Search

The current third-line (and beyond) treatment options for RAS-mutant metastatic colorectal cancer have yielded limited efficacy. At the time of study start, the combination of sotorasib, a KRAS (Kirsten rat sarcoma viral oncogene homolog)-G12C inhibitor, and panitumumab, an epidermal growth factor receptor (EGFR) inhibitor, was hypothesized to overcome treatment-induced resistance. This phase 1b substudy of the CodeBreaK 101 master protocol evaluated sotorasib plus panitumumab in patients with chemotherapy-refractory KRASG12C-mutated metastatic colorectal cancer. Here, we report the results in a dose-exploration cohort and a dose-expansion cohort. Patients received sotorasib (960 mg, once daily) plus panitumumab (6 mg kg−1, once every 2 weeks). The primary endpoints were safety and tolerability. Secondary endpoints included efficacy and pharmacokinetics. Exploratory biomarkers at baseline were assessed. Forty-eight patients (dose-exploration cohort, n= 8; dose-expansion cohort, n= 40) were treated. Treatment-related adverse events of any grade and grade ≥3 occurred in 45 (94%) and 13 (27%) patients, respectively. In the dose-expansion cohort, the confirmed objective response rate was 30.0% (95% confidence interval (CI) 16.6%, 46.5%). Median progression-free survival was 5.7 months (95% CI 4.2, 7.7 months). Median overall survival was 15.2 months (95% CI 12.5 months, not estimable). Prevalent genomic coalterations included APC(84%), TP53(74%), SMAD4(33%), PIK3CA(28%) and EGFR(26%). Sotorasib–panitumumab demonstrated acceptable safety with promising efficacy in chemotherapy-refractory KRASG12C-mutated metastatic colorectal cancer. ClinicalTrials.gov identifier: NCT04185883.

KRASis the most frequently mutated oncogene in cancer and encodes a key signalling protein in tumours1,2. The KRAS(G12C) mutant has a cysteine residue that has been exploited to design covalent inhibitors that have promising preclinical activity3–5. Here we optimized a series of inhibitors, using novel binding interactions to markedly enhance their potency and selectivity. Our efforts have led to the discovery of AMG 510, which is, to our knowledge, the first KRAS(G12C) inhibitor in clinical development. In preclinical analyses, treatment with AMG 510 led to the regression of KRASG12Ctumours and improved the anti-tumour efficacy of chemotherapy and targeted agents. In immune-competent mice, treatment with AMG 510 resulted in a pro-inflammatory tumour microenvironment and produced durable cures alone as well as in combination with immune-checkpoint inhibitors. Cured mice rejected the growth of isogenic KRASG12Dtumours, which suggests adaptive immunity against shared antigens. Furthermore, in clinical trials, AMG 510 demonstrated anti-tumour activity in the first dosing cohorts and represents a potentially transformative therapy for patients for whom effective treatments are lacking.

The Aurora kinase family of kinases (Aurora A, B, and C) are involved in multiple mitotic events, and aberrant expression of these kinases is associated with tumorigenesis. Aurora A and Aurora B are validated anticancer targets, and the development of Aurora kinase inhibitors has progressed from preclinical to clinical studies. A variety of Aurora A, B and pan-Aurora kinase inhibitors have entered the clinic. The main side effects include febrile neutropenia, stomatitis, gastrointestinal toxicity, hypertension, and fatigue. Responses including complete remissions have been described in diverse, advanced malignancies, most notably ovarian cancer and acute myelogenous leukemia. This review highlights the biologic rationale for Aurora kinase as a target, and clinical trials involving Aurora kinase inhibitors, with particular emphasis on published early phase studies, and the observed anti-tumor activity of these agents.

Despite a wealth of preclinical studies, it is unclear whether PIK3CAor phosphatase and tensin homolog (PTEN) gene aberrations are actionable in the clinical setting. Of 1,656 patients with advanced, refractory cancers tested for PIK3CAor PTEN abnormalities, PIK3CAmutations were found in 9% (146/1,589), and PTEN loss and/or mutation was found in 13% (149/1,157). In multicovariable analysis, treatment with a phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) inhibitor was the only independent factor predicting response to therapy in individuals harboring a PIK3CAor PTENaberration. The rate of stable disease ≥6 months/partial response reached 45% in a subgroup of individuals with H1047R PIK3CAmutations. Aberrations in the PI3K/AKT/mTOR pathway are common and potentially actionable in patients with diverse advanced cancers. This work provides further important clinical validation for continued and accelerated use of biomarker-driven trials incorporating rational drug combinations.

IMPORTANCE Approximately 10% to 25% of patients treated with BRAF inhibitors develop cutaneous squamous cell carcinoma (SCC), but the mechanism responsible has not yet been determined. We report what we believe to be the first case in which Merkel cell polyomavirus (MCPyV) and human papillomavirus subtype 17 (HPV-17) were associated with cutaneous SCC that developed during treatment with the BRAF inhibitor dabrafenib. OBSERVATIONS A 62-year-old woman with V600E BRAF -mutant metastatic melanoma enrolled in a phase 1 trial of dabrafenib, a selective inhibitor of V600-mutant BRAF kinase. During the first 6 weeks of treatment, the patient developed multiple skin lesions, including a 6-mm crusted papule on the left eyebrow, which was resected and, on pathology examination, revealed SCC. The DNA extracted from paraffin-embedded tissue was amplified by polymerase chain reaction for detection of MCPyV and epidermodysplasia verruciformis HPV (EV-HPV) types. Analysis of the cloned and sequenced polymerase chain reaction products revealed the presence of MCPyV and HPV-17 DNA. Other EV-HPV subtypes were not detected. CONCLUSIONS AND RELEVANCE To our knowledge, this is the first report demonstrating the coexistence of MCPyV and HPV-17 in cutaneous SCC. Because both viruses have oncogenic potential, their role in the development of BRAF inhibitor–related SCC merits further investigation.

Dabrafenib is an inhibitor of BRAF kinase that is selective for mutant BRAF. We aimed to assess its safety and tolerability and to establish a recommended phase 2 dose in patients with incurable solid tumours, especially those with melanoma and untreated, asymptomatic brain metastases.

Preclinical models have suggested that HDAC and mTOR inhibitors have synergistic antineoplastic activity in Hodgkin lymphoma and other cancers by reducing the activity of AKT, mTOR and HDAC.We designed a phase I study to determine the safety of the mTOR inhibitor sirolimus (1mg-5mg PO daily q 28 days) and HDAC inhibitor vorinostat (100mg-400mg PO daily q 28 days) in advanced cancers with an expansion cohort at the recommended phase 2 dose (RP2D) of sirolimus 4mg and vorinostat 300mg for patients with refractory classical Hodgkin lymphoma. The expansion cohort included optional pre- and post-treatment tumor biopsies, peripheral blood mononuclear cells (PBMCs), plasma/serum collections for pharmacodynamic (PD) and pharmacokinetic (PK) endpoints.A total of 16 patients (men, n=8; women, n=8), median age 33 years, median of 6.5 prior therapies (including autologous SCT [n=15], autologous and allogeneic SCT [n=4]) were enrolled in dose escalation (n=1) or RP2D (n=15) cohorts. At the median follow-up of 3.2 months, 15 (94%) patients demonstrated decreased FDG uptake including 2 CRs (13%) and 5 PRs (31%) using CHESON criteria, with a total CR+PR rate of 44%. The median reduction of tumor was -27% (-100% to +20%, Figure). The estimated median time-to-treatment failure has not been reached and 63% of the patients continued on therapy with further improvement in their level of disease response. Major grade 3-4 treatment-related toxicities included grade 3 thrombocytopenia (4 patients, 25%), grade 4 thrombocytopenia (6, 38%), grade 3 anemia (1, 6%), febrile neutropenia (1, 6%) and led to treatment interruptions and/or dose modifications in 10 (63%) patients. Five (31%) patients had archival tissue available for targeted next-generation sequencing and one patient had a loss of TSC2, an abnormality that putatively activates mTOR. This patient has had a continuing response to therapy (-56%) for 8.4+ months. PD studies in pre- and post-treatment tumor biopsies, PBMCs and plasma as well as PK analysis continue.The combination of sirolimus and vorinostat is well tolerated with encouraging activity in very heavily pretreated patients with Hodgkin lymphoma refractory to standard therapies. Enrollment continues.Off Label Use: sirolimus - mTOR inhibitor vorinostat - HDAC inhibitor.

Preclinical models have suggested that HDAC and mTOR inhibitors have synergistic antineoplastic activity in Hodgkin lymphoma and other cancers by reducing the activity of AKT, mTOR and HDAC.

Hepatosplenic T-cell lymphoma is a rare peripheral T-cell lymphoma, and less than 100 cases have been described in the literature since the entity was first proposed in 1990. This condition is characterized by malignant T-cell proliferation in the sinusoids of the liver, sinuses and red pulp of the spleen, and sinuses of the bone marrow. The commonly reported T-cell phenotype is CD2+, CD3+, CD4−, CD5−, CD7±, CD8−, with either gamma-delta or alpha-beta T-cell receptor expression. Associated cytogenetic abnormalities include isochromosome 7q with or without trisomy 8. Approximately 10–20% of patients have a history of immunocompromise. Treatment to date with standard anthracycline containing chemotherapy regimens has been disappointing with variable response rates, high relapse rates, and a short median survival. An optimal treatment strategy for this small patient population has not yet been determined. Methods: Eleven cases of pathologically confirmed hepatosplenic T-cell lymphoma seen at M.D. Anderson Cancer Center between January 1990 and June 2006 were identified in the institution’s database. Clinical characteristics and treatment results were retrospectively reviewed. Results: The mean age at the time of diagnosis was 35.3 years (range 8 – 58 years). Six patients were male and five were female. Seven patients had the gamma-delta T-cell receptor phenotype, and three patients had the alpha-beta T-cell receptor phenotype. Cytogenetic abnormalities observed included t(7;14)(q34q13), 46,idem,del(2)(q32q37), 45XY,der(13;14)(q10;q10), 45XY,i(7)(q10),der(13;14)(q10;q10), del(22q).ish22(WCP22x2). One patient had lymphomatous involvement of the skin, a finding not previously reported in hepatosplenic T cell lymphoma. Two patients had a history of significant immunocompromise, including one patient with Sjogren’s disease treated intermittently with prednisolone and methotrexate, and one patient with Crohn’s disease on chronic treatment with mercaptopurine. Complete responses (CR) were achieved in four out of eight patients who received chemotherapy and whose complete records were available. CRs were achieved with the following regimens: (1) Sequential IDSHAP/AMDBIDCOS/MINE, (2) CHOP/methotrexate and autologous stem cell transplant, (3) CHOP, (4) pentostatin/campath and allogeneic stem cell transplant. PET scans in 3 patients and Gallium scans in 5 patients did not correlate with disease activity or clinical response. Mean duration of CR was 8 months (range 2 – 14+ months). Mean overall survival was 11.4 months (range 3 – 25 months), with one patient still alive and in remission at 20 months. Conclusion: In one of the largest series of hepatosplenic T-cell lymphoma patients, we confirm the aggressive clinical course of this subtype of peripheral T-cell lymphoma occurring in a young patient population. We discovered a near-equal incidence of this disease in males and females, contrary to results in earlier series which suggested this disease is usually diagnosed in males. Standard chemotherapy treatment strategies resulted in poor outcomes. However, survival may be improved upon with newer strategies such as the use of alemtuzumab, pentostatin, and high dose chemotherapy with stem cell rescue. New therapeutic strategies are needed to improve the outcome of patients with hepatosplenic T-cell lymphoma.

Hepatosplenic T-cell lymphoma is a rare peripheral T-cell lymphoma, and less than 100 cases have been described in the literature since the entity was first proposed in 1990. This condition is characterized by malignant T-cell proliferation in the sinusoids of the liver, sinuses and red pulp of the spleen, and sinuses of the bone marrow. The commonly reported T-cell phenotype is CD2+, CD3+, CD4−, CD5−, CD7±, CD8−, with either gamma-delta or alpha-beta T-cell receptor expression. Associated cytogenetic abnormalities include isochromosome 7q with or without trisomy 8. Approximately 10–20% of patients have a history of immunocompromise. Treatment to date with standard anthracycline containing chemotherapy regimens has been disappointing with variable response rates, high relapse rates, and a short median survival. An optimal treatment strategy for this small patient population has not yet been determined.