AstraZeneca and Daiichi Sankyo’s datopotamab
deruxtecan plus IMFINZI showed a confirmed objective response rate
of 79%
Two ongoing Phase III trials are evaluating
datopotamab deruxtecan in patients with triple-negative breast
cancer
Updated results from the BEGONIA Phase Ib/II trial for the
cohort of patients treated with datopotamab deruxtecan (Dato-DXd)
plus IMFINZI® (durvalumab) (Arm 7) showed that the combination
demonstrated durable tumor responses and no new safety signals in
patients with previously untreated advanced or metastatic
triple-negative breast cancer (TNBC) with six months additional
follow-up from the previous data cut-off.
These data were presented today in a mini oral session at the
European Society for Medical Oncology (ESMO) 2023 Congress in
Madrid, Spain (379MO).
Datopotamab deruxtecan is a specifically engineered
TROP2-directed DXd antibody drug conjugate (ADC) being jointly
developed by AstraZeneca and Daiichi Sankyo.
Approximately 300,000 people worldwide are diagnosed annually
with TNBC, the most aggressive breast cancer subtype.1,2 Less than
half of patients with metastatic TNBC respond to current 1st-line
treatment options which can include chemotherapy alone or in
combination with an immunotherapy.2-4 Among patients with tumors
that do respond to initial treatment, disease progression is common
and rapid, often occurring within two years.2,4-6
Results showed that datopotamab deruxtecan plus IMFINZI, an anti
PD-L1 therapy, demonstrated a confirmed objective response rate
(ORR) of 79% (n=49 of 62) including six complete responses (CRs)
and 43 partial responses (PRs). Responses were observed regardless
of PD-L1 expression level. Median progression-free survival (PFS)
was 13.8 months (95% confidence interval [CI] 11-not calculable
[NC]) and median duration of response (DoR) was 15.5 months (95% CI
9.9-NC) with 11.7 months of follow-up.
Peter Schmid, MD, Barts Cancer Institute, London, United
Kingdom, and investigator in the trial, said: “These results for
datopotamab deruxtecan plus durvalumab in the first-line
triple-negative breast cancer setting are highly encouraging,
particularly the 79% objective response rate. This magnitude of
response is especially notable given the majority of patients in
this cohort have PD-L1-low tumors, representing a population for
whom treatment has long been limited to standard chemotherapy.”
Cristian Massacesi, Chief Medical Officer and Oncology Chief
Development Officer, AstraZeneca, said: “Progress in the first-line
advanced triple-negative breast cancer setting has been modest for
years and new therapeutic strategies are needed to improve outcomes
for patients with this aggressive breast cancer subtype. These
updated results from the BEGONIA trial reinforce our confidence in
the potential for datopotamab deruxtecan to become a new, important
treatment modality in this setting as we eagerly await results from
our ongoing Phase III triple-negative breast cancer program.”
Mark Rutstein, MD, Global Head, Oncology Clinical Development,
Daiichi Sankyo, said: “Disease progression after initial treatment
is a reality for patients with triple-negative breast cancer,
underscoring the need for more durable treatment options. These
findings showcase the potential of datopotamab deruxtecan in
previously untreated advanced triple-negative breast cancer and,
following the positive results of our TROPION-Breast01 Phase III
trial, build on the growing body of evidence for the potential use
of this TROP2-directed antibody drug conjugate, alone and in
combinations, in several subtypes of breast cancer.”
The safety profile of datopotamab deruxtecan in combination with
IMFINZI was consistent with the known safety profiles of both
agents. Grade 3 or higher treatment-emergent adverse events (TEAEs)
occurred in 57% of patients. The most common Grade 3 or higher
TEAEs were increased amylase (18%), stomatitis (11%), constipation
(2%), fatigue (2%), vomiting (2%) and decreased appetite (2%).
There were three interstitial lung disease (ILD) events adjudicated
as drug-related by an independent committee including two Grade 2
events and one Grade 1 event.
In Arm 7 of the BEGONIA trial (n=62), the majority of patients
(n=54) had tumors with low PD-L1 expression (tumor area positivity
[TAP]<10%). Seven patients had tumors with high PD-L1 expression
(TAP≥10%). As of the February 2, 2023 data cut-off, 29 patients
(47%) remained on study treatment.
Summary of BEGONIA Arm 7 Efficacy Results
Efficacy Measure (as assessed by
investigator)
All Patients (n=62)
ORRi, confirmed (95% CI)
79% (n=49) (66.8-88.3)
CR rate
10% (n=6)
PR rate
69% (n=43)
Median DoR (95% CI)
15.5 months (9.9-not calculable)
Median PFS (95% CI)
13.8 months (11.0-not calculable)
CI, confidence interval; CR; complete
response; DoR, duration of response; ORR, objective response rate;
PFS, progression-free survival; PR, partial response
i ORR is (complete response + partial
response)
AstraZeneca and Daiichi Sankyo have two Phase III trials
evaluating datopotamab deruxtecan in TNBC. TROPION-Breast02 is
comparing datopotamab deruxtecan to chemotherapy in patients with
previously untreated locally recurrent inoperable or metastatic
TNBC who are not candidates for anti-PD-L1 therapy.
TROPION-Breast03 is evaluating datopotamab deruxtecan with and
without IMFINZI versus investigator’s choice of therapy in patients
with Stage I-III TNBC with residual disease after neoadjuvant
therapy.
Several presentations featured during the ESMO 2023 Congress are
showcasing the strength and depth of data for datopotamab
deruxtecan across multiple tumor types and settings, including
results from the TROPION-Lung01 and TROPION-Breast01 Phase III
trials.
IMPORTANT SAFETY INFORMATION FOR IMFINZI® and IMJUDO®
(tremelimumab-actl)
There are no contraindications for IMFINZI® (durvalumab) or
IMJUDO® (tremelimumab-actl).
Severe and Fatal Immune-Mediated Adverse Reactions
Important immune-mediated adverse reactions listed under
Warnings and Precautions may not include all possible severe and
fatal immune-mediated reactions. Immune-mediated adverse reactions,
which may be severe or fatal, can occur in any organ system or
tissue. Immune-mediated adverse reactions can occur at any time
after starting treatment or after discontinuation. Monitor patients
closely for symptoms and signs that may be clinical manifestations
of underlying immune-mediated adverse reactions. Evaluate clinical
chemistries including liver enzymes, creatinine,
adrenocorticotropic hormone (ACTH) level, and thyroid function at
baseline and before each dose. In cases of suspected
immune-mediated adverse reactions, initiate appropriate workup to
exclude alternative etiologies, including infection. Institute
medical management promptly, including specialty consultation as
appropriate. Withhold or permanently discontinue IMFINZI and IMJUDO
depending on severity. See USPI Dosing and Administration for
specific details. In general, if IMFINZI and IMJUDO requires
interruption or discontinuation, administer systemic corticosteroid
therapy (1 mg to 2 mg/kg/day prednisone or equivalent) until
improvement to Grade 1 or less. Upon improvement to Grade 1 or
less, initiate corticosteroid taper and continue to taper over at
least 1 month. Consider administration of other systemic
immunosuppressants in patients whose immune-mediated adverse
reactions are not controlled with corticosteroid therapy.
Immune-Mediated
Pneumonitis
IMFINZI and IMJUDO can cause immune-mediated pneumonitis, which
may be fatal. The incidence of pneumonitis is higher in patients
who have received prior thoracic radiation.
- IMFINZI as a Single Agent
- In patients who did not receive recent prior radiation, the
incidence of immune-mediated pneumonitis was 2.4% (34/1414),
including fatal (<0.1%), and Grade 3-4 (0.4%) adverse reactions.
In patients who received recent prior radiation, the incidence of
pneumonitis (including radiation pneumonitis) in patients with
unresectable Stage III NSCLC following definitive chemoradiation
within 42 days prior to initiation of IMFINZI in PACIFIC was 18.3%
(87/475) in patients receiving IMFINZI and 12.8% (30/234) in
patients receiving placebo. Of the patients who received IMFINZI
(475), 1.1% were fatal and 2.7% were Grade 3 adverse
reactions.
- The frequency and severity of immune-mediated pneumonitis in
patients who did not receive definitive chemoradiation prior to
IMFINZI were similar in patients who received IMFINZI as a single
agent or with ES-SCLC or BTC when given in combination with
chemotherapy.
- IMFINZI with IMJUDO
- Immune‑mediated pneumonitis occurred in 1.3% (5/388) of
patients receiving IMFINZI and IMJUDO, including fatal (0.3%) and
Grade 3 (0.2%) adverse reactions.
- IMFINZI with IMJUDO and Platinum-Based Chemotherapy
- Immune-mediated pneumonitis occurred in 3.5% (21/596) of
patients receiving IMFINZI in combination with IMJUDO and
platinum-based chemotherapy, including fatal (0.5%), and Grade 3
(1%) adverse reactions.
Immune-Mediated Colitis
IMFINZI with IMJUDO and platinum-based chemotherapy can cause
immune-mediated colitis, which may be fatal.
IMFINZI and IMJUDO can cause immune-mediated colitis that is
frequently associated with diarrhea. Cytomegalovirus (CMV)
infection/reactivation has been reported in patients with
corticosteroid-refractory immune-mediated colitis. In cases of
corticosteroid-refractory colitis, consider repeating infectious
workup to exclude alternative etiologies.
- IMFINZI as a Single Agent
- Immune-mediated colitis occurred in 2% (37/1889) of patients
receiving IMFINZI, including Grade 4 (<0.1%) and Grade 3 (0.4%)
adverse reactions.
- IMFINZI with IMJUDO
- Immune‑mediated colitis or diarrhea occurred in 6% (23/388) of
patients receiving IMFINZI and IMJUDO, including Grade 3 (3.6%)
adverse reactions. Intestinal perforation has been observed in
other studies of IMFINZI and IMJUDO.
- IMFINZI with IMJUDO and Platinum-Based Chemotherapy
- Immune-mediated colitis occurred in 6.5% (39/596) of patients
receiving IMFINZI in combination with IMJUDO and platinum-based
chemotherapy including fatal (0.2%) and Grade 3 (2.5%) adverse
reactions. Intestinal perforation and large intestine perforation
were reported in 0.1% of patients.
Immune-Mediated
Hepatitis
IMFINZI and IMJUDO can cause immune-mediated hepatitis, which
may be fatal.
- IMFINZI as a Single Agent
- Immune-mediated hepatitis occurred in 2.8% (52/1889) of
patients receiving IMFINZI, including fatal (0.2%), Grade 4 (0.3%)
and Grade 3 (1.4%) adverse reactions.
- IMFINZI with IMJUDO
- Immune‑mediated hepatitis occurred in 7.5% (29/388) of patients
receiving IMFINZI and IMJUDO, including fatal (0.8%), Grade 4
(0.3%) and Grade 3 (4.1%) adverse reactions.
- IMFINZI with IMJUDO and Platinum-Based Chemotherapy
- Immune-mediated hepatitis occurred in 3.9% (23/596) of patients
receiving IMFINZI in combination with IMJUDO and platinum-based
chemotherapy, including fatal (0.3%), Grade 4 (0.5%), and Grade 3
(2%) adverse reactions.
Immune-Mediated
Endocrinopathies
- Adrenal Insufficiency: IMFINZI and IMJUDO can cause
primary or secondary adrenal insufficiency. For Grade 2 or higher
adrenal insufficiency, initiate symptomatic treatment, including
hormone replacement as clinically indicated.
- IMFINZI as a Single Agent
- Immune-mediated adrenal insufficiency occurred in 0.5% (9/1889)
of patients receiving IMFINZI, including Grade 3 (<0.1%) adverse
reactions.
- IMFINZI with IMJUDO
- Immune-mediated adrenal insufficiency occurred in 1.5% (6/388)
of patients receiving IMFINZI and IMJUDO, including Grade 3 (0.3%)
adverse reactions.
- IMFINZI with IMJUDO and Platinum-Based Chemotherapy
- Immune-mediated adrenal insufficiency occurred in 2.2% (13/596)
of patients receiving IMFINZI in combination with IMJUDO and
platinum-based chemotherapy, including Grade 3 (0.8%) adverse
reactions.
- Hypophysitis: IMFINZI and IMJUDO can cause
immune-mediated hypophysitis. Hypophysitis can present with acute
symptoms associated with mass effect such as headache, photophobia,
or visual field cuts. Hypophysitis can cause hypopituitarism.
Initiate symptomatic treatment including hormone replacement as
clinically indicated.
- IMFINZI as a Single Agent
- Grade 3 hypophysitis/hypopituitarism occurred in <0.1%
(1/1889) of patients who received IMFINZI.
- IMFINZI with IMJUDO
- Immune-mediated hypophysitis/hypopituitarism occurred in 1%
(4/388) of patients receiving IMFINZI and IMJUDO.
- IMFINZI with IMJUDO and Platinum-Based Chemotherapy
- Immune-mediated hypophysitis occurred in 1.3% (8/596) of
patients receiving IMFINZI in combination with IMJUDO and
platinum-based chemotherapy, including Grade 3 (0.5%) adverse
reactions.
- Thyroid Disorders (Thyroiditis, Hyperthyroidism, and
Hypothyroidism): IMFINZI and IMJUDO can cause immune-mediated
thyroid disorders. Thyroiditis can present with or without
endocrinopathy. Hypothyroidism can follow hyperthyroidism. Initiate
hormone replacement therapy for hypothyroidism or institute medical
management of hyperthyroidism as clinically indicated.
- IMFINZI as a Single Agent
- Immune-mediated thyroiditis occurred in 0.5% (9/1889) of
patients receiving IMFINZI, including Grade 3 (<0.1%) adverse
reactions.
- Immune-mediated hyperthyroidism occurred in 2.1% (39/1889) of
patients receiving IMFINZI.
- Immune-mediated hypothyroidism occurred in 8.3% (156/1889) of
patients receiving IMFINZI, including Grade 3 (<0.1%) adverse
reactions.
- IMFINZI with IMJUDO
- Immune-mediated thyroiditis occurred in 1.5% (6/388) of
patients receiving IMFINZI and IMJUDO.
- Immune-mediated hyperthyroidism occurred in 4.6% (18/388) of
patients receiving IMFINZI and IMJUDO, including Grade 3 (0.3%)
adverse reactions.
- Immune-mediated hypothyroidism occurred in 11% (42/388) of
patients receiving IMFINZI and IMJUDO.
- IMFINZI with IMJUDO and Platinum-Based Chemotherapy
- Immune-mediated thyroiditis occurred in 1.2% (7/596) of
patients receiving IMFINZI in combination with IMJUDO and
platinum-based chemotherapy.
- Immune-mediated hyperthyroidism occurred in 5% (30/596) of
patients receiving IMFINZI in combination with IMJUDO and
platinum-based chemotherapy, including Grade 3 (0.2%) adverse
reactions.
- Immune-mediated hypothyroidism occurred in 8.6% (51/596) of
patients receiving IMFINZI in combination with IMJUDO and
platinum-based chemotherapy, including Grade 3 (0.5%) adverse
reactions.
- Type 1 Diabetes Mellitus, which can present with diabetic
ketoacidosis: Monitor patients for hyperglycemia or other signs
and symptoms of diabetes. Initiate treatment with insulin as
clinically indicated.
- IMFINZI as a Single Agent
- Grade 3 immune-mediated Type 1 diabetes mellitus occurred in
<0.1% (1/1889) of patients receiving IMFINZI.
- IMFINZI with IMJUDO
- Two patients (0.5%, 2/388) had events of hyperglycemia
requiring insulin therapy that had not resolved at last
follow-up.
- IMFINZI with IMJUDO and Platinum-Based Chemotherapy
- Immune-mediated Type 1 diabetes mellitus occurred in 0.5%
(3/596) of patients receiving IMFINZI in combination with IMJUDO
and platinum-based chemotherapy including Grade 3 (0.3%) adverse
reactions.
Immune-Mediated Nephritis with Renal
Dysfunction
IMFINZI and IMJUDO can cause immune-mediated nephritis.
- IMFINZI as a Single Agent
- Immune-mediated nephritis occurred in 0.5% (10/1889) of
patients receiving IMFINZI, including Grade 3 (<0.1%) adverse
reactions.
- IMFINZI with IMJUDO
- Immune-mediated nephritis occurred in 1% (4/388) of patients
receiving IMFINZI and IMJUDO, including Grade 3 (0.5%) adverse
reactions.
- IMFINZI with IMJUDO and Platinum-Based Chemotherapy
- Immune-mediated nephritis occurred in 0.7% (4/596) of patients
receiving IMFINZI in combination with IMJUDO and platinum-based
chemotherapy, including Grade 3 (0.2%) adverse reactions.
Immune-Mediated Dermatology
Reactions
IMFINZI and IMJUDO can cause immune-mediated rash or dermatitis.
Exfoliative dermatitis, including Stevens-Johnson Syndrome (SJS),
drug rash with eosinophilia and systemic symptoms (DRESS), and
toxic epidermal necrolysis (TEN), has occurred with PD-1/L-1 and
CTLA-4 blocking antibodies. Topical emollients and/or topical
corticosteroids may be adequate to treat mild to moderate
non-exfoliative rashes.
- IMFINZI as a Single Agent
- Immune-mediated rash or dermatitis occurred in 1.8% (34/1889)
of patients receiving IMFINZI, including Grade 3 (0.4%) adverse
reactions.
- IMFINZI with IMJUDO
- Immune-mediated rash or dermatitis occurred in 4.9% (19/388) of
patients receiving IMFINZI and IMJUDO, including Grade 4 (0.3%) and
Grade 3 (1.5%) adverse reactions.
- IMFINZI with IMJUDO and Platinum-Based Chemotherapy
- Immune-mediated rash or dermatitis occurred in 7.2% (43/596) of
patients receiving IMFINZI in combination with IMJUDO and
platinum-based chemotherapy, including Grade 3 (0.3%) adverse
reactions.
Immune-Mediated
Pancreatitis
IMFINZI in combination with IMJUDO can cause immune-mediated
pancreatitis. Immune-mediated pancreatitis occurred in 2.3% (9/388)
of patients receiving IMFINZI and IMJUDO, including Grade 4 (0.3%)
and Grade 3 (1.5%) adverse reactions.
Other Immune-Mediated Adverse
Reactions
The following clinically significant, immune-mediated adverse
reactions occurred at an incidence of less than 1% each in patients
who received IMFINZI and IMJUDO or were reported with the use of
other immune-checkpoint inhibitors.
- Cardiac/vascular: Myocarditis, pericarditis,
vasculitis.
- Nervous system: Meningitis, encephalitis, myelitis and
demyelination, myasthenic syndrome/myasthenia gravis (including
exacerbation), Guillain-Barré syndrome, nerve paresis, autoimmune
neuropathy.
- Ocular: Uveitis, iritis, and other ocular inflammatory
toxicities can occur. Some cases can be associated with retinal
detachment. Various grades of visual impairment to include
blindness can occur. If uveitis occurs in combination with other
immune-mediated adverse reactions, consider a
Vogt-Koyanagi-Harada-like syndrome, as this may require treatment
with systemic steroids to reduce the risk of permanent vision
loss.
- Gastrointestinal: Pancreatitis including increases in
serum amylase and lipase levels, gastritis, duodenitis.
- Musculoskeletal and connective tissue disorders:
Myositis/polymyositis, rhabdomyolysis and associated sequelae
including renal failure, arthritis, polymyalgia rheumatic.
- Endocrine: Hypoparathyroidism.
- Other (hematologic/immune): Hemolytic anemia, aplastic
anemia, hemophagocytic lymphohistiocytosis, systemic inflammatory
response syndrome, histiocytic necrotizing lymphadenitis (Kikuchi
lymphadenitis), sarcoidosis, immune thrombocytopenia, solid organ
transplant rejection.
Infusion-Related Reactions
IMFINZI and IMJUDO can cause severe or life-threatening
infusion-related reactions. Monitor for signs and symptoms of
infusion-related reactions. Interrupt, slow the rate of, or
permanently discontinue IMFINZI and IMJUDO based on the severity.
See USPI Dosing and Administration for specific details. For Grade
1 or 2 infusion-related reactions, consider using pre-medications
with subsequent doses.
- IMFINZI as a Single Agent
- Infusion-related reactions occurred in 2.2% (42/1889) of
patients receiving IMFINZI, including Grade 3 (0.3%) adverse
reactions.
- IMFINZI with IMJUDO
- Infusion-related reactions occurred in 10 (2.6%) patients
receiving IMFINZI and IMJUDO.
- IMFINZI with IMJUDO and Platinum-Based Chemotherapy
- Infusion-related reactions occurred in 2.9% (17/596) of
patients receiving IMFINZI in combination with IMJUDO and
platinum-based chemotherapy, including Grade 3 (0.3%) adverse
reactions.
Complications of Allogeneic HSCT after IMFINZI
Fatal and other serious complications can occur in patients who
receive allogeneic hematopoietic stem cell transplantation (HSCT)
before or after being treated with a PD-1/L-1 blocking antibody.
Transplant-related complications include hyperacute
graft-versus-host-disease (GVHD), acute GVHD, chronic GVHD, hepatic
veno-occlusive disease (VOD) after reduced intensity conditioning,
and steroid-requiring febrile syndrome (without an identified
infectious cause). These complications may occur despite
intervening therapy between PD-1/L-1 blockade and allogeneic HSCT.
Follow patients closely for evidence of transplant-related
complications and intervene promptly. Consider the benefit versus
risks of treatment with a PD-1/L-1 blocking antibody prior to or
after an allogeneic HSCT.
Embryo-Fetal Toxicity
Based on their mechanism of action and data from animal studies,
IMFINZI and IMJUDO can cause fetal harm when administered to a
pregnant woman. Advise pregnant women of the potential risk to a
fetus. In females of reproductive potential, verify pregnancy
status prior to initiating IMFINZI and IMJUDO and advise them to
use effective contraception during treatment with IMFINZI and
IMJUDO and for 3 months after the last dose of IMFINZI and
IMJUDO.
Lactation
There is no information regarding the presence of IMFINZI and
IMJUDO in human milk; however, because of the potential for serious
adverse reactions in breastfed infants from IMFINZI and IMJUDO,
advise women not to breastfeed during treatment and for 3 months
after the last dose.
Adverse Reactions
- In patients with Stage III NSCLC in the PACIFIC study receiving
IMFINZI (n=475), the most common adverse reactions (≥20%) were
cough (40%), fatigue (34%), pneumonitis or radiation pneumonitis
(34%), upper respiratory tract infections (26%), dyspnea (25%), and
rash (23%). The most common Grade 3 or 4 adverse reactions (≥3%)
were pneumonia (7%) and pneumonitis/radiation pneumonitis
(3.4%).
- In patients with Stage III NSCLC in the PACIFIC study receiving
IMFINZI (n=475), discontinuation due to adverse reactions occurred
in 15% of patients in the IMFINZI arm. Serious adverse reactions
occurred in 29% of patients receiving IMFINZI. The most frequent
serious adverse reactions (≥2%) were pneumonitis or radiation
pneumonitis (7%) and pneumonia (6%). Fatal pneumonitis or radiation
pneumonitis and fatal pneumonia occurred in <2% of patients and
were similar across arms.
- In patients with mNSCLC in the POSEIDON study receiving IMFINZI
and IMJUDO plus platinum-based chemotherapy (n=330), the most
common adverse reactions (occurring in ≥20% of patients) were
nausea (42%), fatigue (36%), musculoskeletal pain (29%), decreased
appetite (28%), rash (27%), and diarrhea (22%).
- In patients with mNSCLC in the POSEIDON study receiving IMFINZI
in combination with IMJUDO and platinum-based chemotherapy (n=330),
permanent discontinuation of IMFINZI or IMJUDO due to an adverse
reaction occurred in 17% of patients. Serious adverse reactions
occurred in 44% of patients, with the most frequent serious adverse
reactions reported in at least 2% of patients being pneumonia
(11%), anemia (5%), diarrhea (2.4%), thrombocytopenia (2.4%),
pyrexia (2.4%), and febrile neutropenia (2.1%). Fatal adverse
reactions occurred in a total of 4.2% of patients.
- In patients with extensive-stage SCLC in the CASPIAN study
receiving IMFINZI plus chemotherapy (n=265), the most common
adverse reactions (≥20%) were nausea (34%), fatigue/asthenia (32%),
and alopecia (31%). The most common Grade 3 or 4 adverse reaction
(≥3%) was fatigue/asthenia (3.4%).
- In patients with extensive-stage SCLC in the CASPIAN study
receiving IMFINZI plus chemotherapy (n=265), IMFINZI was
discontinued due to adverse reactions in 7% of the patients
receiving IMFINZI plus chemotherapy. Serious adverse reactions
occurred in 31% of patients receiving IMFINZI plus chemotherapy.
The most frequent serious adverse reactions reported in at least 1%
of patients were febrile neutropenia (4.5%), pneumonia (2.3%),
anemia (1.9%), pancytopenia (1.5%), pneumonitis (1.1%), and COPD
(1.1%). Fatal adverse reactions occurred in 4.9% of patients
receiving IMFINZI plus chemotherapy.
- In patients with locally advanced or metastatic BTC in the
TOPAZ-1 study receiving IMFINZI (n=338), the most common adverse
reactions (occurring in ≥20% of patients) were fatigue (42%),
nausea (40%), constipation (32%), decreased appetite (26%),
abdominal pain (24%), rash (23%), and pyrexia (20%).
- In patients with locally advanced or metastatic BTC in the
TOPAZ-1 study receiving IMFINZI (n=338), discontinuation due to
adverse reactions occurred in 6% of the patients receiving IMFINZI
plus chemotherapy. Serious adverse reactions occurred in 47% of
patients receiving IMFINZI plus chemotherapy. The most frequent
serious adverse reactions reported in at least 2% of patients were
cholangitis (7%), pyrexia (3.8%), anemia (3.6%), sepsis (3.3%) and
acute kidney injury (2.4%). Fatal adverse reactions occurred in
3.6% of patients receiving IMFINZI plus chemotherapy. These include
ischemic or hemorrhagic stroke (4 patients), sepsis (2 patients),
and upper gastrointestinal hemorrhage (2 patients).
- In patients with unresectable HCC in the HIMALAYA study
receiving IMFINZI and IMJUDO (n=388), the most common adverse
reactions (occurring in ≥20% of patients) were rash (32%), diarrhea
(27%), fatigue (26%), pruritus (23%), musculoskeletal pain (22%),
and abdominal pain (20%).
- In patients with unresectable HCC in the HIMALAYA study
receiving IMFINZI and IMJUDO (n=388), serious adverse reactions
occurred in 41% of patients. Serious adverse reactions in >1% of
patients included hemorrhage (6%), diarrhea (4%), sepsis (2.1%),
pneumonia (2.1%), rash (1.5%), vomiting (1.3%), acute kidney injury
(1.3%), and anemia (1.3%). Fatal adverse reactions occurred in 8%
of patients who received IMJUDO in combination with durvalumab,
including death (1%), hemorrhage intracranial (0.5%), cardiac
arrest (0.5%), pneumonitis (0.5%), hepatic failure (0.5%), and
immune-mediated hepatitis (0.5%). Permanent discontinuation of
treatment regimen due to an adverse reaction occurred in 14% of
patients.
The safety and effectiveness of IMFINZI and IMJUDO have not been
established in pediatric patients.
Indications:
IMFINZI is indicated for the treatment of adult patients with
unresectable Stage III non-small cell lung cancer (NSCLC) whose
disease has not progressed following concurrent platinum-based
chemotherapy and radiation therapy.
IMFINZI, in combination with IMJUDO and platinum-based
chemotherapy, is indicated for the treatment of adult patients with
metastatic NSCLC with no sensitizing epidermal growth factor
receptor (EGFR) mutations or anaplastic lymphoma kinase (ALK)
genomic tumor aberrations.
IMFINZI, in combination with etoposide and either carboplatin or
cisplatin, is indicated for the first-line treatment of adult
patients with extensive-stage small cell lung cancer (ES-SCLC).
IMFINZI, in combination with gemcitabine and cisplatin, is
indicated for the treatment of adult patients with locally advanced
or metastatic biliary tract cancer (BTC).
IMFINZI in combination with IMJUDO is indicated for the
treatment of adult patients with unresectable hepatocellular
carcinoma (uHCC).
Please see Full Prescribing Information including Medication
Guide for IMFINZI and IMJUDO.
Triple-negative breast cancer
Breast cancer is the most common cancer in the world and leading
cause of cancer-related death.1 More than two million breast cancer
cases were diagnosed in 2020 with nearly 685,000 deaths
globally.1
While some breast cancers may test positive for estrogen
receptors, progesterone receptors or overexpression of human
epidermal growth factor receptor 2 (HER2), TNBC tests negative for
all three.2 Approximately 15% of breast cancer tumors (300,000
cases annually) are considered triple-negative which is the most
aggressive breast cancer subtype.1,2 1st-line treatment for
advanced or metastatic TNBC usually consists of chemotherapy alone
or in combination with an immunotherapy – options generally
associated with response rates between 30 to 50%.2-4 Among patients
with tumors that do respond to initial treatment, disease
progression is common and rapid, often occurring within two
years.2,4-6 The average overall survival of patients living with
advanced or metastatic TNBC is 12 to 18 months, with only about 12%
of patients living five years following diagnosis.7,8
TROP2 is a protein broadly expressed in several solid tumors,
including TNBC.9 TROP2 is associated with increased tumor
progression and poor survival in patients with breast
cancer.9,10
BEGONIA
BEGONIA is an open-label, two-part, multicenter Phase Ib/II
trial evaluating IMFINZI in combination with oncology therapies
with or without paclitaxel for the 1st-line treatment of metastatic
TNBC. Arm 7 of the trial is evaluating the safety, tolerability and
preliminary efficacy of datopotamab deruxtecan (6.0 mg/kg) in
combination with IMFINZI (1120 mg) in patients with previously
untreated, unresectable locally advanced or metastatic TNBC. The
primary endpoints are safety and tolerability. Secondary endpoints
are investigator-assessed ORR, PFS and DoR.
Enrollment is currently underway for Arm 8 of the BEGONIA trial,
which is evaluating datopotamab deruxtecan plus IMFINZI in patients
with TNBC whose tumors have high levels of PD-L1 expression.
Datopotamab deruxtecan (Dato-DXd)
Datopotamab deruxtecan (Dato-DXd) is an investigational
TROP2-directed ADC. Designed using Daiichi Sankyo’s proprietary DXd
ADC technology, datopotamab deruxtecan is one of six ADCs in the
oncology pipeline of Daiichi Sankyo, and one of the most advanced
programs in AstraZeneca’s ADC scientific platform. Datopotamab
deruxtecan is comprised of a humanized anti-TROP2 IgG1 monoclonal
antibody, developed in collaboration with Sapporo Medical
University, attached to a number of topoisomerase I inhibitor
payloads (an exatecan derivative, DXd) via tetrapeptide-based
cleavable linkers.
A comprehensive development program called TROPION is underway
globally with more than 12 trials evaluating the efficacy and
safety of datopotamab deruxtecan across multiple TROP2-targetable
tumors, including NSCLC, TNBC and HR-positive, HER2-low or negative
breast cancer. Beyond the TROPION program, datopotamab deruxtecan
is also being evaluated in novel combinations in several ongoing
trials. AstraZeneca is also researching a potential diagnostic test
to help identify patients most likely to benefit from treatment
with datopotamab deruxtecan.
IMFINZI
IMFINZI® (durvalumab) is a human monoclonal antibody that binds
to the PD-L1 protein and blocks the interaction of PD-L1 with the
PD-1 and CD80 proteins, countering the tumor’s immune-evading
tactics and releasing the inhibition of immune responses.
IMFINZI is the only approved immunotherapy and the global
standard of care in the curative-intent setting of unresectable,
Stage III NSCLC in patients whose disease has not progressed after
chemoradiation therapy based on the PACIFIC Phase III trial.
IMFINZI is also approved in the US, EU, Japan, China and many other
countries around the world for the treatment of extensive-stage
small cell lung cancer (SCLC) based on the CASPIAN Phase III trial.
Additionally, IMFINZI is approved in combination with a short
course of IMJUDO® (tremelimumab) and chemotherapy for the treatment
of metastatic NSCLC in the US, EU and Japan based on the POSEIDON
Phase III trial.
In addition to its indications in lung cancer, IMFINZI also is
approved in combination with chemotherapy (gemcitabine plus
cisplatin) in locally advanced or metastatic biliary tract cancer
and in combination with IMJUDO in unresectable hepatocellular
carcinoma in the US, EU, Japan and several other countries based on
the TOPAZ-1 and HIMALAYA Phase III trials, respectively. IMFINZI is
approved in previously treated patients with advanced bladder
cancer in a small number of countries.
Since the first approval in May 2017, more than 200,000 patients
have been treated with IMFINZI.
As part of a broad development program, IMFINZI is being tested
as a single treatment and in combination with other anti-cancer
treatments for patients with SCLC, NSCLC, bladder cancer, several
gastrointestinal cancers and other solid tumors.
Daiichi Sankyo collaboration
AstraZeneca and Daiichi Sankyo entered into a global
collaboration to jointly develop and commercialize fam-trastuzumab
deruxtecan-nxki in March 2019 and datopotamab deruxtecan in July
2020, except in Japan where Daiichi Sankyo maintains exclusive
rights for each ADC. Daiichi Sankyo is responsible for the
manufacturing and supply of fam-trastuzumab deruxtecan-nxki and
datopotamab deruxtecan.
AstraZeneca in breast cancer
Driven by a growing understanding of breast cancer biology,
AstraZeneca is starting to challenge, and redefine, the current
clinical paradigm for how breast cancer is classified and treated
to deliver even more effective treatments to patients in need –
with the bold ambition to one day eliminate breast cancer as a
cause of death.
AstraZeneca has a comprehensive portfolio of approved and
promising compounds in development that leverage different
mechanisms of action to address the biologically diverse breast
cancer tumor environment.
With fam-trastuzumab deruxtecan-nxki, a HER2-directed ADC,
AstraZeneca and Daiichi Sankyo are aiming to improve outcomes in
previously treated HER2-positive and HER2-low metastatic breast
cancer and are exploring its potential in earlier lines of
treatment and in new breast cancer settings.
In HR-positive breast cancer, AstraZeneca continues to improve
outcomes with foundational medicines fulvestrant and goserelin and
aims to reshape the HR-positive space with next-generation SERD and
potential new medicine camizestrant as well as a potential
first-in-class AKT kinase inhibitor, capivasertib. AstraZeneca is
also collaborating with Daiichi Sankyo to explore the potential of
TROP2-directed ADC, datopotamab deruxtecan, in this setting.
PARP inhibitor olaparib is a targeted treatment option that has
been studied in early and metastatic breast cancer patients with an
inherited BRCA mutation. AstraZeneca with Merck & Co., Inc.
(known as MSD outside the US and Canada) continues to research
olaparib in these settings and to explore its potential in earlier
disease.
To bring much-needed treatment options to patients with
triple-negative breast cancer, an aggressive form of breast cancer,
AstraZeneca is evaluating the potential of datopotamab deruxtecan
alone and in combination with immunotherapy IMFINZI, capivasertib
in combination with chemotherapy, and IMFINZI in combination with
other oncology medicines, including olaparib and fam-trastuzumab
deruxtecan-nxki.
AstraZeneca in oncology
AstraZeneca is leading a revolution in oncology with the
ambition to provide cures for cancer in every form, following the
science to understand cancer and all its complexities to discover,
develop and deliver life-changing medicines to patients.
The Company's focus is on some of the most challenging cancers.
It is through persistent innovation that AstraZeneca has built one
of the most diverse portfolios and pipelines in the industry, with
the potential to catalyze changes in the practice of medicine and
transform the patient experience.
AstraZeneca has the vision to redefine cancer care and, one day,
eliminate cancer as a cause of death.
AstraZeneca
AstraZeneca (LSE/STO/Nasdaq: AZN) is a global, science-led
biopharmaceutical company that focuses on the discovery,
development, and commercialization of prescription medicines in
Oncology, Rare Diseases, and BioPharmaceuticals, including
Cardiovascular, Renal & Metabolism, and Respiratory &
Immunology. Based in Cambridge, UK, AstraZeneca operates in over
100 countries and its innovative medicines are used by millions of
patients worldwide. Please visit astrazeneca-us.com and follow the
Company on social media @AstraZeneca.
US Media Mailbox: usmediateam@astrazeneca.com
References
- Sung H, et al. Global Cancer Statistics 2020: GLOBOCAN
Estimates of Incidence and Mortality Worldwide for 36 Cancers in
185 Countries. CA Cancer J Clin. 2021; 10.3322/caac.21660.
- O’Reilly D, et al. Overview of recent advances in metastatic
triple negative breast cancer. World Journal of Clinical Oncology.
2021;12(3): 164-182.
- Bergin A, et al. Triple-negative breast cancer: recent
treatment advances. F1000Res. 2019;
8:10.12688/f1000research.18888.1.
- Zhang Y, et al. Genomic features of rapid versus late relapse
in triple negative breast cancer. BMC Cancer. 2021; 21(568).
- Cortes J, et al. Pembrolizumab plus Chemotherapy in Advanced
Triple-Negative Breast Cancer. N Engl J Med. 2022; 387: 217-226.
10.1056/NEJMoa2202809.
- Emans L, et al. Atezolizumab and nab-Paclitaxel in Advanced
Triple-Negative Breast Cancer: Biomarker Evaluation of the
IMpassion130 Study. JNCI J Natl Cancer Inst. 2021; 113(8):
djab004.
- National Cancer Institute. Surveillance, Epidemiology and End
Results Program. Available at:
https://seer.cancer.gov/statfacts/html/breast-subtypes.html.
Accessed October 2023.
- Sharma P, et al. Biology and Management of Patients with
Triple-Negative Breast Cancer. Oncologist. 2016; 21(9): 1050-62.
10.1634/theoncologist.2016-0067.
- Lin H, et al. Significantly upregulated TACSTD2 and Cyclin D1
correlate with poor prognosis of invasive ductal breast cancer. Exp
Mol Pathol. 2013;94(1):73-8.
- Goldenberg D, et al. The emergence of trophoblast cell-surface
antigen 2 (TROP-2) as a novel cancer target. Oncotarget.
2018;9(48): 28989-29006.
US-81580 Last Updated 10/23
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