Breast Cancer ICYMI

Key clinical point: Margetuximab + chemotherapy vs. trastuzumab + chemotherapy improved progression-free survival (PFS) with an acceptable safety profile in patients with ERBB2-positive advanced breast cancer (ERBB2+ ABC) who progressed on 2 or more prior anti-ERBB2 therapies.

Major finding: Margetuximab + chemotherapy prolonged PFS with a 24% relative risk reduction vs. trastuzumab + chemotherapy (median PFS, 5.8 vs. 4.9 months; hazard ratio, 0.76; P = .03). Safety was comparable between the groups. Infusion-related reactions were higher with margetuximab vs. trastuzumab (13.3% vs. 3.4%; P less than .001) but were mostly prevalent at cycle 1 and resolved within 24 hours.

Study details: Findings are from the phase 3 SOPHIA trial including 536 patients with ERBB2+ ABC who had progressive disease after 2 or more prior anti-ERBB2 therapies. Patients were randomly allocated to receive either margetuximab + chemotherapy (n = 266) or trastuzumab + chemotherapy (n = 270).

Disclosures: This study was supported by MacroGenics, Inc. The lead author reported ties with MacroGenics, Roche, Pfizer, Novartis, Lilly, Merck, Seattle Genetics, Odonate Therapeutics, Eisai, Sermonix Pharmaceuticals, Immunomedics, Daiichi Sankyo, Puma, and Samsung. Other investigators reported owning stocks of, being an employee of, receiving support from, and/or consulting for various pharmaceutical companies including MacroGenics.

Source: Rugo HS et al. JAMA Oncol. 2021 Jan 22. doi: 10.1001/jamaoncol.2020.7932.

Key clinical point: Margetuximab + chemotherapy vs. trastuzumab + chemotherapy improved progression-free survival (PFS) with an acceptable safety profile in patients with ERBB2-positive advanced breast cancer (ERBB2+ ABC) who progressed on 2 or more prior anti-ERBB2 therapies.

Major finding: Margetuximab + chemotherapy prolonged PFS with a 24% relative risk reduction vs. trastuzumab + chemotherapy (median PFS, 5.8 vs. 4.9 months; hazard ratio, 0.76; P = .03). Safety was comparable between the groups. Infusion-related reactions were higher with margetuximab vs. trastuzumab (13.3% vs. 3.4%; P less than .001) but were mostly prevalent at cycle 1 and resolved within 24 hours.

Study details: Findings are from the phase 3 SOPHIA trial including 536 patients with ERBB2+ ABC who had progressive disease after 2 or more prior anti-ERBB2 therapies. Patients were randomly allocated to receive either margetuximab + chemotherapy (n = 266) or trastuzumab + chemotherapy (n = 270).

Disclosures: This study was supported by MacroGenics, Inc. The lead author reported ties with MacroGenics, Roche, Pfizer, Novartis, Lilly, Merck, Seattle Genetics, Odonate Therapeutics, Eisai, Sermonix Pharmaceuticals, Immunomedics, Daiichi Sankyo, Puma, and Samsung. Other investigators reported owning stocks of, being an employee of, receiving support from, and/or consulting for various pharmaceutical companies including MacroGenics.

Source: Rugo HS et al. JAMA Oncol. 2021 Jan 22. doi: 10.1001/jamaoncol.2020.7932.

Key clinical point: Margetuximab + chemotherapy vs. trastuzumab + chemotherapy improved progression-free survival (PFS) with an acceptable safety profile in patients with ERBB2-positive advanced breast cancer (ERBB2+ ABC) who progressed on 2 or more prior anti-ERBB2 therapies.

Major finding: Margetuximab + chemotherapy prolonged PFS with a 24% relative risk reduction vs. trastuzumab + chemotherapy (median PFS, 5.8 vs. 4.9 months; hazard ratio, 0.76; P = .03). Safety was comparable between the groups. Infusion-related reactions were higher with margetuximab vs. trastuzumab (13.3% vs. 3.4%; P less than .001) but were mostly prevalent at cycle 1 and resolved within 24 hours.

Study details: Findings are from the phase 3 SOPHIA trial including 536 patients with ERBB2+ ABC who had progressive disease after 2 or more prior anti-ERBB2 therapies. Patients were randomly allocated to receive either margetuximab + chemotherapy (n = 266) or trastuzumab + chemotherapy (n = 270).

Disclosures: This study was supported by MacroGenics, Inc. The lead author reported ties with MacroGenics, Roche, Pfizer, Novartis, Lilly, Merck, Seattle Genetics, Odonate Therapeutics, Eisai, Sermonix Pharmaceuticals, Immunomedics, Daiichi Sankyo, Puma, and Samsung. Other investigators reported owning stocks of, being an employee of, receiving support from, and/or consulting for various pharmaceutical companies including MacroGenics.

Source: Rugo HS et al. JAMA Oncol. 2021 Jan 22. doi: 10.1001/jamaoncol.2020.7932.

Key clinical point: Paclitaxel dose reduction does not necessarily result in improved neuropathy outcomes in patients with breast cancer prescribed weekly paclitaxel schedules.

Major finding: Patients receiving reduced-dose vs. full-dose paclitaxel had worse patient-reported symptom burden (Functional Assessment of Cancer Therapy/Gynecologic Oncology Group-Neurotoxicity, 40.2 vs. 45.9) and clinical neuropathy outcomes (Total Neuropathy Score clinical version, 4.3 vs. 3.3; all P less than .05).

Study details: Findings are from the assessment of women with breast cancer prescribed weekly paclitaxel (80 mg/m²) for 12 weeks. Posttreatment outcomes were assessed at 3.6 months in 105 women who underwent subsequent dose reduction.

Disclosures: This study was supported by grants from the Cancer Institute NSW Program and National Health and Medical Research Council of Australia. M Friedlander reported ties with various pharmaceutical companies. The other authors did not have any financial disclosures.

Source: Timmins HC et al. Oncologist. 2021 Feb 1. doi: 10.1002/onco.13697.

Key clinical point: Paclitaxel dose reduction does not necessarily result in improved neuropathy outcomes in patients with breast cancer prescribed weekly paclitaxel schedules.

Major finding: Patients receiving reduced-dose vs. full-dose paclitaxel had worse patient-reported symptom burden (Functional Assessment of Cancer Therapy/Gynecologic Oncology Group-Neurotoxicity, 40.2 vs. 45.9) and clinical neuropathy outcomes (Total Neuropathy Score clinical version, 4.3 vs. 3.3; all P less than .05).

Study details: Findings are from the assessment of women with breast cancer prescribed weekly paclitaxel (80 mg/m²) for 12 weeks. Posttreatment outcomes were assessed at 3.6 months in 105 women who underwent subsequent dose reduction.

Disclosures: This study was supported by grants from the Cancer Institute NSW Program and National Health and Medical Research Council of Australia. M Friedlander reported ties with various pharmaceutical companies. The other authors did not have any financial disclosures.

Source: Timmins HC et al. Oncologist. 2021 Feb 1. doi: 10.1002/onco.13697.

Key clinical point: Paclitaxel dose reduction does not necessarily result in improved neuropathy outcomes in patients with breast cancer prescribed weekly paclitaxel schedules.

Major finding: Patients receiving reduced-dose vs. full-dose paclitaxel had worse patient-reported symptom burden (Functional Assessment of Cancer Therapy/Gynecologic Oncology Group-Neurotoxicity, 40.2 vs. 45.9) and clinical neuropathy outcomes (Total Neuropathy Score clinical version, 4.3 vs. 3.3; all P less than .05).

Study details: Findings are from the assessment of women with breast cancer prescribed weekly paclitaxel (80 mg/m²) for 12 weeks. Posttreatment outcomes were assessed at 3.6 months in 105 women who underwent subsequent dose reduction.

Disclosures: This study was supported by grants from the Cancer Institute NSW Program and National Health and Medical Research Council of Australia. M Friedlander reported ties with various pharmaceutical companies. The other authors did not have any financial disclosures.

Source: Timmins HC et al. Oncologist. 2021 Feb 1. doi: 10.1002/onco.13697.

Key clinical point: Intensive screening for distant metastasis during posttreatment follow-up was not associated with improved overall survival (OS) in disease-free patients initially diagnosed with nonmetastatic breast cancer.

Major finding: OS was not significantly different among patients receiving intensive vs. less intensive screening (adjusted hazard ratio, 1.21; P = .124).

Study details: This retrospective study evaluated the effect of intensive (n=199) vs. less intensive (n=199) screening on survival in 398 patients initially diagnosed with nonmetastatic, resectable breast cancer who eventually developed distant metastasis after initial curative treatment.

Disclosures: This study was supported by grants received by the Korea Health Industry Development Institute funded by the Ministry of Health & Welfare, Republic of Korea, and the National Research Foundation of Korea grant funded by the Ministry of Science and ICT, Republic of Korea. The authors declared no conflicts of interest.

Source: Cheun J-H et al. Sci Rep. 2021 Feb 2. doi: 10.1038/s41598-021-82485-w.

Key clinical point: Intensive screening for distant metastasis during posttreatment follow-up was not associated with improved overall survival (OS) in disease-free patients initially diagnosed with nonmetastatic breast cancer.

Major finding: OS was not significantly different among patients receiving intensive vs. less intensive screening (adjusted hazard ratio, 1.21; P = .124).

Study details: This retrospective study evaluated the effect of intensive (n=199) vs. less intensive (n=199) screening on survival in 398 patients initially diagnosed with nonmetastatic, resectable breast cancer who eventually developed distant metastasis after initial curative treatment.

Disclosures: This study was supported by grants received by the Korea Health Industry Development Institute funded by the Ministry of Health & Welfare, Republic of Korea, and the National Research Foundation of Korea grant funded by the Ministry of Science and ICT, Republic of Korea. The authors declared no conflicts of interest.

Source: Cheun J-H et al. Sci Rep. 2021 Feb 2. doi: 10.1038/s41598-021-82485-w.

Key clinical point: Intensive screening for distant metastasis during posttreatment follow-up was not associated with improved overall survival (OS) in disease-free patients initially diagnosed with nonmetastatic breast cancer.

Major finding: OS was not significantly different among patients receiving intensive vs. less intensive screening (adjusted hazard ratio, 1.21; P = .124).

Study details: This retrospective study evaluated the effect of intensive (n=199) vs. less intensive (n=199) screening on survival in 398 patients initially diagnosed with nonmetastatic, resectable breast cancer who eventually developed distant metastasis after initial curative treatment.

Disclosures: This study was supported by grants received by the Korea Health Industry Development Institute funded by the Ministry of Health & Welfare, Republic of Korea, and the National Research Foundation of Korea grant funded by the Ministry of Science and ICT, Republic of Korea. The authors declared no conflicts of interest.

Source: Cheun J-H et al. Sci Rep. 2021 Feb 2. doi: 10.1038/s41598-021-82485-w.

Key clinical point: By opting initially for breast-conserving therapy (BCT) over mastectomy, majority of women with T1-2 node-negative breast cancer with positive sentinel lymph node (SLN) can avoid completion axillary lymph node dissection (cALND), often done in mastectomy.

Major finding: Patients treated with mastectomy vs. BCT were more likely to receive cALND after positive SLN (71% vs. 26.6%; P less than .001). Extracapsular extension (ECE) in the SLN was observed in 31.6% of patients treated with mastectomy and cALND. However, remaining 68.4% of patients without ECE in the SLN could have avoided cALND if they had chosen BCT initially.

Study details: Findings are from an analysis of 306 women with T1-2 clinically node-negative breast cancer with metastases in the SLN who were treated with mastectomy (n=107) or BCT (n=199).

Disclosures: Programmatic support was provided by the Fashion Footwear Charitable Foundation of New York, Inc., the Margie and Robert E. Peterson Foundation, and the Linda and Jim Lippman. ML Smidt reported receiving a grant from Servier Pharma. The remaining authors had no disclosures.

Source: Vane MLG et al. Ann Surg Oncol. 2021 Feb 14. doi: 10.1245/s10434-021-09674-9. 

Key clinical point: By opting initially for breast-conserving therapy (BCT) over mastectomy, majority of women with T1-2 node-negative breast cancer with positive sentinel lymph node (SLN) can avoid completion axillary lymph node dissection (cALND), often done in mastectomy.

Major finding: Patients treated with mastectomy vs. BCT were more likely to receive cALND after positive SLN (71% vs. 26.6%; P less than .001). Extracapsular extension (ECE) in the SLN was observed in 31.6% of patients treated with mastectomy and cALND. However, remaining 68.4% of patients without ECE in the SLN could have avoided cALND if they had chosen BCT initially.

Study details: Findings are from an analysis of 306 women with T1-2 clinically node-negative breast cancer with metastases in the SLN who were treated with mastectomy (n=107) or BCT (n=199).

Disclosures: Programmatic support was provided by the Fashion Footwear Charitable Foundation of New York, Inc., the Margie and Robert E. Peterson Foundation, and the Linda and Jim Lippman. ML Smidt reported receiving a grant from Servier Pharma. The remaining authors had no disclosures.

Source: Vane MLG et al. Ann Surg Oncol. 2021 Feb 14. doi: 10.1245/s10434-021-09674-9. 

Key clinical point: By opting initially for breast-conserving therapy (BCT) over mastectomy, majority of women with T1-2 node-negative breast cancer with positive sentinel lymph node (SLN) can avoid completion axillary lymph node dissection (cALND), often done in mastectomy.

Major finding: Patients treated with mastectomy vs. BCT were more likely to receive cALND after positive SLN (71% vs. 26.6%; P less than .001). Extracapsular extension (ECE) in the SLN was observed in 31.6% of patients treated with mastectomy and cALND. However, remaining 68.4% of patients without ECE in the SLN could have avoided cALND if they had chosen BCT initially.

Study details: Findings are from an analysis of 306 women with T1-2 clinically node-negative breast cancer with metastases in the SLN who were treated with mastectomy (n=107) or BCT (n=199).

Disclosures: Programmatic support was provided by the Fashion Footwear Charitable Foundation of New York, Inc., the Margie and Robert E. Peterson Foundation, and the Linda and Jim Lippman. ML Smidt reported receiving a grant from Servier Pharma. The remaining authors had no disclosures.

Source: Vane MLG et al. Ann Surg Oncol. 2021 Feb 14. doi: 10.1245/s10434-021-09674-9. 

Key clinical point: The 6-year follow-up data from APHINITY trial confirm invasive disease-free survival (IDFS) benefits of adding pertuzumab to adjuvant trastuzumab and chemotherapy in node-positive human epidermal growth factor receptor 2-positive (HER2+) early breast cancer.

Major finding: At 6 years, IDFS was longer in pertuzumab vs. placebo (91% vs. 88%; hazard ratio [HR], 0.76; 95% CI, 0.64-0.91) group, particularly in node-positive cohort (HR, 0.72; 95% CI, 0.59-0.87) but not in node-negative cohort. The overall survival analysis did not reach the required statistical significance (HR, 0.85; P = .17).

Study details: Findings are from a second interim analysis of the phase 3 APHINITY trial including 4,805 patients with node-positive or high-risk node-negative HER2+ breast cancer randomly allocated to receive chemotherapy with either 1 year of trastuzumab + placebo (n = 2,404) or trastuzumab + pertuzumab (n = 2,400) post-surgery.

Disclosures: This study was supported by F. Hoffmann-La Roche Ltd/Genentech. The lead author reported ties with AstraZeneca, Lilly, MSD, Novartis, Pfizer, Debiopharm Group, Odonate Therapeutics, Menarini, Seattle Genetics, Camel-IDS, Immunomedics, Roche/Genentech, Immutep, Radius Health, Synthon, Servier, Oncolytics, and EU Cancer Mission Board. Other investigators declared ties with various pharmaceutical companies including Roche/Genentech.

Source: Piccart M et al. J Clin Oncol. 2021 Feb 4. doi: 10.1200/JCO.20.01204.

Key clinical point: The 6-year follow-up data from APHINITY trial confirm invasive disease-free survival (IDFS) benefits of adding pertuzumab to adjuvant trastuzumab and chemotherapy in node-positive human epidermal growth factor receptor 2-positive (HER2+) early breast cancer.

Major finding: At 6 years, IDFS was longer in pertuzumab vs. placebo (91% vs. 88%; hazard ratio [HR], 0.76; 95% CI, 0.64-0.91) group, particularly in node-positive cohort (HR, 0.72; 95% CI, 0.59-0.87) but not in node-negative cohort. The overall survival analysis did not reach the required statistical significance (HR, 0.85; P = .17).

Study details: Findings are from a second interim analysis of the phase 3 APHINITY trial including 4,805 patients with node-positive or high-risk node-negative HER2+ breast cancer randomly allocated to receive chemotherapy with either 1 year of trastuzumab + placebo (n = 2,404) or trastuzumab + pertuzumab (n = 2,400) post-surgery.

Disclosures: This study was supported by F. Hoffmann-La Roche Ltd/Genentech. The lead author reported ties with AstraZeneca, Lilly, MSD, Novartis, Pfizer, Debiopharm Group, Odonate Therapeutics, Menarini, Seattle Genetics, Camel-IDS, Immunomedics, Roche/Genentech, Immutep, Radius Health, Synthon, Servier, Oncolytics, and EU Cancer Mission Board. Other investigators declared ties with various pharmaceutical companies including Roche/Genentech.

Source: Piccart M et al. J Clin Oncol. 2021 Feb 4. doi: 10.1200/JCO.20.01204.

Key clinical point: The 6-year follow-up data from APHINITY trial confirm invasive disease-free survival (IDFS) benefits of adding pertuzumab to adjuvant trastuzumab and chemotherapy in node-positive human epidermal growth factor receptor 2-positive (HER2+) early breast cancer.

Major finding: At 6 years, IDFS was longer in pertuzumab vs. placebo (91% vs. 88%; hazard ratio [HR], 0.76; 95% CI, 0.64-0.91) group, particularly in node-positive cohort (HR, 0.72; 95% CI, 0.59-0.87) but not in node-negative cohort. The overall survival analysis did not reach the required statistical significance (HR, 0.85; P = .17).

Study details: Findings are from a second interim analysis of the phase 3 APHINITY trial including 4,805 patients with node-positive or high-risk node-negative HER2+ breast cancer randomly allocated to receive chemotherapy with either 1 year of trastuzumab + placebo (n = 2,404) or trastuzumab + pertuzumab (n = 2,400) post-surgery.

Disclosures: This study was supported by F. Hoffmann-La Roche Ltd/Genentech. The lead author reported ties with AstraZeneca, Lilly, MSD, Novartis, Pfizer, Debiopharm Group, Odonate Therapeutics, Menarini, Seattle Genetics, Camel-IDS, Immunomedics, Roche/Genentech, Immutep, Radius Health, Synthon, Servier, Oncolytics, and EU Cancer Mission Board. Other investigators declared ties with various pharmaceutical companies including Roche/Genentech.

Source: Piccart M et al. J Clin Oncol. 2021 Feb 4. doi: 10.1200/JCO.20.01204.

Key clinical point: Pyrotinib+capecitabine significantly improved progression-free survival (PFS) vs. lapatinib+capecitabine with manageable toxicity in women with human epidermal growth factor receptor 2-positive (HER2+) metastatic breast cancer (MBC) after treatment with trastuzumab and taxanes.

Major finding: Median PFS was significantly longer in the pyrotinib+capecitabine vs. lapatinib+capecitabine group (12.5 vs. 6.8 months; hazard ratio, 0.39; one-sided P less than .0001). Serious adverse events were reported by 10% vs. 8% of patients in the pyrotinib vs. lapatinib group.

Study details: Findings are from an interim analysis of the phase 3 PHOEBE trial including 267 patients with HER2+ MBC previously treated with trastuzumab and taxanes randomly allocated to receive either pyrotinib+capecitabine (n=134) or lapatinib+capecitabine (n=132).

Disclosures: This study was funded by Jiangsu Hengrui Medicine and the National Key R&D Program of China. The lead author reported ties with Hengrui, Novartis, Roche, AstraZeneca, Pfizer, and Eisai. Some other investigators also reported employment or receiving grants and fees from various pharmaceutical companies including Hengrui.

Source: Xu B et al. Lancet Oncol. 2021 Feb 11. doi: 10.1016/S1470-2045(20)30702-6.

Key clinical point: Pyrotinib+capecitabine significantly improved progression-free survival (PFS) vs. lapatinib+capecitabine with manageable toxicity in women with human epidermal growth factor receptor 2-positive (HER2+) metastatic breast cancer (MBC) after treatment with trastuzumab and taxanes.

Major finding: Median PFS was significantly longer in the pyrotinib+capecitabine vs. lapatinib+capecitabine group (12.5 vs. 6.8 months; hazard ratio, 0.39; one-sided P less than .0001). Serious adverse events were reported by 10% vs. 8% of patients in the pyrotinib vs. lapatinib group.

Study details: Findings are from an interim analysis of the phase 3 PHOEBE trial including 267 patients with HER2+ MBC previously treated with trastuzumab and taxanes randomly allocated to receive either pyrotinib+capecitabine (n=134) or lapatinib+capecitabine (n=132).

Disclosures: This study was funded by Jiangsu Hengrui Medicine and the National Key R&D Program of China. The lead author reported ties with Hengrui, Novartis, Roche, AstraZeneca, Pfizer, and Eisai. Some other investigators also reported employment or receiving grants and fees from various pharmaceutical companies including Hengrui.

Source: Xu B et al. Lancet Oncol. 2021 Feb 11. doi: 10.1016/S1470-2045(20)30702-6.

Key clinical point: Pyrotinib+capecitabine significantly improved progression-free survival (PFS) vs. lapatinib+capecitabine with manageable toxicity in women with human epidermal growth factor receptor 2-positive (HER2+) metastatic breast cancer (MBC) after treatment with trastuzumab and taxanes.

Major finding: Median PFS was significantly longer in the pyrotinib+capecitabine vs. lapatinib+capecitabine group (12.5 vs. 6.8 months; hazard ratio, 0.39; one-sided P less than .0001). Serious adverse events were reported by 10% vs. 8% of patients in the pyrotinib vs. lapatinib group.

Study details: Findings are from an interim analysis of the phase 3 PHOEBE trial including 267 patients with HER2+ MBC previously treated with trastuzumab and taxanes randomly allocated to receive either pyrotinib+capecitabine (n=134) or lapatinib+capecitabine (n=132).

Disclosures: This study was funded by Jiangsu Hengrui Medicine and the National Key R&D Program of China. The lead author reported ties with Hengrui, Novartis, Roche, AstraZeneca, Pfizer, and Eisai. Some other investigators also reported employment or receiving grants and fees from various pharmaceutical companies including Hengrui.

Source: Xu B et al. Lancet Oncol. 2021 Feb 11. doi: 10.1016/S1470-2045(20)30702-6.

Infants with type 1 spinal muscular atrophy (SMA) showed promising signs, including an increased expression of functional survival motor neuron (SMN) protein in the blood, after 1 year of treatment with oral risdiplam (Evrysdi, Genentech), according to results of part 1 of the FIREFISH study.

A boost in SMN expression has been linked to improvements in survival and motor function, which was also observed in exploratory efficacy outcomes in the 2-part, phase 2-3, open-label study.

“No surviving infant was receiving permanent ventilation at month 12, and 7 of the 21 infants were able to sit without support, which is not expected in patients with type 1 spinal muscular atrophy, according to historical experience,” reported the FIREFISH Working Group led by Giovanni Baranello, MD, PhD, from the Dubowitz Neuromuscular Centre, National Institute for Health Research Great Ormond Street Hospital Biomedical Research Centre, Great Ormond Street Institute of Child Health University College London, and Great Ormond Street Hospital Trust, London.

However, “it cannot be stated with confidence that there was clinical benefit of the agent because the exploratory clinical endpoints were analyzed post hoc and can only be qualitatively compared with historical cohorts,” they added.

The findings were published online Feb. 24 in the New England Journal of Medicine.
 

A phase 2-3 open-label study

The study enrolled 21 infants with type 1 SMA, between the ages of 1 and 7 months. The majority (n = 17) were treated for 1 year with high-dose risdiplam, reaching 0.2 mg/kg of body weight per day by the twelfth month. Four infants in a low-dose cohort were treated with 0.08 mg/kg by the twelfth month. The medication was administered once daily orally in infants who were able to swallow, or by feeding tube for those who could not.

The primary outcomes of this first part of the study were safety, pharmacokinetics, pharmacodynamics (including the blood SMN protein concentration), and selection of the risdiplam dose for part 2 of the study. Exploratory outcomes included event-free survival, defined as being alive without tracheostomy or the use of permanent ventilation for 16 or more hours per day, and the ability to sit without support for at least 5 seconds.

In terms of safety, the study recorded 24 serious adverse events. “The most common serious adverse events were infections of the respiratory tract, and four infants died of respiratory complications; these findings are consistent with the neuromuscular respiratory failure that characterizes spinal muscular atrophy,” the authors reported. “The risdiplam-associated retinal toxic effects that had been previously observed in monkeys were not observed in the current study,” they added.

Regarding SMN protein levels, a median level of 2.1 times the baseline level was observed within 4 weeks after the initiation of treatment in the high-dose cohort, they reported. By 12 months, these median values had increased to 3.0 times and 1.9 times the baseline values in the low-dose and high-dose cohorts, respectively.

Looking at exploratory efficacy outcomes, 90% of infants survived without ventilatory support, and seven infants in the high-dose cohort were able to sit without support for at least 5 seconds. The higher dose of risdiplam (0.2 mg/kg per day) was selected for part 2 of the study.
 

The first oral treatment option

Risdiplam is the third SMA treatment approved by the Food and Drug Administration, “and has the potential to expand access to treatment for people with SMA,” commented Mary Schroth, MD, chief medical officer of Cure SMA, who was not involved in the research. She added that the exploratory outcomes of the FIREFISH study represent “a significant milestone for symptomatic infants with SMA type 1.”

While the other two approved SMA therapies – nusinersen and onasemnogene abeparvovec – have led to improvements in survival and motor function, they are administered either intrathecally or intravenously respectively, while risdiplam is an oral therapy.

Dr. Schroth says there are currently no studies comparing the different SMA treatments. “Cure SMA is actively collecting real-world experience with risdiplam and other SMA treatments through multiple pathways,” she said. “Every individual and family, in collaboration with their health care provider, should discuss SMA treatments and make the decision that is best for them.”

Writing in Neuroscience Insights, a few months after risdiplam’s FDA approval last summer, Ravindra N. Singh MD, from the department of biomedical sciences, Iowa State University, Ames, wrote that, as an orally deliverable small molecule, risdiplam “is a major advancement for the treatment of SMA.”

Now, the FIREFISH study is “welcome news,” he said in an interview. “The results look promising so far,” he added. “I am cautiously optimistic that risdiplam would prove to be a viable alternative to the currently available invasive approaches. However, long-term studies (with appropriate age and sex-matched cohorts) would be needed to fully rule out the potential side effects of the repeated administrations.”

The therapy “is particularly great news for a group of SMA patients that might have tolerability and/or immune response concerns when it comes to nusinersen and gene therapy,” he noted in his article, adding that the ability to store and ship the drug at ambient temperatures, as well as its comparatively low cost are added benefits.

The study was supported by F. Hoffmann–La Roche. Dr. Baranello disclosed that he serves as a consultant for AveXis, F. Hoffmann-La Roche, and Sarepta Therapeutics, as well as PTC Therapeutics, from whom he also receives speaker honoraria. Dr. Schroth disclosed no personal conflicts and is an employee of Cure SMA. Cure SMA works to develop strategic relationships with corporate partners with the goal of working together to lead the way to a world without SMA. In advancement of that mission, Cure SMA has received funding from multiple corporate sources including Aetna, Biogen, Blue Cross Blue Shield, Genentech, Kaiser Permanente, Novartis Gene Therapies, Scholar Rock, and United HealthCare. Cure SMA has no financial stake in any treatment and does not advocate for one treatment over another. Dr. Singh disclosed that Spinraza (Nusinersen), the first FDA-approved SMA drug, is based on the target (US patent # 7,838,657) that was discovered in his former laboratory at UMASS Medical School, Worcester, Mass.

Infants with type 1 spinal muscular atrophy (SMA) showed promising signs, including an increased expression of functional survival motor neuron (SMN) protein in the blood, after 1 year of treatment with oral risdiplam (Evrysdi, Genentech), according to results of part 1 of the FIREFISH study.

A boost in SMN expression has been linked to improvements in survival and motor function, which was also observed in exploratory efficacy outcomes in the 2-part, phase 2-3, open-label study.

“No surviving infant was receiving permanent ventilation at month 12, and 7 of the 21 infants were able to sit without support, which is not expected in patients with type 1 spinal muscular atrophy, according to historical experience,” reported the FIREFISH Working Group led by Giovanni Baranello, MD, PhD, from the Dubowitz Neuromuscular Centre, National Institute for Health Research Great Ormond Street Hospital Biomedical Research Centre, Great Ormond Street Institute of Child Health University College London, and Great Ormond Street Hospital Trust, London.

However, “it cannot be stated with confidence that there was clinical benefit of the agent because the exploratory clinical endpoints were analyzed post hoc and can only be qualitatively compared with historical cohorts,” they added.

The findings were published online Feb. 24 in the New England Journal of Medicine.
 

A phase 2-3 open-label study

The study enrolled 21 infants with type 1 SMA, between the ages of 1 and 7 months. The majority (n = 17) were treated for 1 year with high-dose risdiplam, reaching 0.2 mg/kg of body weight per day by the twelfth month. Four infants in a low-dose cohort were treated with 0.08 mg/kg by the twelfth month. The medication was administered once daily orally in infants who were able to swallow, or by feeding tube for those who could not.

The primary outcomes of this first part of the study were safety, pharmacokinetics, pharmacodynamics (including the blood SMN protein concentration), and selection of the risdiplam dose for part 2 of the study. Exploratory outcomes included event-free survival, defined as being alive without tracheostomy or the use of permanent ventilation for 16 or more hours per day, and the ability to sit without support for at least 5 seconds.

In terms of safety, the study recorded 24 serious adverse events. “The most common serious adverse events were infections of the respiratory tract, and four infants died of respiratory complications; these findings are consistent with the neuromuscular respiratory failure that characterizes spinal muscular atrophy,” the authors reported. “The risdiplam-associated retinal toxic effects that had been previously observed in monkeys were not observed in the current study,” they added.

Regarding SMN protein levels, a median level of 2.1 times the baseline level was observed within 4 weeks after the initiation of treatment in the high-dose cohort, they reported. By 12 months, these median values had increased to 3.0 times and 1.9 times the baseline values in the low-dose and high-dose cohorts, respectively.

Looking at exploratory efficacy outcomes, 90% of infants survived without ventilatory support, and seven infants in the high-dose cohort were able to sit without support for at least 5 seconds. The higher dose of risdiplam (0.2 mg/kg per day) was selected for part 2 of the study.
 

The first oral treatment option

Risdiplam is the third SMA treatment approved by the Food and Drug Administration, “and has the potential to expand access to treatment for people with SMA,” commented Mary Schroth, MD, chief medical officer of Cure SMA, who was not involved in the research. She added that the exploratory outcomes of the FIREFISH study represent “a significant milestone for symptomatic infants with SMA type 1.”

While the other two approved SMA therapies – nusinersen and onasemnogene abeparvovec – have led to improvements in survival and motor function, they are administered either intrathecally or intravenously respectively, while risdiplam is an oral therapy.

Dr. Schroth says there are currently no studies comparing the different SMA treatments. “Cure SMA is actively collecting real-world experience with risdiplam and other SMA treatments through multiple pathways,” she said. “Every individual and family, in collaboration with their health care provider, should discuss SMA treatments and make the decision that is best for them.”

Writing in Neuroscience Insights, a few months after risdiplam’s FDA approval last summer, Ravindra N. Singh MD, from the department of biomedical sciences, Iowa State University, Ames, wrote that, as an orally deliverable small molecule, risdiplam “is a major advancement for the treatment of SMA.”

Now, the FIREFISH study is “welcome news,” he said in an interview. “The results look promising so far,” he added. “I am cautiously optimistic that risdiplam would prove to be a viable alternative to the currently available invasive approaches. However, long-term studies (with appropriate age and sex-matched cohorts) would be needed to fully rule out the potential side effects of the repeated administrations.”

The therapy “is particularly great news for a group of SMA patients that might have tolerability and/or immune response concerns when it comes to nusinersen and gene therapy,” he noted in his article, adding that the ability to store and ship the drug at ambient temperatures, as well as its comparatively low cost are added benefits.

The study was supported by F. Hoffmann–La Roche. Dr. Baranello disclosed that he serves as a consultant for AveXis, F. Hoffmann-La Roche, and Sarepta Therapeutics, as well as PTC Therapeutics, from whom he also receives speaker honoraria. Dr. Schroth disclosed no personal conflicts and is an employee of Cure SMA. Cure SMA works to develop strategic relationships with corporate partners with the goal of working together to lead the way to a world without SMA. In advancement of that mission, Cure SMA has received funding from multiple corporate sources including Aetna, Biogen, Blue Cross Blue Shield, Genentech, Kaiser Permanente, Novartis Gene Therapies, Scholar Rock, and United HealthCare. Cure SMA has no financial stake in any treatment and does not advocate for one treatment over another. Dr. Singh disclosed that Spinraza (Nusinersen), the first FDA-approved SMA drug, is based on the target (US patent # 7,838,657) that was discovered in his former laboratory at UMASS Medical School, Worcester, Mass.

Infants with type 1 spinal muscular atrophy (SMA) showed promising signs, including an increased expression of functional survival motor neuron (SMN) protein in the blood, after 1 year of treatment with oral risdiplam (Evrysdi, Genentech), according to results of part 1 of the FIREFISH study.

A boost in SMN expression has been linked to improvements in survival and motor function, which was also observed in exploratory efficacy outcomes in the 2-part, phase 2-3, open-label study.

“No surviving infant was receiving permanent ventilation at month 12, and 7 of the 21 infants were able to sit without support, which is not expected in patients with type 1 spinal muscular atrophy, according to historical experience,” reported the FIREFISH Working Group led by Giovanni Baranello, MD, PhD, from the Dubowitz Neuromuscular Centre, National Institute for Health Research Great Ormond Street Hospital Biomedical Research Centre, Great Ormond Street Institute of Child Health University College London, and Great Ormond Street Hospital Trust, London.

However, “it cannot be stated with confidence that there was clinical benefit of the agent because the exploratory clinical endpoints were analyzed post hoc and can only be qualitatively compared with historical cohorts,” they added.

The findings were published online Feb. 24 in the New England Journal of Medicine.
 

A phase 2-3 open-label study

The study enrolled 21 infants with type 1 SMA, between the ages of 1 and 7 months. The majority (n = 17) were treated for 1 year with high-dose risdiplam, reaching 0.2 mg/kg of body weight per day by the twelfth month. Four infants in a low-dose cohort were treated with 0.08 mg/kg by the twelfth month. The medication was administered once daily orally in infants who were able to swallow, or by feeding tube for those who could not.

The primary outcomes of this first part of the study were safety, pharmacokinetics, pharmacodynamics (including the blood SMN protein concentration), and selection of the risdiplam dose for part 2 of the study. Exploratory outcomes included event-free survival, defined as being alive without tracheostomy or the use of permanent ventilation for 16 or more hours per day, and the ability to sit without support for at least 5 seconds.

In terms of safety, the study recorded 24 serious adverse events. “The most common serious adverse events were infections of the respiratory tract, and four infants died of respiratory complications; these findings are consistent with the neuromuscular respiratory failure that characterizes spinal muscular atrophy,” the authors reported. “The risdiplam-associated retinal toxic effects that had been previously observed in monkeys were not observed in the current study,” they added.

Regarding SMN protein levels, a median level of 2.1 times the baseline level was observed within 4 weeks after the initiation of treatment in the high-dose cohort, they reported. By 12 months, these median values had increased to 3.0 times and 1.9 times the baseline values in the low-dose and high-dose cohorts, respectively.

Looking at exploratory efficacy outcomes, 90% of infants survived without ventilatory support, and seven infants in the high-dose cohort were able to sit without support for at least 5 seconds. The higher dose of risdiplam (0.2 mg/kg per day) was selected for part 2 of the study.
 

The first oral treatment option

Risdiplam is the third SMA treatment approved by the Food and Drug Administration, “and has the potential to expand access to treatment for people with SMA,” commented Mary Schroth, MD, chief medical officer of Cure SMA, who was not involved in the research. She added that the exploratory outcomes of the FIREFISH study represent “a significant milestone for symptomatic infants with SMA type 1.”

While the other two approved SMA therapies – nusinersen and onasemnogene abeparvovec – have led to improvements in survival and motor function, they are administered either intrathecally or intravenously respectively, while risdiplam is an oral therapy.

Dr. Schroth says there are currently no studies comparing the different SMA treatments. “Cure SMA is actively collecting real-world experience with risdiplam and other SMA treatments through multiple pathways,” she said. “Every individual and family, in collaboration with their health care provider, should discuss SMA treatments and make the decision that is best for them.”

Writing in Neuroscience Insights, a few months after risdiplam’s FDA approval last summer, Ravindra N. Singh MD, from the department of biomedical sciences, Iowa State University, Ames, wrote that, as an orally deliverable small molecule, risdiplam “is a major advancement for the treatment of SMA.”

Now, the FIREFISH study is “welcome news,” he said in an interview. “The results look promising so far,” he added. “I am cautiously optimistic that risdiplam would prove to be a viable alternative to the currently available invasive approaches. However, long-term studies (with appropriate age and sex-matched cohorts) would be needed to fully rule out the potential side effects of the repeated administrations.”

The therapy “is particularly great news for a group of SMA patients that might have tolerability and/or immune response concerns when it comes to nusinersen and gene therapy,” he noted in his article, adding that the ability to store and ship the drug at ambient temperatures, as well as its comparatively low cost are added benefits.

The study was supported by F. Hoffmann–La Roche. Dr. Baranello disclosed that he serves as a consultant for AveXis, F. Hoffmann-La Roche, and Sarepta Therapeutics, as well as PTC Therapeutics, from whom he also receives speaker honoraria. Dr. Schroth disclosed no personal conflicts and is an employee of Cure SMA. Cure SMA works to develop strategic relationships with corporate partners with the goal of working together to lead the way to a world without SMA. In advancement of that mission, Cure SMA has received funding from multiple corporate sources including Aetna, Biogen, Blue Cross Blue Shield, Genentech, Kaiser Permanente, Novartis Gene Therapies, Scholar Rock, and United HealthCare. Cure SMA has no financial stake in any treatment and does not advocate for one treatment over another. Dr. Singh disclosed that Spinraza (Nusinersen), the first FDA-approved SMA drug, is based on the target (US patent # 7,838,657) that was discovered in his former laboratory at UMASS Medical School, Worcester, Mass.

For patients with triple-negative breast cancer (TNBC), neoadjuvant carboplatin plus docetaxel yields the same pathologic complete response and survival rates as a standard anthracycline-based neoadjuvant regimen – carboplatin and paclitaxel followed by doxorubicin/cyclophosphamide – but with less toxicity, higher completion rates, and at lower cost.

The results come from a phase 2 trial that involved 100 women. The study was published online in February in Clinical Cancer Research.

The doublet provides a safe, effective alternative for patients who are not candidates for treatment with anthracyclines and should be explored further for neoadjuvant deescalation, according to investigators led by Priyanka Sharma, MD, TNBC specialist and professor at the University of Kansas Medical Center, Westwood.

The trial wasn’t powered to demonstrate noninferiority, so it “probably does not provide enough evidence to state that [taxane/platinum] should replace other regimens,” Dr. Sharma said in an interview.

A proper noninferiority trial would require more than 2,500 participants, she said, adding that such a trial is unlikely, because companies are focused on immunotherapies for neoadjuvant TNBC.

“Our study does, however, provide a very effective alternative for patients and providers who want to use or prefer an anthracycline-sparing neoadjuvant chemotherapy regimen. We are very encouraged” by the findings, Dr. Sharma said.

This is “a provocative study that should make us pause and reevaluate our current approach. Further study of this approach in early-stage TNBC is warranted,” Melinda L. Telli, MD, associate professor of medicine and director of the breast cancer program at Stanford (Calif.) University, said when asked for comment.

Avoiding the risks associated with anthracycline “is great. I would be particularly enthusiastic using this regimen in patients with known increased risk of cardiac toxicity,” said Amy Tiersten, MD, a breast cancer specialist and professor at Mount Sinai Hospital, New York.

Anthracycline-based regimens are the standard of care for neoadjuvant TNBC. They typically include a taxane with or without carboplatin plus an anthracycline/cyclophosphamide combination. The regimen is highly active, but there is a small but serious risk for cardiomyopathy and leukemia with anthracycline/cyclophosphamide. In the current trial, one woman in the anthracycline arm died of secondary acute myeloid leukemia.

Given its tolerability and effectiveness, a taxane/carboplatin doublet might serve as a good backbone for the addition of novel immunotherapies in trials. Dr. Sharma is the principal investigator in one such trial, a phase 2 trial of carboplatin/docetaxel plus pembrolizumab for stage I–III TNBC.
 

Study details

The Neoadjuvant Study of Two Platinum Regimens in Stage I–III Triple Negative Breast Cancer (NeoSTOP) involved 100 women with stage I–III TNBC.

In the experimental arm, 52 women received carboplatin AUC 6 plus docetaxel 75 mg/m² every 21 days for six cycles.

In the standard-of-care anthracycline arm, 48 women received carboplatin AUC 6 every 21 days for four cycles plus paclitaxel 80 mg/m² weekly for 12 weeks, followed by doxorubicin 60 mg/m² plus cyclophosphamide 600 mg/m² every 2 weeks for four cycles.

Docetaxel and paclitaxel in the two regimens are interchangeable because they have shown equal efficacy in adjuvant trials, Dr. Sharma said.

At surgery, 54% of women in both arms had a breast/axilla pathologic complete response – the primary endpoint – and 67% in both arms had a residual cancer burden of 0-1. Event-free and overall survival (about 55% at 3 years for both) were similar with the two regimens.

Grade 3/4 adverse events were more common in the anthracycline arm. They included neutropenia, which occurred in 60% of women in the anthracycline arm, vs. 8% with the doublet; and febrile neutropenia, which occurred in 19% with anthracycline, vs. none with the doublet.

The toxicity profile of the anthracycline regimen was comparable to those in previous reports.

Ninety-two percent of the docetaxel/carboplatin group completed all six cycles; 72% of women in the anthracycline arm completed 10 or more doses of paclitaxel, and 85% completed all 4 carboplatin doses.

Mean costs of treatment, patient transportation, and lost productivity were $36,720 in the anthracycline arm, vs. $33,148 with the doublet.

The two arms were well balanced with respect to patient characteristics. The median age was 51 years, 30% of patients had axillary lymph node–positive disease, and 16% had ER/PgR expression of 1% to 10%. Of the study population, 17% carried deleterious BRCA1/2 mutations. Women were enrolled from July 2015 to May 2018. Median follow-up was 38 months.

Of the study population, 17% had stage I disease, so NeoSTOP included a lower-risk population than some neoadjuvant trials. However, there was no significant change in pathologic complete response rates in the two arms after exclusion of women with stage I disease (doublet, 50%; anthracycline, 54%).

The study was funded by the University of Kansas Cancer Center, the Breast Cancer Research Foundation, and the National Institute of General Medical Sciences. The investigators disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

For patients with triple-negative breast cancer (TNBC), neoadjuvant carboplatin plus docetaxel yields the same pathologic complete response and survival rates as a standard anthracycline-based neoadjuvant regimen – carboplatin and paclitaxel followed by doxorubicin/cyclophosphamide – but with less toxicity, higher completion rates, and at lower cost.

The results come from a phase 2 trial that involved 100 women. The study was published online in February in Clinical Cancer Research.

The doublet provides a safe, effective alternative for patients who are not candidates for treatment with anthracyclines and should be explored further for neoadjuvant deescalation, according to investigators led by Priyanka Sharma, MD, TNBC specialist and professor at the University of Kansas Medical Center, Westwood.

The trial wasn’t powered to demonstrate noninferiority, so it “probably does not provide enough evidence to state that [taxane/platinum] should replace other regimens,” Dr. Sharma said in an interview.

A proper noninferiority trial would require more than 2,500 participants, she said, adding that such a trial is unlikely, because companies are focused on immunotherapies for neoadjuvant TNBC.

“Our study does, however, provide a very effective alternative for patients and providers who want to use or prefer an anthracycline-sparing neoadjuvant chemotherapy regimen. We are very encouraged” by the findings, Dr. Sharma said.

This is “a provocative study that should make us pause and reevaluate our current approach. Further study of this approach in early-stage TNBC is warranted,” Melinda L. Telli, MD, associate professor of medicine and director of the breast cancer program at Stanford (Calif.) University, said when asked for comment.

Avoiding the risks associated with anthracycline “is great. I would be particularly enthusiastic using this regimen in patients with known increased risk of cardiac toxicity,” said Amy Tiersten, MD, a breast cancer specialist and professor at Mount Sinai Hospital, New York.

Anthracycline-based regimens are the standard of care for neoadjuvant TNBC. They typically include a taxane with or without carboplatin plus an anthracycline/cyclophosphamide combination. The regimen is highly active, but there is a small but serious risk for cardiomyopathy and leukemia with anthracycline/cyclophosphamide. In the current trial, one woman in the anthracycline arm died of secondary acute myeloid leukemia.

Given its tolerability and effectiveness, a taxane/carboplatin doublet might serve as a good backbone for the addition of novel immunotherapies in trials. Dr. Sharma is the principal investigator in one such trial, a phase 2 trial of carboplatin/docetaxel plus pembrolizumab for stage I–III TNBC.
 

Study details

The Neoadjuvant Study of Two Platinum Regimens in Stage I–III Triple Negative Breast Cancer (NeoSTOP) involved 100 women with stage I–III TNBC.

In the experimental arm, 52 women received carboplatin AUC 6 plus docetaxel 75 mg/m² every 21 days for six cycles.

In the standard-of-care anthracycline arm, 48 women received carboplatin AUC 6 every 21 days for four cycles plus paclitaxel 80 mg/m² weekly for 12 weeks, followed by doxorubicin 60 mg/m² plus cyclophosphamide 600 mg/m² every 2 weeks for four cycles.

Docetaxel and paclitaxel in the two regimens are interchangeable because they have shown equal efficacy in adjuvant trials, Dr. Sharma said.

At surgery, 54% of women in both arms had a breast/axilla pathologic complete response – the primary endpoint – and 67% in both arms had a residual cancer burden of 0-1. Event-free and overall survival (about 55% at 3 years for both) were similar with the two regimens.

Grade 3/4 adverse events were more common in the anthracycline arm. They included neutropenia, which occurred in 60% of women in the anthracycline arm, vs. 8% with the doublet; and febrile neutropenia, which occurred in 19% with anthracycline, vs. none with the doublet.

The toxicity profile of the anthracycline regimen was comparable to those in previous reports.

Ninety-two percent of the docetaxel/carboplatin group completed all six cycles; 72% of women in the anthracycline arm completed 10 or more doses of paclitaxel, and 85% completed all 4 carboplatin doses.

Mean costs of treatment, patient transportation, and lost productivity were $36,720 in the anthracycline arm, vs. $33,148 with the doublet.

The two arms were well balanced with respect to patient characteristics. The median age was 51 years, 30% of patients had axillary lymph node–positive disease, and 16% had ER/PgR expression of 1% to 10%. Of the study population, 17% carried deleterious BRCA1/2 mutations. Women were enrolled from July 2015 to May 2018. Median follow-up was 38 months.

Of the study population, 17% had stage I disease, so NeoSTOP included a lower-risk population than some neoadjuvant trials. However, there was no significant change in pathologic complete response rates in the two arms after exclusion of women with stage I disease (doublet, 50%; anthracycline, 54%).

The study was funded by the University of Kansas Cancer Center, the Breast Cancer Research Foundation, and the National Institute of General Medical Sciences. The investigators disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

For patients with triple-negative breast cancer (TNBC), neoadjuvant carboplatin plus docetaxel yields the same pathologic complete response and survival rates as a standard anthracycline-based neoadjuvant regimen – carboplatin and paclitaxel followed by doxorubicin/cyclophosphamide – but with less toxicity, higher completion rates, and at lower cost.

The results come from a phase 2 trial that involved 100 women. The study was published online in February in Clinical Cancer Research.

The doublet provides a safe, effective alternative for patients who are not candidates for treatment with anthracyclines and should be explored further for neoadjuvant deescalation, according to investigators led by Priyanka Sharma, MD, TNBC specialist and professor at the University of Kansas Medical Center, Westwood.

The trial wasn’t powered to demonstrate noninferiority, so it “probably does not provide enough evidence to state that [taxane/platinum] should replace other regimens,” Dr. Sharma said in an interview.

A proper noninferiority trial would require more than 2,500 participants, she said, adding that such a trial is unlikely, because companies are focused on immunotherapies for neoadjuvant TNBC.

“Our study does, however, provide a very effective alternative for patients and providers who want to use or prefer an anthracycline-sparing neoadjuvant chemotherapy regimen. We are very encouraged” by the findings, Dr. Sharma said.

This is “a provocative study that should make us pause and reevaluate our current approach. Further study of this approach in early-stage TNBC is warranted,” Melinda L. Telli, MD, associate professor of medicine and director of the breast cancer program at Stanford (Calif.) University, said when asked for comment.

Avoiding the risks associated with anthracycline “is great. I would be particularly enthusiastic using this regimen in patients with known increased risk of cardiac toxicity,” said Amy Tiersten, MD, a breast cancer specialist and professor at Mount Sinai Hospital, New York.

Anthracycline-based regimens are the standard of care for neoadjuvant TNBC. They typically include a taxane with or without carboplatin plus an anthracycline/cyclophosphamide combination. The regimen is highly active, but there is a small but serious risk for cardiomyopathy and leukemia with anthracycline/cyclophosphamide. In the current trial, one woman in the anthracycline arm died of secondary acute myeloid leukemia.

Given its tolerability and effectiveness, a taxane/carboplatin doublet might serve as a good backbone for the addition of novel immunotherapies in trials. Dr. Sharma is the principal investigator in one such trial, a phase 2 trial of carboplatin/docetaxel plus pembrolizumab for stage I–III TNBC.
 

Study details

The Neoadjuvant Study of Two Platinum Regimens in Stage I–III Triple Negative Breast Cancer (NeoSTOP) involved 100 women with stage I–III TNBC.

In the experimental arm, 52 women received carboplatin AUC 6 plus docetaxel 75 mg/m² every 21 days for six cycles.

In the standard-of-care anthracycline arm, 48 women received carboplatin AUC 6 every 21 days for four cycles plus paclitaxel 80 mg/m² weekly for 12 weeks, followed by doxorubicin 60 mg/m² plus cyclophosphamide 600 mg/m² every 2 weeks for four cycles.

Docetaxel and paclitaxel in the two regimens are interchangeable because they have shown equal efficacy in adjuvant trials, Dr. Sharma said.

At surgery, 54% of women in both arms had a breast/axilla pathologic complete response – the primary endpoint – and 67% in both arms had a residual cancer burden of 0-1. Event-free and overall survival (about 55% at 3 years for both) were similar with the two regimens.

Grade 3/4 adverse events were more common in the anthracycline arm. They included neutropenia, which occurred in 60% of women in the anthracycline arm, vs. 8% with the doublet; and febrile neutropenia, which occurred in 19% with anthracycline, vs. none with the doublet.

The toxicity profile of the anthracycline regimen was comparable to those in previous reports.

Ninety-two percent of the docetaxel/carboplatin group completed all six cycles; 72% of women in the anthracycline arm completed 10 or more doses of paclitaxel, and 85% completed all 4 carboplatin doses.

Mean costs of treatment, patient transportation, and lost productivity were $36,720 in the anthracycline arm, vs. $33,148 with the doublet.

The two arms were well balanced with respect to patient characteristics. The median age was 51 years, 30% of patients had axillary lymph node–positive disease, and 16% had ER/PgR expression of 1% to 10%. Of the study population, 17% carried deleterious BRCA1/2 mutations. Women were enrolled from July 2015 to May 2018. Median follow-up was 38 months.

Of the study population, 17% had stage I disease, so NeoSTOP included a lower-risk population than some neoadjuvant trials. However, there was no significant change in pathologic complete response rates in the two arms after exclusion of women with stage I disease (doublet, 50%; anthracycline, 54%).

The study was funded by the University of Kansas Cancer Center, the Breast Cancer Research Foundation, and the National Institute of General Medical Sciences. The investigators disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Poor adherence and high discontinuance rates frequently compromise achieving optimal triptan therapy in managing acute migraine headaches, a new Danish study shows.

“Few people continue on triptans either due to lack of efficacy or too many adverse events,” said Alan Rapoport, MD, clinical professor of neurology at the University of California, Los Angeles. “Some people overuse triptans when they are available and work well, but the patients are not properly informed, and do not listen.”

Migraine headaches fall among some of the most common neurologic disorders and claims the No. 2 spot in diseases that contribute to life lived with disability. An estimated 11.7% have migraine episodes annually, and the disorder carries a high prevalence through the duration of the patient’s life.

Triptans were noted as being a highly effective solution for acute migraine management when they were first introduced in the early 1990s and still remain the first-line treatment for acute migraine management not adequately controlled by ordinary analgesics and NSAIDs. As a drug class, the side-effect profile of triptans can vary, but frequent users run the risk of medication overuse headache, a condition noted by migraines of increased frequency and intensity.
 

25 years of triptan use

Study investigators conducted a nationwide, register-based cohort study using data collected from 7,435,758 Danish residents who accessed the public health care system between Jan. 1, 1994, and Oct. 31, 2019. The time frame accounts for a period of 139.0 million person-years when the residents were both alive and living in Denmark. Their findings were published online Feb. 14, 2021, in Cephalalgia.

Researchers evaluated and summarized purchases of all triptans in all dosage forms sold in Denmark during that time frame. These were sumatriptan, naratriptan, zolmitriptan, rizatriptan, almotriptan, eletriptan, and frovatriptan. Based on their finding, 381,695 patients purchased triptans at least one time. Triptan users were more likely to be female (75.7%) than male (24.3%).

Dr. Rapoport, who was not involved in the study, feels the differences in use between genders extrapolate to the U.S. migraine population as well. “Three times more women have migraines than men and buy triptans in that ratio,” he said.

Any patient who purchased at least one of any triptan at any point during the course of the study was classified as a triptan user. Triptan overuse is defined as using a triptan greater for at least 10 days a month for 3 consecutive months, as defined by the International Classification of Headache Disorders. It’s important to note that triptan are prescribed to patients for only two indications – migraines and cluster headaches. However, cluster headaches are extremely rare.

The study’s investigators summarized data collected throughout Denmark for more than a quarter of a century. The findings show an increase in triptan use from 345 defined daily doses to 945 defined daily doses per 1,000 residents per year along with an increased prevalence on triptan use from 5.17 to 14.57 per 1,000 inhabitants. In addition, 12.3% of the Danish residents who had migraines bought a triptan between 2014 and 2019 – data Dr. Rapoport noted falls in lines with trends in other Western countries, which range between 12% and 13%.

Nearly half of the first-time triptan buyers (43%) did not purchase another triptan for 5 years. In conflict with established guidelines, 90% of patients that discontinued triptan-based treatment had tried only one triptan type.

One important factor contributing to the ease of data collection is that the Danish population has free health care, coupled with sizable reimbursements for their spending. The country’s accessible health care system negates the effects of barriers related to price and availability while engendering data that more accurately reflects the patients’ experience based on treatment need and satisfaction.

“In a cohort with access to free clinical consultations and low medication costs, we observed low rates of triptan adherence, likely due to disappointing efficacy and/or unpleasant side effects rather than economic considerations. Triptan success continues to be hindered by poor implementation of clinical guidelines and high rates of treatment discontinuance,” the researchers concluded.

“The most surprising thing about this study is it is exactly what I would have expected if triptans in the U.S. were free,” Dr. Rapoport said.

Dr. Rapoport is the editor in chief of Neurology Reviews and serves as a consultant to several pharmaceutical companies.

Poor adherence and high discontinuance rates frequently compromise achieving optimal triptan therapy in managing acute migraine headaches, a new Danish study shows.

“Few people continue on triptans either due to lack of efficacy or too many adverse events,” said Alan Rapoport, MD, clinical professor of neurology at the University of California, Los Angeles. “Some people overuse triptans when they are available and work well, but the patients are not properly informed, and do not listen.”

Migraine headaches fall among some of the most common neurologic disorders and claims the No. 2 spot in diseases that contribute to life lived with disability. An estimated 11.7% have migraine episodes annually, and the disorder carries a high prevalence through the duration of the patient’s life.

Triptans were noted as being a highly effective solution for acute migraine management when they were first introduced in the early 1990s and still remain the first-line treatment for acute migraine management not adequately controlled by ordinary analgesics and NSAIDs. As a drug class, the side-effect profile of triptans can vary, but frequent users run the risk of medication overuse headache, a condition noted by migraines of increased frequency and intensity.
 

25 years of triptan use

Study investigators conducted a nationwide, register-based cohort study using data collected from 7,435,758 Danish residents who accessed the public health care system between Jan. 1, 1994, and Oct. 31, 2019. The time frame accounts for a period of 139.0 million person-years when the residents were both alive and living in Denmark. Their findings were published online Feb. 14, 2021, in Cephalalgia.

Researchers evaluated and summarized purchases of all triptans in all dosage forms sold in Denmark during that time frame. These were sumatriptan, naratriptan, zolmitriptan, rizatriptan, almotriptan, eletriptan, and frovatriptan. Based on their finding, 381,695 patients purchased triptans at least one time. Triptan users were more likely to be female (75.7%) than male (24.3%).

Dr. Rapoport, who was not involved in the study, feels the differences in use between genders extrapolate to the U.S. migraine population as well. “Three times more women have migraines than men and buy triptans in that ratio,” he said.

Any patient who purchased at least one of any triptan at any point during the course of the study was classified as a triptan user. Triptan overuse is defined as using a triptan greater for at least 10 days a month for 3 consecutive months, as defined by the International Classification of Headache Disorders. It’s important to note that triptan are prescribed to patients for only two indications – migraines and cluster headaches. However, cluster headaches are extremely rare.

The study’s investigators summarized data collected throughout Denmark for more than a quarter of a century. The findings show an increase in triptan use from 345 defined daily doses to 945 defined daily doses per 1,000 residents per year along with an increased prevalence on triptan use from 5.17 to 14.57 per 1,000 inhabitants. In addition, 12.3% of the Danish residents who had migraines bought a triptan between 2014 and 2019 – data Dr. Rapoport noted falls in lines with trends in other Western countries, which range between 12% and 13%.

Nearly half of the first-time triptan buyers (43%) did not purchase another triptan for 5 years. In conflict with established guidelines, 90% of patients that discontinued triptan-based treatment had tried only one triptan type.

One important factor contributing to the ease of data collection is that the Danish population has free health care, coupled with sizable reimbursements for their spending. The country’s accessible health care system negates the effects of barriers related to price and availability while engendering data that more accurately reflects the patients’ experience based on treatment need and satisfaction.

“In a cohort with access to free clinical consultations and low medication costs, we observed low rates of triptan adherence, likely due to disappointing efficacy and/or unpleasant side effects rather than economic considerations. Triptan success continues to be hindered by poor implementation of clinical guidelines and high rates of treatment discontinuance,” the researchers concluded.

“The most surprising thing about this study is it is exactly what I would have expected if triptans in the U.S. were free,” Dr. Rapoport said.

Dr. Rapoport is the editor in chief of Neurology Reviews and serves as a consultant to several pharmaceutical companies.

Poor adherence and high discontinuance rates frequently compromise achieving optimal triptan therapy in managing acute migraine headaches, a new Danish study shows.

“Few people continue on triptans either due to lack of efficacy or too many adverse events,” said Alan Rapoport, MD, clinical professor of neurology at the University of California, Los Angeles. “Some people overuse triptans when they are available and work well, but the patients are not properly informed, and do not listen.”

Migraine headaches fall among some of the most common neurologic disorders and claims the No. 2 spot in diseases that contribute to life lived with disability. An estimated 11.7% have migraine episodes annually, and the disorder carries a high prevalence through the duration of the patient’s life.

Triptans were noted as being a highly effective solution for acute migraine management when they were first introduced in the early 1990s and still remain the first-line treatment for acute migraine management not adequately controlled by ordinary analgesics and NSAIDs. As a drug class, the side-effect profile of triptans can vary, but frequent users run the risk of medication overuse headache, a condition noted by migraines of increased frequency and intensity.
 

25 years of triptan use

Study investigators conducted a nationwide, register-based cohort study using data collected from 7,435,758 Danish residents who accessed the public health care system between Jan. 1, 1994, and Oct. 31, 2019. The time frame accounts for a period of 139.0 million person-years when the residents were both alive and living in Denmark. Their findings were published online Feb. 14, 2021, in Cephalalgia.

Researchers evaluated and summarized purchases of all triptans in all dosage forms sold in Denmark during that time frame. These were sumatriptan, naratriptan, zolmitriptan, rizatriptan, almotriptan, eletriptan, and frovatriptan. Based on their finding, 381,695 patients purchased triptans at least one time. Triptan users were more likely to be female (75.7%) than male (24.3%).

Dr. Rapoport, who was not involved in the study, feels the differences in use between genders extrapolate to the U.S. migraine population as well. “Three times more women have migraines than men and buy triptans in that ratio,” he said.

Any patient who purchased at least one of any triptan at any point during the course of the study was classified as a triptan user. Triptan overuse is defined as using a triptan greater for at least 10 days a month for 3 consecutive months, as defined by the International Classification of Headache Disorders. It’s important to note that triptan are prescribed to patients for only two indications – migraines and cluster headaches. However, cluster headaches are extremely rare.

The study’s investigators summarized data collected throughout Denmark for more than a quarter of a century. The findings show an increase in triptan use from 345 defined daily doses to 945 defined daily doses per 1,000 residents per year along with an increased prevalence on triptan use from 5.17 to 14.57 per 1,000 inhabitants. In addition, 12.3% of the Danish residents who had migraines bought a triptan between 2014 and 2019 – data Dr. Rapoport noted falls in lines with trends in other Western countries, which range between 12% and 13%.

Nearly half of the first-time triptan buyers (43%) did not purchase another triptan for 5 years. In conflict with established guidelines, 90% of patients that discontinued triptan-based treatment had tried only one triptan type.

One important factor contributing to the ease of data collection is that the Danish population has free health care, coupled with sizable reimbursements for their spending. The country’s accessible health care system negates the effects of barriers related to price and availability while engendering data that more accurately reflects the patients’ experience based on treatment need and satisfaction.

“In a cohort with access to free clinical consultations and low medication costs, we observed low rates of triptan adherence, likely due to disappointing efficacy and/or unpleasant side effects rather than economic considerations. Triptan success continues to be hindered by poor implementation of clinical guidelines and high rates of treatment discontinuance,” the researchers concluded.

“The most surprising thing about this study is it is exactly what I would have expected if triptans in the U.S. were free,” Dr. Rapoport said.

Dr. Rapoport is the editor in chief of Neurology Reviews and serves as a consultant to several pharmaceutical companies.

In the United States, breast cancer mortality rates dropped every year for women across all age groups between 1989 and 2010, but after that, the trend stalled for those younger than 40 years.

“It’s clear that mortality rates in women under 40 are no longer decreasing,” lead author R. Edward Hendrick, PhD, clinical professor from the department of radiology at the University of Colorado at Denver, Aurora, stated in a press release. “I estimate that, in 2-3 years, the mortality rate will be increasing significantly in these women.”

These findings were published online Feb. 9, 2021, in Radiology.

The authors speculate that the findings may be related to recommendations for mammography screening.

For their study, the authors analyzed National Center for Health Statistics data for 1969-2017 and delay-adjusted invasive breast cancer incidence rates from the Surveillance, Epidemiology, and End Results program.

They found that breast cancer mortality rates decreased significantly by 1.5%-3.4% per year for all age groups from 1989 to 2010, and by 1.2%-2.2% per year after 2010 for those aged 40-79 years. However, the rates increased after 2010 by a nonsignificant 2.8% per year for women aged 20-29 years and 0.3% per year for those aged 30-39 years.

Distant-stage breast cancer incidence rates increased by more than 4% per year after the year 2000 in women aged 20-39 years.

“Our hope is that these findings focus more attention and research on breast cancer in younger women and what is behind this rapid increase in late-stage cancers,” Dr. Hendrick stated in the press release.

He and his colleagues speculate that the contrast between the upward trend in women aged younger than 40 years and the downward trend in older women highlights the value of mammography and may reflect the benefits of regular screening, which is not currently recommended for women younger than 40 who are not at high risk for breast cancer.

However, other groups, including the American College of Radiology and the Society for Breast Imaging, support starting annual mammograms at age 40 years.

An expert who was approached for comment noted that the incidence of breast cancer increases with age.

It is more common in women as they age, so screening recommendations do not include women aged younger than 40 years unless they are at very high risk for breast cancer, noted Joann G. Elmore, MD, MPH, professor of medicine at the University of California, Los Angeles.

“The majority of deaths due to breast cancer are in women over age 40. The breast cancer mortality rates per 100,000 as shown [in this study] are about 3 patients/100,000 for the under 40 age group, about 30/100,000 in the 40-69 age group, and about 80/100,000 in the 70 and above age group,” she pointed out.

Dr. Elmore was a coauthor of an editorial regarding the 2019 evidence-based guidance statement from the American College of Physicians . That guidance, which was endorsed by the U.S. Preventive Services Task Force, recommended screening every other year for average-risk women aged 50-74 years, as reported by this news organization.

In their editorial, Dr. Elmore and coauthor Christoph Lee, MD, of the University of Washington, Seattle, applauded the ACP’s approach but stressed that the guidance is not a perfect product and does not “clearly illuminate the full path ahead for every woman.”

Breast cancer screening guidelines continue to evolve, they said, concluding that “physicians are left to use their best judgment based on available research and expert recommendations.”

A version of this article first appeared on Medscape.com.

In the United States, breast cancer mortality rates dropped every year for women across all age groups between 1989 and 2010, but after that, the trend stalled for those younger than 40 years.

“It’s clear that mortality rates in women under 40 are no longer decreasing,” lead author R. Edward Hendrick, PhD, clinical professor from the department of radiology at the University of Colorado at Denver, Aurora, stated in a press release. “I estimate that, in 2-3 years, the mortality rate will be increasing significantly in these women.”

These findings were published online Feb. 9, 2021, in Radiology.

The authors speculate that the findings may be related to recommendations for mammography screening.

For their study, the authors analyzed National Center for Health Statistics data for 1969-2017 and delay-adjusted invasive breast cancer incidence rates from the Surveillance, Epidemiology, and End Results program.

They found that breast cancer mortality rates decreased significantly by 1.5%-3.4% per year for all age groups from 1989 to 2010, and by 1.2%-2.2% per year after 2010 for those aged 40-79 years. However, the rates increased after 2010 by a nonsignificant 2.8% per year for women aged 20-29 years and 0.3% per year for those aged 30-39 years.

Distant-stage breast cancer incidence rates increased by more than 4% per year after the year 2000 in women aged 20-39 years.

“Our hope is that these findings focus more attention and research on breast cancer in younger women and what is behind this rapid increase in late-stage cancers,” Dr. Hendrick stated in the press release.

He and his colleagues speculate that the contrast between the upward trend in women aged younger than 40 years and the downward trend in older women highlights the value of mammography and may reflect the benefits of regular screening, which is not currently recommended for women younger than 40 who are not at high risk for breast cancer.

However, other groups, including the American College of Radiology and the Society for Breast Imaging, support starting annual mammograms at age 40 years.

An expert who was approached for comment noted that the incidence of breast cancer increases with age.

It is more common in women as they age, so screening recommendations do not include women aged younger than 40 years unless they are at very high risk for breast cancer, noted Joann G. Elmore, MD, MPH, professor of medicine at the University of California, Los Angeles.

“The majority of deaths due to breast cancer are in women over age 40. The breast cancer mortality rates per 100,000 as shown [in this study] are about 3 patients/100,000 for the under 40 age group, about 30/100,000 in the 40-69 age group, and about 80/100,000 in the 70 and above age group,” she pointed out.

Dr. Elmore was a coauthor of an editorial regarding the 2019 evidence-based guidance statement from the American College of Physicians . That guidance, which was endorsed by the U.S. Preventive Services Task Force, recommended screening every other year for average-risk women aged 50-74 years, as reported by this news organization.

In their editorial, Dr. Elmore and coauthor Christoph Lee, MD, of the University of Washington, Seattle, applauded the ACP’s approach but stressed that the guidance is not a perfect product and does not “clearly illuminate the full path ahead for every woman.”

Breast cancer screening guidelines continue to evolve, they said, concluding that “physicians are left to use their best judgment based on available research and expert recommendations.”

A version of this article first appeared on Medscape.com.

In the United States, breast cancer mortality rates dropped every year for women across all age groups between 1989 and 2010, but after that, the trend stalled for those younger than 40 years.

“It’s clear that mortality rates in women under 40 are no longer decreasing,” lead author R. Edward Hendrick, PhD, clinical professor from the department of radiology at the University of Colorado at Denver, Aurora, stated in a press release. “I estimate that, in 2-3 years, the mortality rate will be increasing significantly in these women.”

These findings were published online Feb. 9, 2021, in Radiology.

The authors speculate that the findings may be related to recommendations for mammography screening.

For their study, the authors analyzed National Center for Health Statistics data for 1969-2017 and delay-adjusted invasive breast cancer incidence rates from the Surveillance, Epidemiology, and End Results program.

They found that breast cancer mortality rates decreased significantly by 1.5%-3.4% per year for all age groups from 1989 to 2010, and by 1.2%-2.2% per year after 2010 for those aged 40-79 years. However, the rates increased after 2010 by a nonsignificant 2.8% per year for women aged 20-29 years and 0.3% per year for those aged 30-39 years.

Distant-stage breast cancer incidence rates increased by more than 4% per year after the year 2000 in women aged 20-39 years.

“Our hope is that these findings focus more attention and research on breast cancer in younger women and what is behind this rapid increase in late-stage cancers,” Dr. Hendrick stated in the press release.

He and his colleagues speculate that the contrast between the upward trend in women aged younger than 40 years and the downward trend in older women highlights the value of mammography and may reflect the benefits of regular screening, which is not currently recommended for women younger than 40 who are not at high risk for breast cancer.

However, other groups, including the American College of Radiology and the Society for Breast Imaging, support starting annual mammograms at age 40 years.

An expert who was approached for comment noted that the incidence of breast cancer increases with age.

It is more common in women as they age, so screening recommendations do not include women aged younger than 40 years unless they are at very high risk for breast cancer, noted Joann G. Elmore, MD, MPH, professor of medicine at the University of California, Los Angeles.

“The majority of deaths due to breast cancer are in women over age 40. The breast cancer mortality rates per 100,000 as shown [in this study] are about 3 patients/100,000 for the under 40 age group, about 30/100,000 in the 40-69 age group, and about 80/100,000 in the 70 and above age group,” she pointed out.

Dr. Elmore was a coauthor of an editorial regarding the 2019 evidence-based guidance statement from the American College of Physicians . That guidance, which was endorsed by the U.S. Preventive Services Task Force, recommended screening every other year for average-risk women aged 50-74 years, as reported by this news organization.

In their editorial, Dr. Elmore and coauthor Christoph Lee, MD, of the University of Washington, Seattle, applauded the ACP’s approach but stressed that the guidance is not a perfect product and does not “clearly illuminate the full path ahead for every woman.”

Breast cancer screening guidelines continue to evolve, they said, concluding that “physicians are left to use their best judgment based on available research and expert recommendations.”

A version of this article first appeared on Medscape.com.