EGFR Inhibition Enhances the Cellular Uptake and Antitumor-Activity of the HER3 Antibody-Drug Conjugate HER3-DXd.

Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI) are the standard-of-care treatment for EGFR-mutant non-small cell lung cancers (NSCLC). However, most patients develop acquired drug resistance to EGFR TKIs. HER3 is a unique pseudokinase member of the ERBB family that functions by dimerizing with other ERBB family members (EGFR and HER2) and is frequently overexpressed in EGFR-mutant NSCLC. Although EGFR TKI resistance mechanisms do not lead to alterations in HER3, we hypothesized that targeting HER3 might improve efficacy of EGFR TKI. HER3-DXd is an antibody-drug conjugate (ADC) comprised of HER3-targeting antibody linked to a topoisomerase I inhibitor currently in clinical development. In this study, we evaluated the efficacy of HER3-DXd across a series of EGFR inhibitor-resistant, patient-derived xenografts and observed it to be broadly effective in HER3-expressing cancers. We further developed a preclinical strategy to enhance the efficacy of HER3-DXd through osimertinib pretreatment, which increased membrane expression of HER3 and led to enhanced internalization and efficacy of HER3-DXd. The combination of osimertinib and HER3-DXd may be an effective treatment approach and should be evaluated in future clinical trials in EGFR-mutant NSCLC patients. SIGNIFICANCE: EGFR inhibition leads to increased HER3 membrane expression and promotes HER3-DXd ADC internalization and efficacy, supporting the clinical development of the EGFR inhibitor/HER3-DXd combination in EGFR-mutant lung cancer.See related commentary by Lim et al., p. 18.

Oncogenic switch and single-agent MET inhibitor sensitivity in a subset of EGFR-mutant lung cancer.

The clinical efficacy of epidermal growth factor receptor (EGFR)­targeted therapy in EGFR-mutant non­small cell lung cancer is limited by the development of drug resistance. One mechanism of EGFR inhibitor resistance occurs through amplification of the human growth factor receptor (MET) proto-oncogene, which bypasses EGFR to reactivate downstream signaling. Tumors exhibiting concurrent EGFR mutation and MET amplification are historically thought to be codependent on the activation of both oncogenes. Hence, patients whose tumors harbor both alterations are commonly treated with a combination of EGFR and MET tyrosine kinase inhibitors (TKIs). Here, we identify and characterize six patient-derived models of EGFR-mutant, MET-amplified lung cancer that have switched oncogene dependence to rely exclusively on MET activation for survival. We demonstrate in this MET-driven subset of EGFR TKI-refractory cancers that canonical EGFR downstream signaling was governed by MET, even in the presence of sustained mutant EGFR expression and activation. In these models, combined EGFR and MET inhibition did not result in greater efficacy in vitro or in vivo compared to single-agent MET inhibition. We further identified a reduced EGFR:MET mRNA expression stoichiometry as associated with MET oncogene dependence and single-agent MET TKI sensitivity. Tumors from 10 of 11 EGFR inhibitor­resistant EGFR-mutant, MET-amplified patients also exhibited a reduced EGFR:MET mRNA ratio. Our findings reveal that a subset of EGFR-mutant, MET-amplified lung cancers develop dependence on MET activation alone, suggesting that such patients could be treated with a single-agent MET TKI rather than the current standard-of-care EGFR and MET inhibitor combination regimens.

Variation of Anatomical and Physiological Parameters that Affect Estimates of ACL Loading During Drop Landing.

BACKGROUND: Anterior cruciate ligament (ACL) loading during drop landing has been recently studied with a sagittal plane knee model developed by Kernozek and Ragan using mean anatomical and physiological parameters obtained from cadaveric and clinical data. It is unknown how estimates in ACL load may be altered due to variations in anatomical and physiological parameters used from other research. METHODS: USING THE SAME MODEL, THESE PARAMETERS WERE SYSTEMATICALLY VARIED, INCLUDING: tibial slope, moment arms of the patellar tendon, hamstring, and gastrocnemius at the knee and ankle, patellar tendon and hamstring line of force, ACL stiffness, and nonlinear muscle activation parameters. To determine the sensitivity of the model to changes in these parameters, each was varied independently by ±5% and by ranges reported in the literature. Changes in maximum ACL load and shear force components of the patellar tendon, hamstring, and tibio-femoral contact force were calculated from drop landing data of 21 subjects. RESULTS: The variation in ACL load during drop landing from its nominal value was largest (-100% to 176%) when extremes in reported tibial slope values were utilized. Variation in the next most important parameter, patellar tendon line of force, affected ACL load by -72% to 88%. CONCLUSION: Variations in tibial slope and patellar tendon line of force had the greatest influence on estimated ACL loading during drop landing. Differences in these parameters between subjects may be just as important to ACL loading as the kinematic and kinetic performance differences observed in landing.

Results of a multicenter open-label randomized trial evaluating infusion duration of zoledronic acid in multiple myeloma patients (the ZMAX trial).

Zoledronic acid, an intravenous (IV) bisphosphonate, is a standard treatment for multiple myeloma (MM) but may exacerbate preexisting renal dysfunction. The incidence of zoledronic acid-induced renal dysfunction may correlate with infusion duration. In this randomized, multicenter, open-label study, 176 patients with MM, at least one bone lesion, and stable renal function with a serum creatinine (SCr) level < 3 mg/dL received zoledronic acid 4 mg (in 250 mL) as a 15- or 30-minute IV infusion every 3-4 weeks. At month 12, 20% (17 patients) in the 15-minute and 16% (13 patients) in the 30-minute arm experienced a clinically relevant but nonsignificant SCr-level increase (P = 0.44). By 24 months, the proportion of patients with a clinically relevant SCr-level increase was similar between arms (15-minute 28% [24 patients] vs 30-minute 27% [23 patients], P = 0.9014). Median zoledronic acid end-of-infusion concentrations were higher with the shorter infusion (15-minute 249 ng/mL vs 30-minute 172 ng/mL), and prolonging the infusion beyond 15 minutes did not influence adverse events related to zoledronic acid. For patients with MM, the safety profile of IV zoledronic acid is similar between those receiving a 15- or 30-minute infusion; therefore, determining the appropriate infusion duration of zoledronic acid should be based on individual patient considerations.

Lack of correlation between epidermal growth factor receptor status and response to Panitumumab monotherapy in metastatic colorectal cancer.

PURPOSE: Panitumumab, a fully human anti-epidermal growth factor receptor (EGFR) monoclonal antibody, is approved as monotherapy for the treatment of metastatic colorectal cancer. We evaluated the association of tumor EGFR expression levels with outcomes in patients with chemorefractory metastatic colorectal cancer. EXPERIMENTAL DESIGN: Two phase II, multicenter, single-arm, open-label studies enrolled chemorefractory patients with tumors expressing low/negative (1-9%/<1%; Low/Negative EGFR study) or high (> or =10%; High EGFR study) levels of EGFR. Patients received panitumumab 6 mg/kg every two weeks until disease progression or intolerance. End points included objective response rate (per response evaluation criteria in solid tumors), progression-free survival (PFS), overall survival (OS), and safety. Exploratory analyses by tumor KRAS status were carried out. RESULTS: A total of 203 patients (Low/Negative EGFR) and 185 patients (High EGFR) enrolled in the studies. The overall response rate was 5.7% [95% confidence interval (95% CI), 2.6-10.5] in patients with low/negative EGFR and 4.2% (95% CI, 1.6-9.0) in patients with high EGFR; the response rate at week 16 was 4% in both studies (all partial responses). Median PFS times were 8.1 weeks (95% CI, 7.1-12.6), 8.1 weeks (95% CI, 7.4-11.1), and 7.3 weeks (95% CI, 7.1-7.6) in patients with negative, low, and high levels of EGFR expression, respectively. PFS and OS were longer in patients with wild-type KRAS than those with mutant KRAS. As expected, most adverse events were skin related. CONCLUSIONS: These studies confirm previous reports that tumor EGFR expression levels are not associated with efficacy with an anti-EGFR antibody and that anti-EGFR antibody therapy should be limited to those patients whose tumors express wild-type KRAS.

Results of a phase II open-label study of capecitabine in combination with irinotecan as first-line treatment for metastatic colorectal cancer.

BACKGROUND: Between July 2001 and September 2002, 49 eligible patients were enrolled in an open-label phase II study to assess the efficacy and safety of first-line treatment with capecitabine/irinotecan in metastatic colorectal cancer. PATIENTS AND METHODS: Patients received capecitabine (1000 mg/m2 twice daily) on days 1-14 and irinotecan (240 mg/m2) on day 1 of a 21-day cycle. Patients enrolled had a median age of 64.5 years, and 6% of patients had an Eastern Cooperative Oncology Group performance status of 2. Fifty-seven percent of patients were male. RESULTS: Forty-two patients were evaluable for response. There was 1 complete response (2%), 18 partial responses (43%), 20 cases of stable disease (48%), and 3 cases of disease progression (7%), for an overall response rate of 45% (95% CI, 30%-60%). The median duration of response was 5.7 months (range, 2.5-II.3 months). Median survival was 13.4 months (range, 1.2-28.8 months) and median progression-free survival was 6.2 months (range, 1.2-17.5 months). At 1 year, the estimated survival rate was 54% and the estimated progression-free survival rate was II%. The median number of cycles received was 6 (range, 1-18 cycles), and most patients (80%) required a dose modification because of diarrhea, nausea, and/or neutropenia. Grade 1/2 hand-foot syndrome occurred in 8 patients (16%). Grade 3/4 toxicities experienced by > or = 5% of patients included diarrhea (20%), neutropenia (12%), dehydration (10%), nausea (10%), anemia (6%), fatigue (6%), pain (6%), and vomiting (6%). CONCLUSIONS: First-line capecitabine/ irinotecan is an active combination for the treatment of metastatic colorectal cancer and feasible for use in the community-based setting. Despite significant toxicity with the regimen, the treatment was manageable with dose reduction or delay and should be investigated in phase III trials.