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– Cabozantinib in combination with atezolizumab demonstrated promising preliminary efficacy and a favorable safety profile in cohorts of patients with clear cell and non-clear cell renal cell carcinoma –
– Data presented during the
“Given the broad experience with cabozantinib as monotherapy for advanced kidney cancer, it’s very exciting to see the growing body of clinical evidence that demonstrates encouraging tolerability and clinical activity when combining cabozantinib with atezolizumab in this disease,” said Dr.
Clear Cell RCC Expansion Cohort (abstract 702O):
Initial results from the clear cell RCC expansion cohort (cohort 1) are being presented by
At a median follow-up of 25.8 months for the cabozantinib 40 mg dose group, the objective response rate (ORR) per Response Evaluation Criteria in Solid Tumors (RECIST) v. 1.1, the trial’s primary endpoint for the expansion cohorts, was 53%, with one complete response; disease control rate was 94%. Median progression-free survival (PFS) was 19.5 months (95% confidence interval [CI] 11.0–NR) with 17 events observed among 34 patients. Median duration of response was not yet reached.
At a median follow-up of 15.3 months for the cabozantinib 60 mg dose group, ORR per RECIST v. 1.1 was 58%, with four complete responses; disease control rate was 92%. Median PFS was 15.1 months (95% CI 8.2–22.3) with 19 events observed among 36 patients. Median duration of response for all responding patients was 15.4 months.
For both dose groups combined, positive PD-L1 status at baseline and higher levels of CD8+ T cells each showed a significant positive association with overall response.
In the 40 mg dose group, treatment-related grade 3/4 adverse events (AEs) occurring in ≥5% of patients were diarrhea (9%), fatigue (6%), hypertension (24%) and hypophosphatemia (15%); the discontinuation rate for either cabozantinib or atezolizumab due to treatment-related AEs was 24%, and 15% discontinued both study treatments due to treatment-related AEs. In the 60 mg dose group, treatment-related grade 3/4 were diarrhea (19%), fatigue (6%), hypertension (14%), alanine aminotransferase (ALT) increased (14%), aspartate aminotransferase (AST) increased (6%), lipase increased (8%) and mucosal inflammation (6%); the discontinuation rate for either study treatment due to treatment-related AEs was 19%, and 6% discontinued both study treatments due to treatment-related AEs.
Non-Clear Cell RCC Expansion Cohort (abstract 709P):
Initial results from the non-clear cell expansion cohort (cohort 10) were presented by Dr.
At a median follow-up of 13 months, ORR per RECIST v1.1 was 33%, and disease control rate was 93%. Median PFS was 9.5 months (95% CI 5.5-NE), and median duration of response was 8.3 months.
Treatment-related grade 3/4 AEs occurred in 37% of patients, and hypophosphatemia (13%) was the most common grade 3/4 AE. Seventeen percent of patients discontinued either study treatment for treatment-related AEs, and 3% discontinued both study treatments for treatment-related AEs.
“Following on our pivotal CheckMate -9ER data, we are thrilled to share these additional findings at the
More information about COSMIC-021 is available at ClinicalTrials.gov (NCT03170960).
About the COSMIC-021 Study
COSMIC-021 is a multicenter, phase 1b, open-label study that is divided into two parts: a dose-escalation phase and an expansion cohort phase. The dose-escalation phase was designed to enroll patients either with advanced RCC with or without prior systemic therapy or with inoperable, locally advanced, metastatic or recurrent urothelial carcinoma (UC), (including renal, pelvis, ureter, urinary bladder and urethra) after prior platinum-based therapy. Ultimately, all 12 patients enrolled in this stage of the trial were patients with advanced RCC. The dose-escalation phase of the study determined that both 40 mg and 60 mg daily doses of cabozantinib in combination with atezolizumab (1200 mg infusion once every 3 weeks) were safe and tolerable without dose-limiting toxicities. These results were presented at the
In the expansion phase, the trial is enrolling 24 cohorts in 12 tumor types: RCC, UC, non-small cell lung cancer (NSCLC), castrate-resistant prostate cancer (CRPC), hepatocellular carcinoma (HCC), triple-negative breast cancer, epithelial ovarian cancer, endometrial cancer, gastric or gastroesophageal junction adenocarcinoma, colorectal adenocarcinoma, head and neck cancer, and differentiated thyroid cancer. Up to 1,720 patients may enroll in this phase of the trial: each expansion cohort will initially enroll approximately 30 patients, and up to 10 cohorts may further expand enrollment, resulting in up to 1,000 patients across such potential additional expansion cohorts.
Four of the cohorts are exploratory: three are enrolling approximately 30 patients each with advanced UC, CRPC or NSCLC to be treated with cabozantinib as a single agent, and one is enrolling approximately 10 patients with advanced CRPC to be treated with single-agent atezolizumab. Exploratory cohorts have the option to be expanded up to 80 patients (cabozantinib) and 30 patients (atezolizumab) total.
The American Cancer Society’s 2020 statistics cite kidney cancer as among the top ten most commonly diagnosed forms of cancer among both men and women in the
About 70% of RCC cases are known as “clear cell” carcinomas, based on histology.4 The majority of clear cell RCC tumors have below-normal levels of a protein called
About CABOMETYX® (cabozantinib)
Important Safety Information
Warnings and Precautions
Hemorrhage: Severe and fatal hemorrhages occurred with CABOMETYX. The incidence of Grade 3 to 5 hemorrhagic events was 5% in CABOMETYX patients in RCC and HCC studies. Discontinue CABOMETYX for Grade 3 or 4 hemorrhage. Do not administer CABOMETYX to patients who have a recent history of hemorrhage, including hemoptysis, hematemesis, or melena.
Perforations and Fistulas: Gastrointestinal (GI) perforations, including fatal cases, occurred in 1% of CABOMETYX patients. Fistulas, including fatal cases, occurred in 1% of CABOMETYX patients. Monitor patients for signs and symptoms of perforations and fistulas, including abscess and sepsis. Discontinue CABOMETYX in patients who experience a Grade 4 fistula or a GI perforation.
Thrombotic Events: CABOMETYX increased the risk of thrombotic events. Venous thromboembolism occurred in 7% (including 4% pulmonary embolism) and arterial thromboembolism in 2% of CABOMETYX patients. Fatal thrombotic events occurred in CABOMETYX patients. Discontinue CABOMETYX in patients who develop an acute myocardial infarction or serious arterial or venous thromboembolic event requiring medical intervention.
Hypertension and Hypertensive Crisis: CABOMETYX can cause hypertension, including hypertensive crisis. Hypertension occurred in 36% (17% Grade 3 and <1% Grade 4) of CABOMETYX patients. Do not initiate CABOMETYX in patients with uncontrolled hypertension. Monitor blood pressure regularly during CABOMETYX treatment. Withhold CABOMETYX for hypertension that is not adequately controlled with medical management; when controlled, resume at a reduced dose. Discontinue CABOMETYX for severe hypertension that cannot be controlled with anti-hypertensive therapy or for hypertensive crisis.
Diarrhea: Diarrhea occurred in 63% of CABOMETYX patients. Grade 3 diarrhea occurred in 11% of CABOMETYX patients. Withhold CABOMETYX until improvement to Grade 1 and resume at a reduced dose for intolerable Grade 2 diarrhea, Grade 3 diarrhea that cannot be managed with standard antidiarrheal treatments, or Grade 4 diarrhea.
Palmar-Plantar Erythrodysesthesia (PPE): PPE occurred in 44% of CABOMETYX patients. Grade 3 PPE occurred in 13% of CABOMETYX patients. Withhold CABOMETYX until improvement to Grade 1 and resume at a reduced dose for intolerable Grade 2 PPE or Grade 3 PPE.
Proteinuria: Proteinuria occurred in 7% of CABOMETYX patients. Monitor urine protein regularly during CABOMETYX treatment. Discontinue CABOMETYX in patients who develop nephrotic syndrome.
Osteonecrosis of the Jaw (ONJ): ONJ occurred in <1% of CABOMETYX patients. ONJ can manifest as jaw pain, osteomyelitis, osteitis, bone erosion, tooth or periodontal infection, toothache, gingival ulceration or erosion, persistent jaw pain, or slow healing of the mouth or jaw after dental surgery. Perform an oral examination prior to CABOMETYX initiation and periodically during treatment. Advise patients regarding good oral hygiene practices. Withhold CABOMETYX for at least 3 weeks prior to scheduled dental surgery or invasive dental procedures, if possible. Withhold CABOMETYX for development of ONJ until complete resolution.
Impaired Wound Healing: Wound complications occurred with CABOMETYX. Withhold CABOMETYX for at least 3 weeks prior to elective surgery. Do not administer CABOMETYX for at least 2 weeks after major surgery and until adequate wound healing is observed. The safety of resumption of CABOMETYX after resolution of wound healing complications has not been established.
Reversible Posterior Leukoencephalopathy Syndrome (RPLS): RPLS, a syndrome of subcortical vasogenic edema diagnosed by characteristic findings on MRI, can occur with CABOMETYX. Evaluate for RPLS in patients presenting with seizures, headache, visual disturbances, confusion, or altered mental function. Discontinue CABOMETYX in patients who develop RPLS.
Embryo-Fetal Toxicity: CABOMETYX can cause fetal harm. Advise pregnant women and females of reproductive potential of the potential risk to a fetus. Verify the pregnancy status of females of reproductive potential prior to initiating CABOMETYX and advise them to use effective contraception during treatment and for 4 months after the last dose.
The most commonly reported (≥25%) adverse reactions are: diarrhea, fatigue, decreased appetite, PPE, nausea, hypertension, and vomiting.
Strong CYP3A4 Inhibitors: If coadministration with strong CYP3A4 inhibitors cannot be avoided, reduce the CABOMETYX dosage. Avoid grapefruit or grapefruit juice.
Strong CYP3A4 Inducers: If coadministration with strong CYP3A4 inducers cannot be avoided, increase the CABOMETYX dosage.
USE IN SPECIFIC POPULATIONS
Lactation: Advise women not to breastfeed during CABOMETYX treatment and for 4 months after the final dose.
Hepatic Impairment: In patients with moderate hepatic impairment, reduce the CABOMETYX dosage. CABOMETYX is not recommended for use in patients with severe hepatic impairment.
Please see accompanying full Prescribing Information https://cabometyx.com/downloads/CABOMETYXUSPI.pdf.
Founded in 1994,
This press release contains forward-looking statements, including, without limitation, statements related to: the potential of cabozantinib in combination with immune checkpoint inhibitor therapy for the treatment of advanced RCC; and Exelixis’ plans to reinvest in its business to maximize the potential of the company’s pipeline, including through targeted business development activities and internal drug discovery. Any statements that refer to expectations, projections or other characterizations of future events or circumstances are forward-looking statements and are based upon Exelixis’ current plans, assumptions, beliefs, expectations, estimates and projections. Forward-looking statements involve risks and uncertainties. Actual results and the timing of events could differ materially from those anticipated in the forward-looking statements as a result of these risks and uncertainties, which include, without limitation: complexities and the unpredictability of the regulatory review and approval processes in the
TECENTRIQ® (atezolizumab) is a registered trademark of
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Senior Director, Public Affairs and Advocacy Relations