Premature Birth Complications: Short and Long-Term Health Effects
Study Finds Lower Relapse Risk In Triple-negative Breast Cancer With High Immune Cell Levels
Women with triple-negative breast cancer, and high levels of immune cells in the tumors, have a lower relapse risk after surgery, even without chemotherapy, according to a recent study published in JAMA.
Triple-negative breast cancer accounts for about 15% of all breast cancer diagnoses worldwide. Compared to other breast cancers, those affected are younger and more often of African American, Hispanic, and Indian descent. In Sweden, about a thousand cases are diagnosed each year.
This type of cancer involves the absence of three so-called receptors, which reduces treatment options. Triple-negative breast cancer is also faster growing and more likely to spread, and relapses occur more often than for other breast cancers after treatment.
The current study involves 12 research teams from three continents. Barbro Linderholm, Associate Professor of Oncology at the University of Gothenburg and Senior Physician at Sahlgrenska University Hospital, is responsible for the Swedish part.
Differences in survival ratesThe study includes data from a total of 1,966 participants worldwide with early-stage triple-negative breast cancer. This means that the tumors were small and had not spread. The patients had been treated with various combinations of surgery and radiation but not with chemotherapy.
The results show that the level of immune cells, tumor-infiltrating lymphocytes that can recognize and destroy cancer cells, was a strong prognostic biomarker, even when cytostatics were not part of the treatment.
Five years after surgery, 95% of study participants, whose tumor tissue samples from the breast tumor showed high levels of immune cells, were alive. The survival rate in the group with low immune cell levels was 82%.
Currently, the level of immune cells in tissue samples is not routinely measured or reported in triple-negative or other breast cancers, and the highly demanding cytostatics is usually part of standard treatment.
Very good prognosis"According to the current health care program, the absolute majority of patients with triple-negative breast cancer receive cytostatics, in combination with surgery and radiation, even for small tumors, but our results show a very good prognosis for this group even without cytostatics, in those who naturally have elevated levels of immune cells in the tumors," says Linderholm.
The authors of the study call for further research and clinical studies to investigate whether patients with a favorable prognosis, i.E. High levels of tumor-infiltrating lymphocytes in tumor tissue samples, could avoid intensive treatment with cytostatics.
The method to evaluate the proportion of immune cells is fast and cheap as it can be done in a regular pathology laboratory, and it is not necessary to send samples off for analysis.
"The findings from the study are not sufficient for introduction into clinical practice, but this will now be investigated in an international prospective study where we will compare the prognosis of patients with high levels of immune cells in the breast tumor with or without cytostatics," concludes Linderholm.
More information: Roberto A. Leon-Ferre et al, Tumor-Infiltrating Lymphocytes in Triple-Negative Breast Cancer, JAMA (2024). DOI: 10.1001/jama.2024.3056
Citation: Study finds lower relapse risk in triple-negative breast cancer with high immune cell levels (2024, April 17) retrieved 29 April 2024 from https://medicalxpress.Com/news/2024-04-relapse-triple-negative-breast-cancer.Html
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Man, 32, Who Blamed 'bone-white Poos' On A Hangover Is Left Fighting For Life With A Year To Live
A MAN who blamed his 'bone white poos' and dark pee on a hangover was given a year to live after doctors diagnosed him with cancer.
Matthew Rosenblum was just 32 when he noticed his poop was jarringly light after a night out but a doctor reportedly told him: "If you have cancer, I will roll over in my grave."
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Matthew Rosenblum was 32 when he noticed his poos were strangely light and his pee darkCredit: The Patient Story6
It took months before he was diagnosed with stage 4 pancreatic cancerCredit: The Patient Story6
Doctors told Matthew he'd probably only live one to three years, even with treatmentCredit: The Patient StoryInitially, the former PhD candidate wasn't too phased by the colour of his stools and pee, chalking them up to hangover as he'd had a few drinks the previous night.
"I had dark urine and bone-white stool," Matthew told The Patient Story.
"I didn't even notice the stool colour for a while," he recalled.
"At first, I thought I was hungover. I had a few beers the night before so I drank some Gatorade and lay in bed, but the urine did not get lighter."
It wasn't until Matthew's palms and feet started to itch uncontrollably that he decided to visit a doctor.
Even then, it took months, multiple trips to doctors before he was diagnosed with pancreatic cancer.
Doctors gave Matthew a bleak prognosis, giving him one to three years to live even with treatment.
"People think that pancreatic cancer is an old person's disease," he told The Patient Story.
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Two women left with disease that thickens the lungs after having brows done"I think that's why no one ever looked, because no one ever even thought that I could have pancreatic cancer.
"I've heard over and over again that I'm too young."
I'm a doctor, NEVER ignore these pancreatic cancer symptomsIn the UK, pancreatic cancer is most commonly diagnosed in people over the age of 75. Around 10,500 people are affected each year.
FIRST SIGNSHaving been diagnosed with Crohn's disease seven years earlier, Matthew was no stranger to "gastrointestinal distress", one of the most obvious symptoms of pancreatic cancer.
"I probably wouldn't have noticed even if I didn't have Crohn's," he said.
Aside from tummy troubles, Matthew also lost some weight in the months leading up to January 2021.
This is when he was struck with more "distinct" symptoms, such as the "bone-white" poop, dark urine and itching on the palms of his hands and bottom of his feet.
Matthew said: "The bathroom symptoms were pretty jarring, seeing urine that dark and poop that pale, but the itching was probably the worst.
"It was worse at night. I never felt anything like it before and those are hard places to scratch.
"After a whole night of itching, I put my hands and feet in the tub under hot water to numb the sensation."
He noted that not all pancreatic cancer patients experience itching.
"The earlier symptoms are very nuanced, can go unnoticed, and can also be misdiagnosed as a multitude of other things," Matthew said.
"By the time you're experiencing symptoms, the cancer has spread outside of the pancreas. I don't want to say it's too late, but that's what conventional wisdom is."
What the colour of your poo means
YOU might think paying attention to your poo is gross, but it can give you vital clues about your health.
Here's different colours can tell you:
Source: Guts UK
THE ROAD TO DIAGNOSISMatthew visited an urgent care centre 48 hours later where he was told that his blood was high in bilirubin - a byproduct of broken-down red blood cells that influences stool colour - and told to go to A&E.
High levels of bilirubin can indicate a blockage in the bile duct, a tube-like structure that connects the liver to the small bowel.
Ultrasounds revealed narrowing of this tube, which doctors attempted to stretch using a stent.
Matthew recalled: "There was no sense of urgency. I was an otherwise healthy person with a history of colitis.
"They didn't think that this was anything scary."
But his symptoms returned after they removed the stent, leading doctors to conclude that they were caused by his gallbladder.
Matthew had surgery to remove the organ, but still suffered symptoms.
Visiting his gastroenterologist in late April 2021, she told him: "I don't know what's happening, but you for sure don't have cancer.
"If you have cancer, I will roll over in my grave."
Matthew left her office feeling "pretty confident" but just three hours later, his results came back to show that he had a tumour in the opening at the start of the small intestine where the pancreatic and bile ducts join, known as the ampulla of Vater.
'ABRASIVE' TREATMENTMatthew was scheduled for surgery to remove part of his pancreas and small intestine - but this didn't go to plan.
"My surgeon told me that they cut me open and, contrary to what they thought, found a tumour on the head of my pancreas that had spread outside of the pancreas.
"Metastatic pancreatic cancer is considered inoperable so when they saw that, they closed me up," he explained.
Doctors suspected that Matthew had a mutation of his BRCA2 gene, which is associated with several forms of cancer, including breast and pancreatic.
He was told by his oncologist: "With treatment, you might have one to three good years left, but that's it."
Matthew started a six-month course of chemotherapy in May 2021, using a potent concoction of drugs which were '"really, really abrasive" but failed to stop the cancer from growing and spreading to his liver.
"At this point, I was not confident that I would be a special case or a miracle. I thought this was it," he said.
What are the symptoms of pancreatic cancer?
PANCREATIC cancer doesn't usually cause symptoms in the early stages.
As the cancer grows it can start to cause symptoms like:
Symptoms of pancreatic cancer can be vague. They can be caused by other conditions, but it's important to get them checked by a doctor.
Source: CRUK
BEATING THE ODDSDoctors switched Matthew to a new combination of chemo drugs, which banished some of the spots on his liver.
"I thought I was still dying sooner rather than later so I was trying to have fun and it certainly made having fun a lot easier."
By March 2022, doctors couldn't identify any cancer outside of Matthew's primary tumour and were able to perform a successful Whipple surgery to remove the majority of the cancer.
Since then, Matthew has had scans to monitor his cancer on a three-monthly basis.
"I get a scan every three months for the next six years, but the chances of me living out those six years are astronomically small," he explained.
"Pancreatic cancer has a remarkably low five-year survival rate. It's unlikely that I will see all of that time, at least on paper."
Despite his bleak prognosis, Matthew advised others in his situation not to lose hope.
"We assume that if treatment will work, it will work immediately.
"In my experience, that's not true. Sometimes things get worse before they get better and it's not a reason to lose heart."
He went on: "It's important to remember that you are not a statistic.
"I was diagnosed with something I wasn't supposed to have at my age. It was very unlikely.
"It was supposed to kill me and I didn't die so, in a sense, I beat the odds not once, but twice."
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Matthew underwent two gruelling rounds of chemotherapyCredit: The Patient Story6
He also had surgery to remove the cancer from his pancreasCredit: The Patient Story6
"It was supposed to kill me and I didn't die so, in a sense, I beat the odds not once, but twice," Matthew saidCredit: The Patient StoryENHERTU® (fam-trastuzumab Deruxtecan-nxki) Improved PFS In HER2-low And Ultralow
ENHERTU demonstrated statistically significant and clinically meaningful improvement in progression-free survival in HR-positive, HER2-low metastatic breast cancer following one or more lines of endocrine therapy in DESTINY-Breast06 Phase III trial
AstraZeneca and Daiichi Sankyo's ENHERTU also demonstrated a clinically meaningful progression-free survival improvement in patients with HER2-ultralow expression
WILMINGTON, Del., April 29, 2024--(BUSINESS WIRE)--Positive high-level results from the DESTINY-Breast06 Phase III trial showed that ENHERTU® (fam-trastuzumab deruxtecan-nxki) demonstrated a statistically significant and clinically meaningful improvement in progression-free survival (PFS) compared to standard-of-care chemotherapy in the primary trial population of patients with HR-positive, HER2-low (IHC 1+ or 2+/ISH-) metastatic breast cancer following one or more lines of endocrine therapy.
A statistically significant and clinically meaningful improvement in PFS was also observed in the overall trial population (patients with HER2-low and HER2-ultralow [defined as IHC 0 with membrane staining; IHC >0<1+] metastatic breast cancer). A prespecified subgroup analysis showed the clinically meaningful improvement was consistent between patients with HER2-low and HER2-ultralow expression.
Overall survival (OS) data were not mature at the time of the analysis; however, ENHERTU showed an early trend towards an OS improvement versus standard-of-care chemotherapy in patients with HER2-low metastatic breast cancer and in the overall trial population. The trial will continue as planned to further assess OS and other secondary endpoints.
Susan Galbraith, Executive Vice President, Oncology R&D, AstraZeneca, said: "DESTINY-Breast06 shows that ENHERTU could become a new standard of care for patients with HER2-low and HER2-ultralow metastatic breast cancer following one or more lines of endocrine therapy. These data underscore the potential for treatment with ENHERTU across the spectrum of HR-positive breast cancer, further redefining the treatment of metastatic breast cancer."
Story continues
Ken Takeshita, Global Head, R&D, Daiichi Sankyo, said: "The topline results from DESTINY-Breast06 highlight the importance of continuing to challenge current treatment paradigms and established breast cancer classifications to evolve how we treat patients with HR-positive, HER2-expressing metastatic breast cancer. Building on the practice-changing data seen in DESTINY-Breast04, these results reinforce the potential for use of ENHERTU earlier in the treatment landscape and in an even broader patient population."
ENHERTU is a specifically engineered HER2-directed DXd antibody drug conjugate (ADC) discovered by Daiichi Sankyo and being jointly developed and commercialized by AstraZeneca and Daiichi Sankyo.
It is estimated that approximately 60-65% of HR-positive, HER2-negative breast cancers are HER2-low and potentially an additional 25% may be HER2-ultralow.1,2 Endocrine therapies are widely used in the early lines of treatment for HR-positive metastatic breast cancer; however after two lines of treatment, further efficacy from endocrine therapy is often limited.3 The current standard of care following endocrine therapy is chemotherapy, which is associated with poor response rates and outcomes.3-6
The safety profile of ENHERTU was consistent with previous breast cancer clinical trials with no new safety signals identified.
The data will be presented at a forthcoming medical meeting and shared with global regulatory authorities.
Important Safety Information
Indications
ENHERTU is a HER2-directed antibody and topoisomerase inhibitor conjugate indicated for the treatment of adult patients with:
Unresectable or metastatic HER2-low (IHC 1+ or IHC 2+/ISH-) breast cancer, as determined by an FDA-approved test, who have received a prior chemotherapy in the metastatic setting or developed disease recurrence during or within 6 months of completing adjuvant chemotherapy
Unresectable or metastatic non-small cell lung cancer (NSCLC) whose tumors have activating HER2 (ERBB2) mutations, as detected by an FDA-approved test, and who have received a prior systemic therapy
This indication is approved under accelerated approval based on objective response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.
Unresectable or metastatic HER2-positive (IHC3+) solid tumors who have received prior systemic treatment and have no satisfactory alternative treatment options
This indication is approved under accelerated approval based on objective response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.
WARNING: INTERSTITIAL LUNG DISEASE and EMBRYO-FETAL TOXICITY
Interstitial lung disease (ILD) and pneumonitis, including fatal cases, have been reported with ENHERTU. Monitor for and promptly investigate signs and symptoms including cough, dyspnea, fever, and other new or worsening respiratory symptoms. Permanently discontinue ENHERTU in all patients with Grade 2 or higher ILD/pneumonitis. Advise patients of the risk and to immediately report symptoms.
Exposure to ENHERTU during pregnancy can cause embryo-fetal harm. Advise patients of these risks and the need for effective contraception.
Contraindications
None.
Warnings and Precautions
Interstitial Lung Disease / Pneumonitis
Severe, life-threatening, or fatal interstitial lung disease (ILD), including pneumonitis, can occur in patients treated with ENHERTU. A higher incidence of Grade 1 and 2 ILD/pneumonitis has been observed in patients with moderate renal impairment. Advise patients to immediately report cough, dyspnea, fever, and/or any new or worsening respiratory symptoms. Monitor patients for signs and symptoms of ILD. Promptly investigate evidence of ILD. Evaluate patients with suspected ILD by radiographic imaging. Consider consultation with a pulmonologist. For asymptomatic ILD/pneumonitis (Grade 1), interrupt ENHERTU until resolved to Grade 0, then if resolved in ≤28 days from date of onset, maintain dose. If resolved in >28 days from date of onset, reduce dose one level. Consider corticosteroid treatment as soon as ILD/pneumonitis is suspected (e.G., ≥0.5 mg/kg/day prednisolone or equivalent). For symptomatic ILD/pneumonitis (Grade 2 or greater), permanently discontinue ENHERTU. Promptly initiate systemic corticosteroid treatment as soon as ILD/pneumonitis is suspected (e.G., ≥1 mg/kg/day prednisolone or equivalent) and continue for at least 14 days followed by gradual taper for at least 4 weeks.
HER2-Positive or HER2-Low Metastatic Breast Cancer, HER2-Mutant NSCLC, and Solid Tumors (Including IHC 3+) (5.4 mg/kg)
In patients with metastatic breast cancer, HER2-mutant NSCLC, and other solid tumors treated with ENHERTU 5.4 mg/kg, ILD occurred in 12% of patients. Median time to first onset was 5.5 months (range: 0.9 to 31.5). Fatal outcomes due to ILD and/or pneumonitis occurred in 1.0% of patients treated with ENHERTU.
HER2-Positive Locally Advanced or Metastatic Gastric Cancer (6.4 mg/kg)
In patients with locally advanced or metastatic HER2-positive gastric or GEJ adenocarcinoma treated with ENHERTU 6.4 mg/kg, ILD occurred in 10% of patients. Median time to first onset was 2.8 months (range: 1.2 to 21).
Neutropenia
Severe neutropenia, including febrile neutropenia, can occur in patients treated with ENHERTU. Monitor complete blood counts prior to initiation of ENHERTU and prior to each dose, and as clinically indicated. For Grade 3 neutropenia (Absolute Neutrophil Count [ANC] <1.0 to 0.5 x 109/L), interrupt ENHERTU until resolved to Grade 2 or less, then maintain dose. For Grade 4 neutropenia (ANC <0.5 x 109/L), interrupt ENHERTU until resolved to Grade 2 or less, then reduce dose by one level. For febrile neutropenia (ANC <1.0 x 109/L and temperature >38.3º C or a sustained temperature of ≥38º C for more than 1 hour), interrupt ENHERTU until resolved, then reduce dose by one level.
HER2-Positive or HER2-Low Metastatic Breast Cancer, HER2-Mutant NSCLC, and Solid Tumors (Including IHC 3+) (5.4 mg/kg)
In patients with metastatic breast cancer, HER2-mutant NSCLC, and other solid tumors treated with ENHERTU 5.4 mg/kg, a decrease in neutrophil count was reported in 63% of patients. Seventeen percent had Grade 3 or 4 decreased neutrophil count. Median time to first onset of decreased neutrophil count was 22 days (range: 2 to 939). Febrile neutropenia was reported in 1% of patients.
HER2-Positive Locally Advanced or Metastatic Gastric Cancer (6.4 mg/kg)
In patients with locally advanced or metastatic HER2-positive gastric or GEJ adenocarcinoma treated with ENHERTU 6.4 mg/kg, a decrease in neutrophil count was reported in 72% of patients. Fifty-one percent had Grade 3 or 4 decreased neutrophil count. Median time to first onset of decreased neutrophil count was 16 days (range: 4 to 187). Febrile neutropenia was reported in 4.8% of patients.
Left Ventricular Dysfunction
Patients treated with ENHERTU may be at increased risk of developing left ventricular dysfunction. Left ventricular ejection fraction (LVEF) decrease has been observed with anti-HER2 therapies, including ENHERTU. Assess LVEF prior to initiation of ENHERTU and at regular intervals during treatment as clinically indicated. Manage LVEF decrease through treatment interruption. When LVEF is >45% and absolute decrease from baseline is 10-20%, continue treatment with ENHERTU. When LVEF is 40-45% and absolute decrease from baseline is <10%, continue treatment with ENHERTU and repeat LVEF assessment within 3 weeks. When LVEF is 40-45% and absolute decrease from baseline is 10-20%, interrupt ENHERTU and repeat LVEF assessment within 3 weeks. If LVEF has not recovered to within 10% from baseline, permanently discontinue ENHERTU. If LVEF recovers to within 10% from baseline, resume treatment with ENHERTU at the same dose. When LVEF is <40% or absolute decrease from baseline is >20%, interrupt ENHERTU and repeat LVEF assessment within 3 weeks. If LVEF of <40% or absolute decrease from baseline of >20% is confirmed, permanently discontinue ENHERTU. Permanently discontinue ENHERTU in patients with symptomatic congestive heart failure. Treatment with ENHERTU has not been studied in patients with a history of clinically significant cardiac disease or LVEF <50% prior to initiation of treatment.
HER2-Positive or HER2-Low Metastatic Breast Cancer, HER2-Mutant NSCLC, and Solid Tumors (Including IHC 3+) (5.4 mg/kg)
In patients with metastatic breast cancer, HER2-mutant NSCLC, and other solid tumors treated with ENHERTU 5.4 mg/kg, LVEF decrease was reported in 3.8% of patients, of which 0.6% were Grade 3.
HER2-Positive Locally Advanced or Metastatic Gastric Cancer (6.4 mg/kg)
In patients with locally advanced or metastatic HER2-positive gastric or GEJ adenocarcinoma treated with ENHERTU 6.4 mg/kg, no clinical adverse events of heart failure were reported; however, on echocardiography, 8% were found to have asymptomatic Grade 2 decrease in LVEF.
Embryo-Fetal Toxicity
ENHERTU can cause fetal harm when administered to a pregnant woman. Advise patients of the potential risks to a fetus. Verify the pregnancy status of females of reproductive potential prior to the initiation of ENHERTU. Advise females of reproductive potential to use effective contraception during treatment and for 7 months after the last dose of ENHERTU. Advise male patients with female partners of reproductive potential to use effective contraception during treatment with ENHERTU and for 4 months after the last dose of ENHERTU.
Additional Dose Modifications
Thrombocytopenia
For Grade 3 thrombocytopenia (platelets <50 to 25 x 109/L) interrupt ENHERTU until resolved to Grade 1 or less, then maintain dose. For Grade 4 thrombocytopenia (platelets <25 x 109/L) interrupt ENHERTU until resolved to Grade 1 or less, then reduce dose by one level.
Adverse Reactions
HER2-Positive and HER2-Low Metastatic Breast Cancer, HER2-Mutant NSCLC, and Solid Tumors (Including IHC 3+) (5.4 mg/kg)
The pooled safety population reflects exposure to ENHERTU 5.4 mg/kg intravenously every 3 weeks in 1799 patients in Study DS8201-A-J101 (NCT02564900), DESTINY-Breast01, DESTINY-Breast02, DESTINY-Breast03, DESTINY-Breast04, DESTINY-Lung01, DESTINY-Lung02, DESTINY-CRC02, and DESTINY-PanTumor02. Among these patients, 65% were exposed for >6 months and 38% were exposed for >1 year. In this pooled safety population, the most common (≥20%) adverse reactions, including laboratory abnormalities, were nausea (73%), decreased white blood cell count (70%), decreased hemoglobin (66%), decreased neutrophil count (63%), decreased lymphocyte count (58%), fatigue (56%), decreased platelet count (48%), increased aspartate aminotransferase (47%), increased alanine aminotransferase (43%), vomiting (40%), increased blood alkaline phosphatase (38%), alopecia (34%), constipation (33%), decreased appetite (32%), decreased blood potassium (31%), diarrhea (29%), musculoskeletal pain (24%), and abdominal pain (20%).
HER2-Positive Metastatic Breast Cancer
DESTINY-Breast03
The safety of ENHERTU was evaluated in 257 patients with unresectable or metastatic HER2-positive breast cancer who received at least one dose of ENHERTU 5.4 mg/kg intravenously once every three weeks in DESTINY-Breast03. The median duration of treatment was 14 months (range: 0.7 to 30).
Serious adverse reactions occurred in 19% of patients receiving ENHERTU. Serious adverse reactions in >1% of patients who received ENHERTU were vomiting, interstitial lung disease, pneumonia, pyrexia, and urinary tract infection. Fatalities due to adverse reactions occurred in 0.8% of patients including COVID-19 and sudden death (one patient each).
ENHERTU was permanently discontinued in 14% of patients, of which ILD/pneumonitis accounted for 8%. Dose interruptions due to adverse reactions occurred in 44% of patients treated with ENHERTU. The most frequent adverse reactions (>2%) associated with dose interruption were neutropenia, leukopenia, anemia, thrombocytopenia, pneumonia, nausea, fatigue, and ILD/pneumonitis. Dose reductions occurred in 21% of patients treated with ENHERTU. The most frequent adverse reactions (>2%) associated with dose reduction were nausea, neutropenia, and fatigue.
The most common (≥20%) adverse reactions, including laboratory abnormalities, were nausea (76%), decreased white blood cell count (74%), decreased neutrophil count (70%), increased aspartate aminotransferase (67%), decreased hemoglobin (64%), decreased lymphocyte count (55%), increased alanine aminotransferase (53%), decreased platelet count (52%), fatigue (49%), vomiting (49%), increased blood alkaline phosphatase (49%), alopecia (37%), decreased blood potassium (35%), constipation (34%), musculoskeletal pain (31%), diarrhea (29%), decreased appetite (29%), headache (22%), respiratory infection (22%), abdominal pain (21%), increased blood bilirubin (20%), and stomatitis (20%).
HER2-Low Metastatic Breast Cancer
DESTINY-Breast04
The safety of ENHERTU was evaluated in 371 patients with unresectable or metastatic HER2-low (IHC 1+ or IHC 2+/ISH-) breast cancer who received ENHERTU 5.4 mg/kg intravenously once every 3 weeks in DESTINY-Breast04. The median duration of treatment was 8 months (range: 0.2 to 33) for patients who received ENHERTU.
Serious adverse reactions occurred in 28% of patients receiving ENHERTU. Serious adverse reactions in >1% of patients who received ENHERTU were ILD/pneumonitis, pneumonia, dyspnea, musculoskeletal pain, sepsis, anemia, febrile neutropenia, hypercalcemia, nausea, pyrexia, and vomiting. Fatalities due to adverse reactions occurred in 4% of patients including ILD/pneumonitis (3 patients); sepsis (2 patients); and ischemic colitis, disseminated intravascular coagulation, dyspnea, febrile neutropenia, general physical health deterioration, pleural effusion, and respiratory failure (1 patient each).
ENHERTU was permanently discontinued in 16% of patients, of which ILD/pneumonitis accounted for 8%. Dose interruptions due to adverse reactions occurred in 39% of patients treated with ENHERTU. The most frequent adverse reactions (>2%) associated with dose interruption were neutropenia, fatigue, anemia, leukopenia, COVID-19, ILD/pneumonitis, increased transaminases, and hyperbilirubinemia. Dose reductions occurred in 23% of patients treated with ENHERTU. The most frequent adverse reactions (>2%) associated with dose reduction were fatigue, nausea, thrombocytopenia, and neutropenia.
The most common (≥20%) adverse reactions, including laboratory abnormalities, were nausea (76%), decreased white blood cell count (70%), decreased hemoglobin (64%), decreased neutrophil count (64%), decreased lymphocyte count (55%), fatigue (54%), decreased platelet count (44%), alopecia (40%), vomiting (40%), increased aspartate aminotransferase (38%), increased alanine aminotransferase (36%), constipation (34%), increased blood alkaline phosphatase (34%), decreased appetite (32%), musculoskeletal pain (32%), diarrhea (27%), and decreased blood potassium (25%).
HER2-Mutant Unresectable or Metastatic NSCLC (5.4 mg/kg)
DESTINY-Lung02 evaluated two dose levels (5.4 mg/kg [n=101] and 6.4 mg/kg [n=50]); however, only the results for the recommended dose of 5.4 mg/kg intravenously every 3 weeks are described below due to increased toxicity observed with the higher dose in patients with NSCLC, including ILD/pneumonitis.
The safety of ENHERTU was evaluated in 101 patients with HER2-mutant unresectable or metastatic NSCLC who received ENHERTU 5.4 mg/kg intravenously once every three weeks until disease progression or unacceptable toxicity in DESTINY-Lung02. Nineteen percent of patients were exposed for >6 months.
Serious adverse reactions occurred in 30% of patients receiving ENHERTU. Serious adverse reactions in >1% of patients who received ENHERTU were ILD/pneumonitis, thrombocytopenia, dyspnea, nausea, pleural effusion, and increased troponin I. Fatality occurred in 1 patient with suspected ILD/pneumonitis (1%).
ENHERTU was permanently discontinued in 8% of patients. Adverse reactions which resulted in permanent discontinuation of ENHERTU were ILD/pneumonitis, diarrhea, decreased blood potassium, hypomagnesemia, myocarditis, and vomiting. Dose interruptions of ENHERTU due to adverse reactions occurred in 23% of patients. Adverse reactions which required dose interruption (>2%) included neutropenia and ILD/pneumonitis. Dose reductions due to an adverse reaction occurred in 11% of patients.
The most common (≥20%) adverse reactions, including laboratory abnormalities, were nausea (61%), decreased white blood cell count (60%), decreased hemoglobin (58%), decreased neutrophil count (52%), decreased lymphocyte count (43%), decreased platelet count (40%), decreased albumin (39%), increased aspartate aminotransferase (35%), increased alanine aminotransferase (34%), fatigue (32%), constipation (31%), decreased appetite (30%), vomiting (26%), increased alkaline phosphatase (22%), and alopecia (21%).
HER2-Positive Locally Advanced or Metastatic Gastric Cancer (6.4 mg/kg)
The safety of ENHERTU was evaluated in 187 patients with locally advanced or metastatic HER2-positive gastric or GEJ adenocarcinoma in DESTINY-Gastric01. Patients intravenously received at least one dose of either ENHERTU (N=125) 6.4 mg/kg every 3 weeks or either irinotecan (N=55) 150 mg/m2 biweekly or paclitaxel (N=7) 80 mg/m2 weekly for 3 weeks. The median duration of treatment was 4.6 months (range: 0.7 to 22.3) for patients who received ENHERTU.
Serious adverse reactions occurred in 44% of patients receiving ENHERTU 6.4 mg/kg. Serious adverse reactions in >2% of patients who received ENHERTU were decreased appetite, ILD, anemia, dehydration, pneumonia, cholestatic jaundice, pyrexia, and tumor hemorrhage. Fatalities due to adverse reactions occurred in 2.4% of patients: disseminated intravascular coagulation, large intestine perforation, and pneumonia occurred in one patient each (0.8%).
ENHERTU was permanently discontinued in 15% of patients, of which ILD accounted for 6%. Dose interruptions due to adverse reactions occurred in 62% of patients treated with ENHERTU. The most frequent adverse reactions (>2%) associated with dose interruption were neutropenia, anemia, decreased appetite, leukopenia, fatigue, thrombocytopenia, ILD, pneumonia, lymphopenia, upper respiratory tract infection, diarrhea, and decreased blood potassium. Dose reductions occurred in 32% of patients treated with ENHERTU. The most frequent adverse reactions (>2%) associated with dose reduction were neutropenia, decreased appetite, fatigue, nausea, and febrile neutropenia.
The most common (≥20%) adverse reactions, including laboratory abnormalities, were decreased hemoglobin (75%), decreased white blood cell count (74%), decreased neutrophil count (72%), decreased lymphocyte count (70%), decreased platelet count (68%), nausea (63%), decreased appetite (60%), increased aspartate aminotransferase (58%), fatigue (55%), increased blood alkaline phosphatase (54%), increased alanine aminotransferase (47%), diarrhea (32%), decreased blood potassium (30%), vomiting (26%), constipation (24%), increased blood bilirubin (24%), pyrexia (24%), and alopecia (22%).
HER2-Positive (IHC3+) Unresectable or Metastatic Solid Tumors
The safety of ENHERTU was evaluated in 347 adult patients with unresectable or metastatic HER2-positive (IHC3+) solid tumors who received ENHERTU 5.4 mg/kg intravenously once every 3 weeks in DESTINY-Breast01, DESTINY-PanTumor02, DESTINY-Lung01, and DESTINY-CRC02. The median duration of treatment was 8.3 months (range 0.7 to 30.2).
Serious adverse reactions occurred in 34% of patients receiving ENHERTU. Serious adverse reactions in >1% of patients who received ENHERTU were sepsis, pneumonia, vomiting, urinary tract infection, abdominal pain, nausea, pneumonitis, pleural effusion, hemorrhage, COVID-19, fatigue, acute kidney injury, anemia, cellulitis, and dyspnea. Fatalities due to adverse reactions occurred in 6.3% of patients including ILD/pneumonitis (2.3%), cardiac arrest (0.6%), COVID-19 (0.6%), and sepsis (0.6%). The following events occurred in one patient each (0.3%): acute kidney injury, cerebrovascular accident, general physical health deterioration, pneumonia, and hemorrhagic shock.
ENHERTU was permanently discontinued in 15% of patients, of which ILD/pneumonitis accounted for 10%. Dose interruptions due to adverse reactions occurred in 48% of patients. The most frequent adverse reactions (>2%) associated with dose interruption were decreased neutrophil count, anemia, COVID-19, fatigue, decreased white blood cell count, and ILD/pneumonitis. Dose reductions occurred in 27% of patients treated with ENHERTU. The most frequent adverse reactions (>2%) associated with dose reduction were fatigue, nausea, decreased neutrophil count, ILD/pneumonitis, and diarrhea.
The most common (≥20%) adverse reactions, including laboratory abnormalities, were decreased white blood cell count (75%), nausea (69%), decreased hemoglobin (67%), decreased neutrophil count (66%), fatigue (59%), decreased lymphocyte count (58%), decreased platelet count (51%), increased aspartate aminotransferase (45%), increased alanine aminotransferase (44%), increased blood alkaline phosphatase (36%), vomiting (35%), decreased appetite (34%), alopecia (34%), diarrhea (31%), decreased blood potassium (29%), constipation (28%), decreased sodium (22%), stomatitis (20%), and upper respiratory tract infection (20%).
Use in Specific Populations
Pregnancy: ENHERTU can cause fetal harm when administered to a pregnant woman. Advise patients of the potential risks to a fetus. There are clinical considerations if ENHERTU is used in pregnant women, or if a patient becomes pregnant within 7 months after the last dose of ENHERTU.
Lactation: There are no data regarding the presence of ENHERTU in human milk, the effects on the breastfed child, or the effects on milk production. Because of the potential for serious adverse reactions in a breastfed child, advise women not to breastfeed during treatment with ENHERTU and for 7 months after the last dose.
Females and Males of Reproductive Potential: Pregnancy testing: Verify pregnancy status of females of reproductive potential prior to initiation of ENHERTU. Contraception: Females: ENHERTU can cause fetal harm when administered to a pregnant woman. Advise females of reproductive potential to use effective contraception during treatment with ENHERTU and for 7 months after the last dose. Males: Advise male patients with female partners of reproductive potential to use effective contraception during treatment with ENHERTU and for 4 months after the last dose. Infertility: ENHERTU may impair male reproductive function and fertility.
Pediatric Use: Safety and effectiveness of ENHERTU have not been established in pediatric patients.
Geriatric Use: Of the 1287 patients with HER2-positive or HER2-low breast cancer treated with ENHERTU 5.4 mg/kg, 22% were ≥65 years and 3.8% were ≥75 years. No overall differences in efficacy within clinical studies were observed between patients ≥65 years of age compared to younger patients. There was a higher incidence of Grade 3-4 adverse reactions observed in patients aged ≥65 years (59%) as compared to younger patients (49%). Of the 101 patients with HER2-mutant unresectable or metastatic NSCLC treated with ENHERTU 5.4 mg/kg, 40% were ≥65 years and 8% were ≥75 years. No overall differences in efficacy or safety were observed between patients ≥65 years of age compared to younger patients. Of the 125 patients with HER2-positive locally advanced or metastatic gastric or GEJ adenocarcinoma treated with ENHERTU 6.4 mg/kg in DESTINY-Gastric01, 56% were ≥65 years and 14% were ≥75 years. No overall differences in efficacy or safety were observed between patients ≥65 years of age compared to younger patients. Of the 192 patients with HER2-positive (IHC 3+) unresectable or metastatic solid tumors treated with ENHERTU 5.4 mg/kg in DESTINY-PanTumor02, DESTINY-Lung01, or DESTINY-CRC02, 39% were 65 years or older and 9% were 75 years or older. No overall differences in efficacy or safety were observed between patients ≥65 years of age compared to younger patients.
Renal Impairment: A higher incidence of Grade 1 and 2 ILD/pneumonitis has been observed in patients with moderate renal impairment. Monitor patients with moderate renal impairment more frequently. The recommended dosage of ENHERTU has not been established for patients with severe renal impairment (CLcr <30 mL/min).
Hepatic Impairment: In patients with moderate hepatic impairment, due to potentially increased exposure, closely monitor for increased toxicities related to the topoisomerase inhibitor, DXd. The recommended dosage of ENHERTU has not been established for patients with severe hepatic impairment (total bilirubin >3 times ULN and any AST).
To report SUSPECTED ADVERSE REACTIONS, contact Daiichi Sankyo, Inc. At 1-877-437-7763 or FDA at 1-800-FDA-1088 or fda.Gov/medwatch.
Please see accompanying full Prescribing Information, including Boxed WARNINGS, and Medication Guide.
Notes
DESTINY-Breast06
DESTINY-Breast06 is a global, randomized, open-label, Phase III trial evaluating the efficacy and safety of ENHERTU (5.4 mg/kg) versus investigator's choice of chemotherapy (capecitabine, paclitaxel or nab-paclitaxel) in patients with HR-positive, HER2-low (IHC 1+ or 2+/ISH-) or HER2-ultralow (defined as IHC 0 with membrane staining; IHC >0<1+) advanced or metastatic breast cancer. Patients in the trial had no prior chemotherapy for advanced or metastatic disease and either experienced disease progression within 6 months of starting 1st-line treatment with an endocrine therapy combined with a CDK4/6 inhibitor or received at least two previous lines of endocrine therapies in the metastatic setting.
The primary endpoint is PFS in the HR-positive, HER2-low patient population as measured by blinded independent central review (BICR). Key secondary endpoints include OS in patients with HER2-low expression and PFS by BICR and OS in the overall trial population (HER2-low and HER2-ultralow). Other secondary endpoints include objective response rate, duration of response, time to first subsequent treatment or death, time to second subsequent treatment or death and safety. Analysis of the HER2-ultralow subgroup was not powered to demonstrate statistical significance.
DESTINY-Breast06 enrolled 866 patients (n=713 for HER2-low and n=153 for HER2-ultralow) at multiple sites in Asia, Europe, North America and South America. For more information about the trial, visit ClinicalTrials.Gov.
Breast cancer and HER2 expression
Breast cancer is the second most common cancer and one of the leading causes of cancer-related deaths worldwide.7 More than two million breast cancer cases were diagnosed in 2022 with more than 665,000 deaths globally.7 While survival rates are high for those diagnosed with early breast cancer, only approximately 30% of patients who are diagnosed with or progress to metastatic disease are expected to live five years after their diagnosis.8
HR-positive, HER2-negative is the most common breast cancer subtype, accounting for approximately 70% of all breast cancers.8 HER2 is a tyrosine kinase receptor growth-promoting protein expressed on the surface of many types of tumors, including breast cancer.9 Patients with high levels of HER2 expression (IHC 3+ or 2+/ISH+) are classified as HER2-positive and treated with HER2-targeted therapies, representing approximately 15-20% of all breast cancers.10 Historically, tumors that were not classified as HER2-positive were classified as HER2-negative; however, many of these tumors still carry some level of HER2 expression.11 It is estimated that approximately 60-65% of HR-positive, HER2-negative breast cancers are HER2-low and potentially an additional 25% may be HER2-ultralow.1,2
Prior to the approval of ENHERTU in HER2-low metastatic breast cancer post chemotherapy based on the DESTINY-Breast04 trial, there were no targeted therapies approved specifically for patients with HER2-low expression.12 There are no targeted therapies specifically approved for patients with HER2-ultralow expression.
ENHERTU
ENHERTU is a HER2-directed ADC. Designed using Daiichi Sankyo's proprietary DXd ADC technology, ENHERTU is the lead ADC in the oncology portfolio of Daiichi Sankyo and the most advanced program in AstraZeneca's ADC scientific platform. ENHERTU consists of a HER2 monoclonal antibody attached to a number of topoisomerase I inhibitor payloads (an exatecan derivative, DXd) via tetrapeptide-based
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