2-mutant solid tumors from a phase I trial (NCT02564900). Most common (>50%) treatment-emergent adverse events (TEAE) were nausea, decreased appetite, and vomiting. Two drug-related TEAEs were associated with fatal outcomes. The confirmed objective response rate (ORR) was 28.3% (17/60). Median progression-free survival (PFS) was 7.2 [95% confidence interval (CI), 4.8-11.1] months. In HER2-mutant non-small cell lung cancer (NSCLC), ORR was 72.7% (8/11), and median PFS was 11.3 (95% CI, 8.1-14.3) months. Confirmed responses were observed in six tumor types, including HER2-expressing NSCLC, colorectal cancer, salivary gland cancer, biliary tract cancer, endometrial cancer, and HER2-mutant NSCLC and breast cancer. Results suggest T-DXd holds promise for HER2-expressing/mutant solid tumors. SIGNIFICANCE: T-DXd demonstrated promising activity in a heterogeneous patient population with heavily pretreated HER2-expressing or HER2-mutant solid tumors, especially HER2-mutant NSCLC. The safety profile was generally acceptable. Interstitial lung disease can be severe and requires prompt monitoring and intervention. Further research of T-DXd is warranted to address these unmet medical needs.See related commentary by Rolfo and Russo, p. 643.This article is highlighted in the In This Issue feature, p. 627.

Antitumor Activity and Safety of Trastuzumab Deruxtecan in Patients With HER2-Low-Expressing Advanced Breast Cancer: Results From a Phase Ib Study.

PURPOSE: Trastuzumab deruxtecan (T-DXd, formerly DS-8201a) is a novel human epidermal growth factor receptor 2 (HER2)-targeted antibody drug conjugate (ADC) with a topoisomerase I inhibitor payload. A dose escalation and expansion phase I study evaluated the safety and activity of T-DXd in patients with advanced HER2-expressing/mutated solid tumors. Here, results for T-DXd at the recommended doses for expansion (RDE) in patients with HER2-low (immunohistochemistry [IHC] 1+ or IHC 2+/in situ hybridization-) breast cancer (ClinicalTrials.gov identifier: NCT02564900) are reported. PATIENTS AND METHODS: Eligible patients had advanced/metastatic HER2-low-expressing breast cancer refractory to standard therapies. The RDE of 5.4 or 6.4 mg/kg T-DXd were administered intravenously once every 3 weeks until withdrawal of consent, unacceptable toxicity, or progressive disease. Antitumor activity and safety were assessed. RESULTS: Between August 2016 and August 2018, 54 patients were enrolled and received ≥ 1 dose of T-DXd at the RDE. Patients were extensively pretreated (median, 7.5 prior therapies). The confirmed objective response rate by independent central review was 20/54 (37.0%; 95% CI, 24.3% to 51.3%) with median duration of response of 10.4 months (95% CI, 8.8 month to not evaluable). Most patients (53/54; 98.1%) experienced ≥ 1 treatment-emergent adverse event (TEAE; grade ≥ 3; 34/54; 63.0%). Common (≥ 5%) grade ≥ 3 TEAEs included decreases in neutrophil, platelet, and WBC counts; anemia; hypokalemia; AST increase; decreased appetite; and diarrhea. Three patients treated at 6.4 mg/kg suffered fatal events associated with T-DXd-induced interstitial lung disease (ILD)/pneumonitis as determined by an independent adjudication committee. CONCLUSION: The novel HER2-targeted ADC, T-DXd, demonstrated promising preliminary antitumor activity in patients with HER2-low breast cancer. Most toxicities were GI or hematologic in nature. ILD is an important identified risk and should be monitored closely and proactively managed.

A phase I study of pexidartinib, a colony-stimulating factor 1 receptor inhibitor, in Asian patients with advanced solid tumors.

Background Pexidartinib, a novel, orally administered small-molecule tyrosine kinase inhibitor, has strong selectivity against colony-stimulating factor 1 receptor. This phase I, nonrandomized, open-label multiple-dose study evaluated pexidartinib safety and efficacy in Asian patients with symptomatic, advanced solid tumors. Materials and Methods Patients received pexidartinib: cohort 1, 600 mg/d; cohort 2, 1000 mg/d for 2 weeks, then 800 mg/d. Primary objectives assessed pexidartinib safety and tolerability, and determined the recommended phase 2 dose; secondary objectives evaluated efficacy and pharmacokinetic profile. Results All 11 patients (6 males, 5 females; median age 64, range 23-82; cohort 1 n = 3; cohort 2 n = 8) experienced at least one treatment-emergent adverse event; 5 experienced at least one grade ≥ 3 adverse event, most commonly (18%) for each of the following: increased aspartate aminotransferase, blood alkaline phosphatase, gamma-glutamyl transferase, and anemia. Recommended phase 2 dose was 1000 mg/d for 2 weeks and 800 mg/d thereafter. Pexidartinib exposure, area under the plasma concentration-time curve from zero to 8 h (AUC0-8h), and maximum observed plasma concentration (Cmax) increased on days 1 and 15 with increasing pexidartinib doses, and time at Cmax (Tmax) was consistent throughout all doses. Pexidartinib exposure and plasma levels of adiponectin and colony-stimulating factor 1 increased following multiple daily pexidartinib administrations. One patient (13%) with tenosynovial giant cell tumor showed objective tumor response. Conclusions This was the first study to evaluate pexidartinib in Asian patients with advanced solid tumors. Pexidartinib was safe and tolerable in this population at the recommended phase 2 dose previously determined for Western patients (funded by Daiichi Sankyo; clinicaltrials.gov number, NCT02734433).