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A recent article characterized dosing recommendations for cabozantinib in people living with HIV (PLWH) and cancer, a group that is often excluded from clinical trials. This study suggests cabozantinib is effective in cancers disproportionately impacting PLWH and has translational implications for the design of studies evaluating drug-drug interactions. See related article by Haigentz et al., p. 5038., (©2023 American Association for Cancer Research.)

On September 17, 2021, the FDA approved cabozantinib (Cabometyx; Exelixis, Inc.) for the treatment of adult and pediatric patients 12 years of age and older with locally advanced or metastatic differentiated thyroid cancer (DTC) that has progressed following prior VEGFR-targeted therapy and who are radioactive iodine (RAI)-refractory or ineligible. This is the first approval for patients with RAI-refractory locally advanced or metastatic DTC who have progressed following prior therapy and the first approval in pediatric patients with DTC. The approval was based on data from COSMIC-311 (Study XL184-311, NCT03690388), an international, randomized, double-blind trial in which patients with locally advanced or metastatic RAI-refractory DTC that progressed during or following treatment with at least one VEGFR-targeting tyrosine kinase inhibitor were treated with either cabozantinib 60 mg orally once daily (N = 170) or placebo with best supportive care (N = 88). The primary efficacy outcome measures were progression-free survival (PFS) and overall response rate (ORR) by blinded independent central review per RECIST 1.1. The median PFS was 11.0 months [95% confidence interval (CI), 7.4-13.8] in the cabozantinib arm compared with 1.9 months (95% CI, 1.9-3.7) in the control arm, with an HR of 0.22 (95% CI, 0.15-0.31). The endpoint of ORR was not met. No new safety signals were identified with the exception of hypocalcemia, which was added as a warning in the product labeling., (©2022 American Association for Cancer Research.)

Purpose: Because the Hedgehog and Notch pathways are often overexpressed in mesenchymal malignancies, we evaluated the efficacy of concurrent inhibition of Notch and Hedgehog signaling using the gamma-secretase inhibitor (GSI) RO4929097 and the smoothened antagonist vismodegib in unresectable or metastatic sarcoma., Patients and Methods: In this investigator-initiated trial, phase Ib used standard 3+3 dose escalation in which patients first received vismodegib once daily for 21 days, followed by the combination of RO4929097 concurrently with vismodegib in 21-day cycles. In phase II, patients were randomized to RO4929097 alone or in combination with vismodegib., Results: Nine patients were treated in phase Ib with no dose-limiting toxicities. RO4929097 at 15 mg daily in combination with 150 mg daily of vismodegib was declared the recommended phase II dose. Most adverse events were grade ≤ 2. In phase II (closed early due to discontinuation of RO4929097 evaluation), 34 patients were randomized to RO4929097 alone and 33 to RO4929097 plus vismodegib. RO4929097 did not interfere with the steady-state concentration of vismodegib, while vismodegib reduced the plasma concentration of RO492909. No patients had an objective response. Neither progression-free nor overall survival differed significantly between treatment arms. Paired tumor biopsies from a subset of patients demonstrated inhibition of cleaved Notch., Conclusions: The combination of RO4929097 plus vismodegib was generally well tolerated. Although accrual to this study was not completed, vismodegib did not meaningfully enhance the clinical efficacy of RO4929097 in an unplanned analysis. GSIs and GSIs plus vismodegib can inhibit intratumoral Notch and downstream phosphorylated Akt signaling., (©2022 American Association for Cancer Research.)

Purpose: The phase III CELESTIAL study demonstrated improved overall survival (OS) and progression-free survival (PFS) with cabozantinib versus placebo in patients with previously treated, advanced hepatocellular carcinoma (HCC). We analyzed outcomes by baseline alpha-fetoprotein (AFP) and on-treatment AFP changes., Patients and Methods: Serum AFP was measured every 8 weeks by blinded, centralized testing. Outcomes were analyzed by baseline AFP bifurcated at 400 ng/mL and by on-treatment AFP response (≥20% decrease from baseline at Week 8). The optimal cutoff for change in AFP at Week 8 was evaluated using maximally selected rank statistics., Results: Median OS for cabozantinib versus placebo was 13.9 versus 10.3 months [HR, 0.81; 95% confidence interval (CI), 0.62-1.04] for patients with baseline AFP <400 ng/mL, and 8.5 versus 5.2 months (HR, 0.71; 95% CI, 0.54-0.94) for patients with baseline AFP ≥400 ng/mL. Week 8 AFP response rate was 50% for cabozantinib versus 13% for placebo. In the cabozantinib arm, median OS for patients with and without AFP response was 16.1 versus 9.1 months (HR, 0.61; 95% CI, 0.45-0.84). AFP response was independently associated with longer OS. The optimal cutoff for association with OS in the cabozantinib arm was ≤0% change in AFP at Week 8 [AFP control; HR 0.50 (95% CI, 0.35-0.71)]. HRs for PFS were consistent with those for OS., Conclusions: Cabozantinib improved outcomes versus placebo across a range of baseline AFP levels. On-treatment AFP response and control rates were higher with cabozantinib than placebo, and were associated with longer OS and PFS with cabozantinib., (©2020 American Association for Cancer Research.)

Purpose: This study assesses the action of panobinostat, a histone deacetylase inhibitor (HDACI), in restoring sensitivity to bicalutamide in a castration-resistant prostate cancer (CRPC) model and the efficacy and safety of the panobinostat/bicalutamide combination in CRPC patients resistant to second-line antiandrogen therapy (2 nd LAARx)., Patients and Methods: The CWR22PC xenograft and isogenic cell line were tested for drug interactions on tumor cell growth and on the androgen receptor (AR), AR-splice variant7, and AR targets. A phase I trial had a 3 × 3 panobinostat dose-escalation design. The phase II study randomized 55 patients to panobinostat 40 mg (A arm) or 20 mg (B arm) triweekly ×2 weeks with bicalutamide 50 mg/day in 3-week cycles. The primary endpoint was to determine the percentage of radiographic progression-free (rPF) patients at 36 weeks versus historic high-dose bicalutamide., Results: In the model, panobinostat/bicalutamide demonstrated synergistic antitumor effect while reducing AR activity. The dose-limiting toxicity was not reached. The probability of remaining rPF exceeded protocol-specified 35% in the A arm and 47.5% and 38.5% in the B arm. The probabilities of remaining rPF were 47.5% in the A arm and 38.5% in the B arm, exceeding the protocol-specified threshold of 35%. A arm/B arm: adverse events (AE), 62%/19%; treatment stopped for AEs, 27.5%/11.5%; dose reduction required, 41%/4%; principal A-arm grade ≥3 AEs, thrombocytopenia (31%) and fatigue (14%)., Conclusions: The 40 mg panobinostat/bicalutamide regimen increased rPF survival in CRPC patients resistant to 2 nd LAARx. Panobinostat toxicity was tolerable with dose reductions. Epigenetic HDACI therapy reduces AR-mediated resistance to bicalutamide in CRPC models with clinical benefit in patients. The combination merits validation using a second-generation antiandrogen., (©2018 American Association for Cancer Research.)

Purpose: Anti-VEGF therapies remain controversial in the treatment of recurrent glioblastoma (GBM). In the current study, we demonstrate that recurrent GBM patients with a specific diffusion MR imaging signature have an overall survival (OS) advantage when treated with cediranib, bevacizumab, cabozantinib, or aflibercept monotherapy at first or second recurrence. These findings were validated using a separate trial comparing bevacizumab with lomustine. Experimental Design: Patients with recurrent GBM and diffusion MRI from the monotherapy arms of 5 separate phase II clinical trials were included: (i) cediranib (NCT00035656); (ii) bevacizumab (BRAIN Trial, AVF3708g; NCT00345163); (iii) cabozantinib (XL184-201; NCT00704288); (iv) aflibercept (VEGF Trap; NCT00369590); and (v) bevacizumab or lomustine (BELOB; NTR1929). Apparent diffusion coefficient (ADC) histogram analysis was performed prior to therapy to estimate "ADC L ," the mean of the lower ADC distribution. Pretreatment ADC L , enhancing volume, and clinical variables were tested as independent prognostic factors for OS. Results: The coefficient of variance (COV) in double baseline ADC L measurements was 2.5% and did not significantly differ ( P = 0.4537). An ADC L threshold of 1.24 μm 2 /ms produced the largest OS differences between patients (HR ∼ 0.5), and patients with an ADC L > 1.24 μm 2 /ms had close to double the OS in all anti-VEGF therapeutic scenarios tested. Training and validation data confirmed that baseline ADC L was an independent predictive biomarker for OS in anti-VEGF therapies, but not in lomustine, after accounting for age and baseline enhancing tumor volume. Conclusions: Pretreatment diffusion MRI is a predictive imaging biomarker for OS in patients with recurrent GBM treated with anti-VEGF monotherapy at first or second relapse. Clin Cancer Res; 23(19); 5745-56. ©2017 AACR ., (©2017 American Association for Cancer Research.)

On April 25, 2016, the FDA approved cabozantinib (Cabometyx; Exelixis, Inc.) for the treatment of advanced renal cell carcinoma (RCC) in patients who have received prior antiangiogenic therapy. The approval was based on data from one randomized, open-label, multicenter study in which patients with RCC who had received prior antiangiogenic therapy were treated with either cabozantinib 60 mg orally once daily (n = 330) or everolimus 10 mg orally once daily (n = 328). The major efficacy outcome measure was progression-free survival (PFS) as assessed by a blinded independent radiology review committee in the first 375 randomized patients. A statistically significant improvement in PFS was seen, with a median PFS of 7.4 and 3.8 months in the cabozantinib and everolimus arms, respectively [hazard ratio (HR), 0.58; 95% confidence interval (CI), 0.45-0.74; P < 0.0001]. At a second interim analysis, a statistically significant improvement in overall survival (OS) in the intent-to-treat population was also demonstrated, with a median OS of 21.4 and 16.5 months in the cabozantinib and everolimus arms, respectively (HR, 0.66; 95% CI, 0.53-0.83; P = 0.0003). The most common (greater than or equal to 25%) adverse reactions included diarrhea, fatigue, nausea, decreased appetite, palmar-plantar erythrodysesthesia syndrome, hypertension, vomiting, weight loss, and constipation. Clin Cancer Res; 23(2); 330-5. ©2016 AACR., (©2016 American Association for Cancer Research.)

Purpose: To investigate the safety, dose-limiting toxicities, and pharmacokinetics of the smoothened inhibitor vismodegib in children with refractory or relapsed medulloblastoma., Experimental Design: Initially, vismodegib was administered daily at 85 mg/m(2) and escalated to 170 mg/m(2). The study was then revised to investigate a flat-dosing schedule of 150 mg for patients with small body surface area (BSA, 0.67-1.32 m(2)) or 300 mg for those who were larger (BSA, 1.33-2.20 m(2)). Pharmacokinetics were performed during the first course of therapy, and the right knees of all patients were imaged to monitor bone toxicity. Immunohistochemical analysis was done to identify patients with Sonic Hedgehog (SHH)-subtype medulloblastoma., Results: Thirteen eligible patients were enrolled in the initial study: 6 received 85 mg/m(2) vismodegib, and 7 received 170 mg/m(2). Twenty eligible patients were enrolled in the flat-dosing part of the study: 10 at each dosage level. Three dose-limiting toxicities were observed, but no drug-related bone toxicity was documented. The median (range) vismodegib penetration in the cerebrospinal fluid (CSF) was 0.53 (0.26-0.78), when expressed as a ratio of the concentration of vismodegib in the CSF to that of the unbound drug in plasma. Antitumor activity was seen in 1 of 3 patients with SHH-subtype disease whose tumors were evaluable, and in none of the patients in the other subgroups., Conclusions: Vismodegib was well tolerated in children with recurrent or refractory medulloblastoma; only two dose-limiting toxicities were observed with flat dosing. The recommended phase II study dose is 150 or 300 mg, depending on the patient's BSA. Clin Cancer Res; 19(22); 6305-12. ©2013 AACR.

Purpose: Patients with hormone receptor-negative breast cancer generally do not benefit from endocrine-targeted therapies. However, a subset with androgen receptor (AR) expression is predicted to respond to antiandrogen therapies. This phase II study explored bicalutamide in AR-positive, estrogen receptor (ER), and progesterone receptor (PgR)-negative metastatic breast cancer., Experimental Design: Tumors from patients with ER/PgR-negative advanced breast cancer were tested centrally for AR [immunohistochemistry (IHC) > 10% nuclear staining considered positive]. If either the primary or a metastatic site was positive, patients were eligible to receive the AR antagonist bicalutamide at a dose of 150 mg daily. Clinical benefit rate (CBR), the primary endpoint, was defined as the total number of patients who show a complete response (CR), partial response (PR), or stable disease (SD) > 6 months; secondary endpoints included progression-free survival (PFS) and toxicity. Correlative studies included measurement of circulating endocrine markers and IHC surrogates for basal-like breast cancer., Results: Of 424 patients with ER/PgR-negative breast cancer, 12% tested AR-positive. The 6-month CBR was 19% [95% confidence interval (CI), 7%-39%] for bicalutamide. The median PFS was 12 weeks (95% CI, 11-22 weeks). Bicalutamide was well-tolerated with no grade 4/5 treatment-related adverse events observed., Conclusion: AR was expressed in 12% of patients with ER/PgR-negative breast cancer screened for this trial. The CBR of 19% observed with bicalutamide shows proof of principle for the efficacy of minimally toxic androgen blockade in a select group of patients with ER/PgR-negative, AR-positive breast cancer., (©2013 AACR.)

Purpose: Vismodegib, an orally bioavailable small-molecule Smoothened inhibitor, is approved for treatment of advanced basal cell carcinoma (BCC). We conducted a pharmacokinetic study of vismodegib in patients with advanced solid tumors to explore the effects of food on drug exposure., Experimental Design: In part I, patients were randomized to fasting overnight (FO), a high fat meal (HF), or a low fat meal (LF) before a single dose of vismodegib 150 mg. Plasma concentrations of vismodegib were determined by a validated liquid chromatography-tandem mass spectrometry assay. Primary endpoints were C(max) and area under the curve (AUC(0-168)). In part II, patients randomized to FO or HF in part I took vismodegib 150 mg daily after fasting; those randomized to LF took it after a meal. Primary endpoints after two weeks were C(max) and AUC(0-24)., Results: Sixty (22 FO, 20 HF, 18 LF) and 52 (25 fasting, 27 fed) patients were evaluable for primary endpoints in parts I and II, respectively. Mean C(max) and AUC(0-168) after a single dose were higher in HF than FO patients [ratios of geometric means (90% CI) = 1.75 (1.30, 2.34) and 1.74 (1.25, 2.42), respectively]. There were no significant differences in C(max) or AUC(0-24) between fasting and fed groups after daily dosing. The frequencies of drug-related toxicities were similar in both groups., Conclusions: A HF meal increases plasma exposure to a single dose of vismodegib, but there are no pharmacokinetic or safety differences between fasting and fed groups at steady-state. Vismodegib may be taken with or without food for daily dosing., (©2013 AACR)

Background: Cabozantinib is an oral MET/VEGFR2 inhibitor. A recent phase II study of cabozantinib (100 mg daily) showed improved bone scans in subjects with metastatic castration-resistant prostate cancer (mCRPC), but adverse events (AE) caused frequent dose reductions. This study was designed to determine the efficacy and tolerability of cabozantinib at lower starting doses., Experimental Design: An adaptive design was used to determine the lowest active daily dose among 60, 40, and 20 mg. The primary endpoint was week 6 bone scan response, defined as ≥30% decrease in bone scan lesion area. The secondary endpoint was change in circulating tumor cells (CTC)., Results: Among 11 evaluable subjects enrolled at 40 mg, there were 9 partial responses (PR), 1 complete response, and 1 stable disease (SD). Of 10 subjects subsequently enrolled at 20 mg, there were 1 PR, 5 SDs, and 4 with progressive disease. Among 13 subjects enrolled on the 40 mg expansion cohort, there were 6 PRs and 7 SDs. No subjects required dose reduction or treatment interruption at 6 or 12 weeks; 3 subjects at dose level 0 discontinued due to AEs by 12 weeks. At 40 mg, median treatment duration was 27 weeks. 58% of subjects with ≥5 CTCs/7.5 mL at baseline converted to <5., Conclusions: Cabozantinib 40 mg daily was associated with a high rate of bone scan response. Cabozantinib 40 mg daily was associated with better tolerability than previously reported for cabozantinib 100 mg daily. These observations informed the design of phase III studies of cabozantinib in mCRPC., (©2013 AACR)

The data and regulatory considerations leading to the U.S. Food and Drug Administration (FDA) January 30, 2012 approval of Erivedge (vismodegib) capsules for the treatment of patients with recurrent, locally advanced, or metastatic basal cell carcinoma (BCC) are described. The FDA's approval decision was based primarily on the results observed in a single-arm, parallel cohort, international trial of vismodegib, administered orally at 150 mg daily until disease progression, in patients with pathologically confirmed, recurrent, locally advanced basal cell carcinoma (laBCC) or metastatic basal cell carcinoma (mBCC). An independent review committee confirmed an overall response rate (ORR) of 30.3% [95% confidence interval (CI): 15.6-48.2] in 33 patients with mBCC and an ORR of 42.9% (95% CI: 30.5-56.0) in 63 patients with laBCC; median response durations were 7.6 months and 7.6 months for patients with mBCC and laBCC, respectively. The most common adverse reactions were muscle spasms, alopecia, dysgeusia, weight loss, fatigue, nausea, diarrhea, decreased appetite, constipation, cough, arthralgias, vomiting, headache, ageusia, insomnia, and upper respiratory tract infection. Animal toxicology studies confirmed that vismodegib is a potent teratogenic agent. Approval was based on durable objective tumor responses supported by knowledge of the pathologic role of Hedgehog signaling in BCC and acceptable toxicity in a population without effective alternative therapies., (©2013 AACR.)

Purpose: Hedgehog pathway inhibition has been suggested as a potential maintenance treatment approach in ovarian cancer through disruption of tumor-stromal interactions. Vismodegib is an orally available Hedgehog pathway inhibitor with clinical activity in advanced basal cell carcinoma and medulloblastoma. This phase II, randomized, double-blind, placebo-controlled trial was designed to provide a preliminary estimate of efficacy in patients with ovarian cancer in second or third complete remission (CR)., Experimental Design: Patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer in second or third CR were randomized 1:1 to vismodegib (GDC-0449; 150 mg daily) or placebo three to 14 weeks after completing chemotherapy. Treatment continued until radiographic progression or toxicity. The primary endpoint was investigator-assessed progression-free survival (PFS)., Results: One hundred four patients were randomized to vismodegib (n = 52) or placebo (n = 52); median PFS was 7.5 months and 5.8 months, respectively [HR 0.79; 95% confidence interval (CI), 0.46-1.35]. The HR was 0.66 (95% CI, 0.36-1.20) for second CR patients (n = 84) and 1.79 (95% CI, 0.50-6.48) for third CR patients (n = 20). The most common adverse events in the vismodegib arm were dysgeusia/ageusia, muscle spasms, and alopecia. Grade 3/4 adverse events occurred in 12 patients (23.1%) with vismodegib and six (11.5%) with placebo. Hedgehog expression was detected in 13.5% of archival tissues., Conclusions: In this study, the sought magnitude of increase in PFS was not achieved for vismodegib maintenance versus placebo in patients with ovarian cancer in second or third CR. The frequency of Hedgehog ligand expression was lower than expected., (©2012 AACR.)

Vismodegib (GDC-0449), an orally bioavailable small-molecule inhibitor of Hedgehog signaling, was recently approved by the U.S. Food and Drug Administration for the treatment of basal cell carcinoma that is either metastatic or locally advanced in patients who are not candidates for surgical resection or radiation. Given the absence of previously defined effective drug therapy for this disease, approval was granted primarily on the basis of outcome of a nonrandomized parallel cohort phase II study of 99 patients with advanced basal cell carcinoma, with a primary endpoint of objective response rate. Response rates of 30.3% and 42.9% were observed in metastatic and locally advanced cohorts in this study, respectively, associated with median progression-free survival in both cohorts of 9.5 months. Ongoing clinical investigations include evaluation of the potential efficacy of vismodegib in a variety of diseases and in combination with other agents. The mechanism of action, preclinical and clinical data, and potential utility in other disease contexts are reviewed here., (©2012 AACR.)

Purpose: This study was designed to evaluate whether less frequent dosing [three times per week (TIW) or once weekly (QW)] of 150 mg vismodegib following a loading dose [150 mg once daily (QD) for 11 days] would result in similar safety, tolerability, and steady-state levels of total and unbound vismodegib as continuous QD dosing., Experimental Design: Sixty-seven patients with advanced solid tumors were stratified by baseline plasma alpha 1-acid glycoprotein (AAG) levels and randomized to one of three vismodegib 150 mg regimens: QD (n = 23), TIW (n = 22), or QW (n = 22) for up to 42 days after an 11-day loading phase (150 mg QD). Total and unbound (dialyzed) plasma vismodegib concentrations were determined by LC-MS/MS., Results: The most frequently reported adverse events were consistent with those in prior monotherapy trials, with similar incidence and severity regardless of dosing schedule. After the 150 mg QD loading phase, a concentration-dependent change in protein binding (3-fold increase in vismodegib fraction unbound) was observed at steady state compared with single dose. Mean total and unbound vismodegib steady-state concentrations were lower after TIW and QW than QD dosing, with an average intrasubject decrease of 50% and 80%, respectively, for unbound drug. Mechanism-based PK model simulations accurately and prospectively predicted the PK results., Conclusions: Vismodegib 150 mg TIW or QW failed to achieve unbound plasma concentrations previously associated with efficacy in patients with advanced basal cell carcinoma and medulloblastoma, even after a QD loading dose period. The 150 mg QD regimen is appropriate for vismodegib based on its clinical activity, tolerability, and favorable unbound concentrations., (©2011 AACR.)

Purpose: The hedgehog (Hh) signaling pathway, a key regulator of cell growth and differentiation during development is implicated in pathogenesis of certain cancers. Vismodegib (GDC-0449) is a small-molecule inhibitor of smoothened, a key component of Hh signaling. This phase I trial assessed GDC-0449 treatment in patients with solid tumors refractory to current therapies or for which no standard therapy existed., Experimental Design: Sixty-eight patients received GDC-0449 at 150 mg/d (n = 41), 270 mg/d (n = 23), or 540 mg/d (n = 4). Adverse events, tumor responses, pharmacokinetics, and pharmacodynamic down-modulation of GLI1 expression in noninvolved skin were assessed., Results: Thirty-three of 68 patients had advanced basal cell carcinoma (BCC), 8 had pancreatic cancer, 1 had medulloblastoma; 17 other types of cancer were also represented. GDC-0449 was generally well-tolerated. Six patients (8.8%) experienced 7 grade 4 events (hyponatremia, fatigue, pyelonephritis, presyncope, resectable pancreatic adenocarcinoma, and paranoia with hyperglycemia), and 27.9% of patients experienced a grade 3 event [most commonly hyponatremia (10.3%), abdominal pain (7.4%), and fatigue (5.9%)]. No maximum tolerated dose was reached. The recommended phase II dose was 150 mg/d, based on achievement of maximal plasma concentration and pharmacodynamic response at this dose. Tumor responses were observed in 20 patients (19 with BCC and 1 unconfirmed response in medulloblastoma), 14 patients had stable disease as best response, and 28 had progressive disease. Evidence of GLI1 down-modulation was observed in noninvolved skin., Conclusions: GDC-0449 has an acceptable safety profile and encouraging anti-tumor activity in advanced BCC and medulloblastoma. Further study in these and other cancer types is warranted., Competing Interests: of Potential Conflicts of Interest The other authors report no conflicts of interest., (©2011 AACR.)