The probability of metastatic disease to the brain from primary NSCLC is correlated with size of the primary tumor, cell type, and intrathoracic lymph node stage.

PurposeSotatercept may represent a novel approach to the treatment of chemotherapy-induced anemia (CIA). We report the results from two phase 2 randomized studies examining the use of sotatercept for the treatment of CIA in patients with metastatic cancer.MethodsIn study A011-08, patients with metastatic breast cancer were randomized to 2:2:2:1 to receive sotatercept 0.1, 0.3, or 0.5 mg/kg, or placebo, respectively, every 28 days. In study ACE-011-NSCL-001, patients with solid tumors treated with platinum-based chemotherapy received sotatercept 15 or 30 mg every 42 days. The primary endpoint for both studies was hematopoietic response, defined as a hemoglobin (Hb) increase of ≥1 g/dL from baseline.ResultsBoth studies were terminated early due to slow patient accrual. Among patients treated with sotatercept in the A011-08 and ACE-011-NSCL-001 studies, more patients achieved a mean Hb increase of ≥1 g/dL in the combined sotatercept 0.3 mg/kg and 15 mg (66.7 %) group and sotatercept 0.5 mg/kg and 30 mg (38.9 %) group versus the sotatercept 0.1 mg/kg (0 %) group. No patients achieved a mean Hb increase of ≥1 g/dL in the placebo group. The incidence of treatment-related adverse events (AEs) was low in both studies, and treatment discontinuations due to AEs were uncommon.ConclusionsAlthough both studies were terminated early, these results indicate that sotatercept is active and has an acceptable safety profile in the treatment of CIA.

Sotatercept is a novel receptor fusion protein that functions as a soluble trap to sequester ligands of activin receptor type IIA (ActRIIA). Preclinically, the murine version of sotatercept increased red blood cells (RBC) in a model of chemotherapy-induced anemia, inhibited tumor growth and metastasis, and exerted anabolic effects on bone in diverse models of multiple myeloma. Clinically, sotatercept increases RBC markedly in healthy volunteers and patients with multiple myeloma. With a rapid onset of action differing from erythropoietin, sotatercept is in clinical development as a potential first-in-class therapeutic for cancer-related anemia, including those characterized by ineffective erythropoiesis as in myelodysplastic syndromes. Anabolic bone activity in early clinical studies and potential antitumor effects make sotatercept a promising therapeutic candidate for multiple myeloma and malignant bone diseases. Antitumor activity has been observed preclinically with small-molecule inhibitors of transforming growth factor-β receptor type I (ALK5) that also antagonize the closely related activin receptors ALK4 and ALK7. LY-2157299, the first such inhibitor to enter clinical studies, has shown an acceptable safety profile so far in patients with advanced cancer. Together, these data identify activin receptor antagonists as attractive therapeutic candidates for multiple diseases.

Chemotherapy or chemoradiation is often used in Stage IIIA non-small cell lung carcinoma before surgical resection (neoadjuvant therapy). In reviewing the histopathology of such tumors after resection, the recognition that the pathologic changes are related to prior therapy and the assessment of tumor regression are both of importance. To refine histologic parameters for tumor regression and describe patterns of tumor reaction to therapy, we identified 30 lobectomy or pneumonectomy specimens from 1996-2000 in which neoadjuvant therapy was received before surgical resection. Histologic patterns of treatment-induced tumor regression were analyzed semiquantitatively and included necrosis, fibrosis, mixed inflammatory infiltrate, foamy macrophages, and giant cells. To identify clinical and histologic parameters that correlate with treatment response, the 30 specimens were graded for tumor regression. No correlation was found between tumor regression and age, gender, or type of therapy (chemoradiation versus chemotherapy alone). Squamous cell carcinoma showed a significantly higher rate of response than adenocarcinoma (P =.04), with a significant number of adenocarcinomas in the nonresponder subgroup (P =.05). Tumor size reduction by radiologic assessment, when compared with histologic regression, did not reveal a statistically significant association. However, a positive correlation was found between extent of fibrosis and radiologic estimate of size reduction.

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