– 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 European Society
for Medical Oncology Virtual Congress 2020 –
Exelixis, Inc. (NASDAQ: EXEL) today announced positive phase 1b
clinical trial results for the combination of cabozantinib
(CABOMETYX®) and atezolizumab (TECENTRIQ®) in patients with locally
advanced or metastatic solid tumors. Data from two expansion
cohorts of the COSMIC-021 trial was presented during the European
Society for Medical Oncology (ESMO) Virtual Congress 2020. Results
from the clear cell renal cell carcinoma (RCC) cohort are being
presented in the GU Proffered Paper Session on September 21, 2020,
and results from the non-clear cell RCC cohort were presented as a
poster available on demand for registrants beginning September 17,
2020 at 9:00 a.m. CEST.
“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. Sumanta Pal, Clinical Professor, City of
Hope, the principal investigator for the COSMIC-021 study. “We are
especially encouraged to see a durable objective response in more
than 50% of patients with previously untreated clear cell RCC,
paired with an acceptable safety profile at both cabozantinib dose
levels evaluated in combination with atezolizumab. We look forward
to learning more about the potential of this combination regimen to
improve outcomes for patients with advanced kidney cancer from the
ongoing phase 3 CONTACT-03 trial.”
Clear Cell RCC Expansion Cohort
(abstract 702O):
Initial results from the clear cell RCC expansion cohort (cohort
1) are being presented by Dr. Pal. The analysis included 70 RCC
patients with clear cell histology who had not received prior
systemic therapy. Patients received atezolizumab in combination
with either a 40 mg or 60 mg daily dose of cabozantinib.
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. Bradley A. McGregor, Clinical Director,
Lank Center for Genitourinary Oncology, Dana-Farber Cancer
Institute. The analysis included 30 patients with non-clear cell
RCC who could have received one prior VEGFR-TKI therapy but could
not have been previously treated with an immune checkpoint
inhibitor or chemotherapy. Four patients (13%) had received prior
VEGFR-TKI therapy. All patients received cabozantinib 40 mg daily
in combination with atezolizumab.
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 ESMO Virtual Congress
2020 that speak to the potential of cabozantinib in combination
with immune checkpoint inhibitor therapy for the treatment of
advanced kidney cancer,” said Gisela Schwab, M.D., President,
Product Development and Medical Affairs and Chief Medical Officer,
Exelixis. “The encouraging durable objective response and disease
control rates demonstrated in both of these cohorts build on the
positive results we’ve seen for cabozantinib in combination with
atezolizumab in other difficult-to-treat tumor types and support
the further evaluation of this regimen for the treatment of renal
cell carcinoma.”
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 European Society
for Medical Oncology 2018 Congress.
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.
Exelixis is the study sponsor of COSMIC-021. Both Ipsen and
Takeda have opted in to participate in the trial and are
contributing to the funding for this study under the terms of the
companies’ respective collaboration agreements with Exelixis. Roche
is providing atezolizumab for the trial.
About RCC
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 U.S.1 Clear cell RCC is the most common
type of kidney cancer in adults.2 If detected in its early stages,
the five-year survival rate for RCC is high; for patients with
advanced or late-stage metastatic RCC, however, the five-year
survival rate is only 12%.2 Approximately 32,000 patients in the
U.S. and 71,000 worldwide will require systemic treatment for
advanced kidney cancer in 2020.3
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 von Hippel-Lindau, which
leads to higher levels of MET, AXL and VEGF.5,6 These proteins
promote tumor angiogenesis (blood vessel growth), growth,
invasiveness and metastasis.7,8,9,10 MET and AXL may provide escape
pathways that drive resistance to VEGF receptor inhibitors.6,7
About CABOMETYX® (cabozantinib)
In the U.S., CABOMETYX tablets are approved for the treatment of
patients with advanced RCC and for the treatment of patients with
HCC who have been previously treated with sorafenib. CABOMETYX
tablets have also received regulatory approvals in the European
Union and additional countries and regions worldwide. In 2016,
Exelixis granted Ipsen exclusive rights for the commercialization
and further clinical development of cabozantinib outside of the
United States and Japan. In 2017, Exelixis granted exclusive rights
to Takeda Pharmaceutical Company Limited for the commercialization
and further clinical development of cabozantinib for all future
indications in Japan.
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.
Adverse Reactions
The most commonly reported (≥25%) adverse reactions are:
diarrhea, fatigue, decreased appetite, PPE, nausea, hypertension,
and vomiting.
Drug Interactions
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.
Avoid St. John’s wort.
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.
About Exelixis
Founded in 1994, Exelixis, Inc. (NASDAQ: EXEL) is a commercially
successful, oncology-focused biotechnology company that strives to
accelerate the discovery, development and commercialization of new
medicines for difficult-to-treat cancers. Following early work in
model system genetics, we established a broad drug discovery and
development platform that has served as the foundation for our
continued efforts to bring new cancer therapies to patients in
need. Our discovery efforts have resulted in four commercially
available products, CABOMETYX® (cabozantinib), COMETRIQ®
(cabozantinib), COTELLIC® (cobimetinib) and MINNEBRO®
(esaxerenone), and we have entered into partnerships with leading
pharmaceutical companies to bring these important medicines to
patients worldwide. Supported by revenues from our marketed
products and collaborations, we are committed to prudently
reinvesting in our business to maximize the potential of our
pipeline. We are supplementing our existing therapeutic assets with
targeted business development activities and internal drug
discovery — all to deliver the next generation of Exelixis
medicines and help patients recover stronger and live longer.
Exelixis is a member of the Standard & Poor’s (S&P) MidCap
400 index, which measures the performance of profitable mid-sized
companies. For more information about Exelixis, please visit
www.exelixis.com, follow @ExelixisInc on Twitter or like Exelixis,
Inc. on Facebook.
Forward-Looking Statements
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 U.S. and elsewhere; Exelixis’ and Roche’s
continuing compliance with applicable legal and regulatory
requirements; the potential failure of the combination of
cabozantinib and atezolizumab to demonstrate safety and/or efficacy
in CONTACT-03; uncertainties inherent in the product development
process; the continuing COVID-19 pandemic and its impact on
Exelixis’ research and development operations, including Exelixis’
ability to initiate new clinical trials and clinical trial sites,
enroll clinical trial patients, conduct trials per protocol, and
conduct drug research and discovery operations and related
activities; the costs of conducting clinical trials, including the
ability or willingness of Exelixis’ collaboration partners to
invest in the resources necessary to complete the trials; Exelixis’
dependence on third-party vendors for the development, manufacture
and supply of cabozantinib; Exelixis’ ability to protect its
intellectual property rights; market competition, including the
potential for competitors to obtain approval for generic versions
of CABOMETYX; changes in economic and business conditions; and
other factors affecting Exelixis and its development programs
discussed under the caption “Risk Factors” in Exelixis’ Quarterly
Report on Form 10-Q filed with the Securities and Exchange
Commission (SEC) on August 6, 2020, and in Exelixis’ future filings
with the SEC. All forward-looking statements in this press release
are based on information available to Exelixis as of the date of
this press release, and Exelixis undertakes no obligation to update
or revise any forward-looking statements contained herein, except
as required by law.
Exelixis, the Exelixis logo, CABOMETYX,
COMETRIQ and COTELLIC are registered U.S. trademarks. MINNEBRO is a
Japanese trademark.
TECENTRIQ® (atezolizumab) is a registered
trademark of Genentech, a member of the Roche Group.
1 American Cancer Society: Cancer Facts & Figures 2020.
Available at:
https://www.cancer.org/content/dam/cancer-org/research/cancer-facts-and-statistics/annual-cancer-facts-and-figures/2020/cancer-facts-and-figures-2020.pdf.
Accessed September 2020. 2 Jonasch, E., Gao, J., Rathmell, W.,
Renal cell carcinoma. BMJ. 2014; 349:g4797. 3 Decision Resources
Report: Renal Cell Carcinoma. October 2014 (internal data on file).
4 American Cancer Society: What is Kidney Cancer? Available at:
https://www.cancer.org/cancer/kidney-cancer/about/what-is-kidney-cancer.html.
Accessed September 2020. 5 Harshman, L., and Choueiri, T. Targeting
the hepatocyte growth factor/c-Met signaling pathway in renal cell
carcinoma. Cancer J. 2013; 19:316-323. 6 Rankin, et al. Direct
regulation of GAS6/AXL signaling by HIF promotes renal metastasis
through SRC and MET. Proc Natl Acad Sci USA. 2014; 111:13373-13378.
7 Zhou, L., Liu, X-D., Sun, M., et al. Targeting MET and AXL
overcomes resistance to sunitinib therapy in renal cell carcinoma.
Oncogene. 2016; 35:2687-2697. 8 Koochekpour, et al. The von
Hippel-Lindau tumor suppressor gene inhibits hepatocyte growth
factor/scatter factor-induced invasion and branching morphogenesis
in renal carcinoma cells. Mol Cell Biol. 1999; 19:5902–5912. 9
Takahashi, A., Sasaki, H., Kim, S., et al. Markedly increased
amounts of messenger RNAs for vascular endothelial growth factor
and placenta growth factor in renal cell carcinoma associated with
angiogenesis. Cancer Res. 1994; 54:4233-4237. 10 Nakagawa, M.,
Emoto, A., Hanada, T., Nasu, N., Nomura, Y. Tubulogenesis by
microvascular endothelial cells is mediated by vascular endothelial
growth factor (VEGF) in renal cell carcinoma. Br J Urol. 1997;
79:681-687.
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Investors Contact: Susan Hubbard EVP, Public Affairs and
Investor Relations Exelixis, Inc. (650) 837-8194
shubbard@exelixis.com
Media Contact: Lindsay Treadway Senior Director, Public
Affairs and Advocacy Relations Exelixis, Inc. (650) 837-7522
ltreadway@exelixis.com
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