TBD Meeting (3274-19)

SAN ANTONIO – The high accuracy and efficiency of circulating tumor DNA (ctDNA) testing allows for routine clinical use in advanced breast cancer, according to investigators.

Will Pass/MDedge News

The plasmaMATCH trial showed that gene level agreement between ctDNA results measured by digital PCR versus sequencing was as high as 99.4%, reported lead author Nicholas Turner, MA, MRCP, PhD, of The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust, London.

Dr. Turner, who presented findings at the San Antonio Breast Cancer Symposium, said that ctDNA testing can detect rare mutations and link patients with targeted therapies that have clinically relevant response rates.

“Multiple somatic mutations are potentially targetable in the treatment of advanced breast cancer,” Dr. Turner said. “In addition, mutations may be acquired [during treatment].”

The diverse and dynamic landscape of mutations in breast cancer creates a need to genotype tumors without repeating biopsies, Dr. Turner said. He noted that ctDNA is one possible means of fulfilling this need, although more prospective research is required to determine clinical utility.

To this end, the investigators conducted the phase II plasmaMATCH trial, a multiple parallel cohort, multicenter study involving 1,044 patients with advanced breast cancer. All patients had ctDNA testing performed prospectively with digital droplet PCR (ddPCR); in addition, ctDNA testing was performed with error-corrected sequencing using Guardant360, either prospectively or retrospectively. If actionable mutations were identified, and consent was provided, then patients entered the treatment cohort, which was composed of 142 participants.

Patients were divided into four parallel treatment cohorts based on ctDNA mutation results and accompanying treatments, as follows:

• (A) ESR1 mutation; extended-dose fulvestrant.
• (B) HER2 mutation; neratinib with or without fulvestrant.
• (C) AKT1 in estrogen receptor–positive disease; capivasertib plus fulvestrant.
• (D) “AKT basket” – AKT1 in estrogen receptor–negative disease or PTEN inactivating mutation; capivasertib.

The primary objective was response rate. For cohort A, at least 13 out of 78 evaluable patients (17%) needed to have a response to infer sufficient efficacy of the matched therapy. For the remaining cohorts, sufficient efficacy was defined by responses in at least 3 out of 16 evaluable patients (19%).

SOURCE: Turner et al. SABCS. 2019 Dec 12. Abstract GS3-06.

SAN ANTONIO – The high accuracy and efficiency of circulating tumor DNA (ctDNA) testing allows for routine clinical use in advanced breast cancer, according to investigators.

Will Pass/MDedge News

The plasmaMATCH trial showed that gene level agreement between ctDNA results measured by digital PCR versus sequencing was as high as 99.4%, reported lead author Nicholas Turner, MA, MRCP, PhD, of The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust, London.

Dr. Turner, who presented findings at the San Antonio Breast Cancer Symposium, said that ctDNA testing can detect rare mutations and link patients with targeted therapies that have clinically relevant response rates.

“Multiple somatic mutations are potentially targetable in the treatment of advanced breast cancer,” Dr. Turner said. “In addition, mutations may be acquired [during treatment].”

The diverse and dynamic landscape of mutations in breast cancer creates a need to genotype tumors without repeating biopsies, Dr. Turner said. He noted that ctDNA is one possible means of fulfilling this need, although more prospective research is required to determine clinical utility.

To this end, the investigators conducted the phase II plasmaMATCH trial, a multiple parallel cohort, multicenter study involving 1,044 patients with advanced breast cancer. All patients had ctDNA testing performed prospectively with digital droplet PCR (ddPCR); in addition, ctDNA testing was performed with error-corrected sequencing using Guardant360, either prospectively or retrospectively. If actionable mutations were identified, and consent was provided, then patients entered the treatment cohort, which was composed of 142 participants.

Patients were divided into four parallel treatment cohorts based on ctDNA mutation results and accompanying treatments, as follows:

• (A) ESR1 mutation; extended-dose fulvestrant.
• (B) HER2 mutation; neratinib with or without fulvestrant.
• (C) AKT1 in estrogen receptor–positive disease; capivasertib plus fulvestrant.
• (D) “AKT basket” – AKT1 in estrogen receptor–negative disease or PTEN inactivating mutation; capivasertib.

The primary objective was response rate. For cohort A, at least 13 out of 78 evaluable patients (17%) needed to have a response to infer sufficient efficacy of the matched therapy. For the remaining cohorts, sufficient efficacy was defined by responses in at least 3 out of 16 evaluable patients (19%).

SOURCE: Turner et al. SABCS. 2019 Dec 12. Abstract GS3-06.

SAN ANTONIO – The high accuracy and efficiency of circulating tumor DNA (ctDNA) testing allows for routine clinical use in advanced breast cancer, according to investigators.

Will Pass/MDedge News

The plasmaMATCH trial showed that gene level agreement between ctDNA results measured by digital PCR versus sequencing was as high as 99.4%, reported lead author Nicholas Turner, MA, MRCP, PhD, of The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust, London.

Dr. Turner, who presented findings at the San Antonio Breast Cancer Symposium, said that ctDNA testing can detect rare mutations and link patients with targeted therapies that have clinically relevant response rates.

“Multiple somatic mutations are potentially targetable in the treatment of advanced breast cancer,” Dr. Turner said. “In addition, mutations may be acquired [during treatment].”

The diverse and dynamic landscape of mutations in breast cancer creates a need to genotype tumors without repeating biopsies, Dr. Turner said. He noted that ctDNA is one possible means of fulfilling this need, although more prospective research is required to determine clinical utility.

To this end, the investigators conducted the phase II plasmaMATCH trial, a multiple parallel cohort, multicenter study involving 1,044 patients with advanced breast cancer. All patients had ctDNA testing performed prospectively with digital droplet PCR (ddPCR); in addition, ctDNA testing was performed with error-corrected sequencing using Guardant360, either prospectively or retrospectively. If actionable mutations were identified, and consent was provided, then patients entered the treatment cohort, which was composed of 142 participants.

Patients were divided into four parallel treatment cohorts based on ctDNA mutation results and accompanying treatments, as follows:

• (A) ESR1 mutation; extended-dose fulvestrant.
• (B) HER2 mutation; neratinib with or without fulvestrant.
• (C) AKT1 in estrogen receptor–positive disease; capivasertib plus fulvestrant.
• (D) “AKT basket” – AKT1 in estrogen receptor–negative disease or PTEN inactivating mutation; capivasertib.

The primary objective was response rate. For cohort A, at least 13 out of 78 evaluable patients (17%) needed to have a response to infer sufficient efficacy of the matched therapy. For the remaining cohorts, sufficient efficacy was defined by responses in at least 3 out of 16 evaluable patients (19%).

SOURCE: Turner et al. SABCS. 2019 Dec 12. Abstract GS3-06.

SAN ANTONIO – For detection of genomic aberrations in patients with advanced breast cancer, sensitivity of circulating tumor DNA (ctDNA) testing is effectively equivalent to that of tumor tissue sequencing, based on results of the plasmaMATCH trial.

Will Pass/MDedge News

When plasma and tumor tissue samples were collected within 60 days of one another, sensitivity of ctDNA testing was 98% for digital droplet PCR (ddPCR) and 100% for targeted sequencing with Guardant360, reported lead author Belinda Kingston, MB, ChB, of The Institute of Cancer Research, London.

In addition to analyzing ctDNA accuracy, Dr. Kingston and colleagues explored characteristics of genomic alterations in relation to one another and to disease subtypes.

“We have defined the genomic landscape of advanced breast cancer using ctDNA analysis,” Dr. Kingston said during a presentation at the San Antonio Breast Cancer Symposium.

The open-label plasmaMATCH trial, conducted at multiple centers in the United Kingdom, involved more than 1,000 patients with advanced breast cancer. The present analysis included 1,025 patients who underwent ctDNA testing via ddPCR, which screened for alterations in PIK3CA, ESR1, AKT1, and ERBB2. Eight hundred patients also underwent ctDNA testing with Guardant360 targeted sequencing (a 73-gene panel), while 77 patients additionally had tumor tissue sequencing performed on a fresh or frozen sample of metastatic tissue (a 16-gene panel).

Results showed that individual gene level agreement between the two ctDNA techniques ranged from 96% to 99% with kappa scores of at least 0.89. As described above, sensitivity of these tests, compared with tumor tissue sequencing, approached 100%.

Following this overview of diagnostic accuracy, Dr. Kingston described a series of genomic trends, focusing first on targetable alterations.

Both ctDNA techniques revealed that ESR1 mutations were common in cases of hormone receptor (HR)-positive disease, including approximately 40% of patients with HER2-negative breast cancer and approximately 20% of patients with HER2-positive breast cancer. In contrast, ESR1 mutations were found in less than 1% of patients with HR-negative disease. Although ERBB2 amplification was predominantly found in patients with HER2-positive breast cancer, this alteration was found in 1%-2% of patients with HER2-negative disease.

For the remainder of the presentation, Dr. Kingston focused on ctDNA targeted sequencing data.

Within this cohort of 800 participants, 92.9% of patients had a ctDNA alteration. The mean number of pathogenic alterations was 2.7; Dr. Kingston noted that, on average, patients with HR-positive, HER2-negative disease had significantly more alterations than did those with triple-negative breast cancer (3.0 vs 1.8; P less than .0001).

“We found that specific genes are enriched in certain breast cancer subtypes,” Dr. Kingston said, pointing out the “notable” rate of ERBB2 mutations (14%) in HER2-amplified disease.

Among patients with HR-positive disease, those who were HER2-negative often had ESR1 and KRAS mutations, whereas those with HER2-positive disease often had ESR1 mutations but not KRAS mutations.

Heterogeneity analysis showed that alterations in certain genes were clonally dominant, including AKT1, PIK3CA, GATA3, and TP53, while others were more often subclonal, including ESR1, RB1, SMAD4, and KRAS.

A closer look at frequency of alterations showed that AKT1, CDH1, and GATA3 were typically found as the only gene alteration present; in contrast, ESR1 alterations were often accompanied by multiple other gene hits.

Returning to targetable genes, the investigators found that there was significant variation in clonal dominance of pathogenic mutations in ESR1 and PIK3CA. A deeper analysis revealed that PIK3CA mutations were often double mutations in HR-positive disease, and that subclonal second mutations were found at APOBEC mutagenesis sites.

Carlos Arteaga, MD, of the University of Texas Southwestern Medical Center, Dallas, commented on the findings after the presentation and asked Dr. Kingston about a potential blind spot in the data.

Will Pass/MDedge News

SOURCE: Kingston et al. SABCS. 2019 Abstract GS3-07.

SAN ANTONIO – For detection of genomic aberrations in patients with advanced breast cancer, sensitivity of circulating tumor DNA (ctDNA) testing is effectively equivalent to that of tumor tissue sequencing, based on results of the plasmaMATCH trial.

Will Pass/MDedge News

When plasma and tumor tissue samples were collected within 60 days of one another, sensitivity of ctDNA testing was 98% for digital droplet PCR (ddPCR) and 100% for targeted sequencing with Guardant360, reported lead author Belinda Kingston, MB, ChB, of The Institute of Cancer Research, London.

In addition to analyzing ctDNA accuracy, Dr. Kingston and colleagues explored characteristics of genomic alterations in relation to one another and to disease subtypes.

“We have defined the genomic landscape of advanced breast cancer using ctDNA analysis,” Dr. Kingston said during a presentation at the San Antonio Breast Cancer Symposium.

The open-label plasmaMATCH trial, conducted at multiple centers in the United Kingdom, involved more than 1,000 patients with advanced breast cancer. The present analysis included 1,025 patients who underwent ctDNA testing via ddPCR, which screened for alterations in PIK3CA, ESR1, AKT1, and ERBB2. Eight hundred patients also underwent ctDNA testing with Guardant360 targeted sequencing (a 73-gene panel), while 77 patients additionally had tumor tissue sequencing performed on a fresh or frozen sample of metastatic tissue (a 16-gene panel).

Results showed that individual gene level agreement between the two ctDNA techniques ranged from 96% to 99% with kappa scores of at least 0.89. As described above, sensitivity of these tests, compared with tumor tissue sequencing, approached 100%.

Following this overview of diagnostic accuracy, Dr. Kingston described a series of genomic trends, focusing first on targetable alterations.

Both ctDNA techniques revealed that ESR1 mutations were common in cases of hormone receptor (HR)-positive disease, including approximately 40% of patients with HER2-negative breast cancer and approximately 20% of patients with HER2-positive breast cancer. In contrast, ESR1 mutations were found in less than 1% of patients with HR-negative disease. Although ERBB2 amplification was predominantly found in patients with HER2-positive breast cancer, this alteration was found in 1%-2% of patients with HER2-negative disease.

For the remainder of the presentation, Dr. Kingston focused on ctDNA targeted sequencing data.

Within this cohort of 800 participants, 92.9% of patients had a ctDNA alteration. The mean number of pathogenic alterations was 2.7; Dr. Kingston noted that, on average, patients with HR-positive, HER2-negative disease had significantly more alterations than did those with triple-negative breast cancer (3.0 vs 1.8; P less than .0001).

“We found that specific genes are enriched in certain breast cancer subtypes,” Dr. Kingston said, pointing out the “notable” rate of ERBB2 mutations (14%) in HER2-amplified disease.

Among patients with HR-positive disease, those who were HER2-negative often had ESR1 and KRAS mutations, whereas those with HER2-positive disease often had ESR1 mutations but not KRAS mutations.

Heterogeneity analysis showed that alterations in certain genes were clonally dominant, including AKT1, PIK3CA, GATA3, and TP53, while others were more often subclonal, including ESR1, RB1, SMAD4, and KRAS.

A closer look at frequency of alterations showed that AKT1, CDH1, and GATA3 were typically found as the only gene alteration present; in contrast, ESR1 alterations were often accompanied by multiple other gene hits.

Returning to targetable genes, the investigators found that there was significant variation in clonal dominance of pathogenic mutations in ESR1 and PIK3CA. A deeper analysis revealed that PIK3CA mutations were often double mutations in HR-positive disease, and that subclonal second mutations were found at APOBEC mutagenesis sites.

Carlos Arteaga, MD, of the University of Texas Southwestern Medical Center, Dallas, commented on the findings after the presentation and asked Dr. Kingston about a potential blind spot in the data.

Will Pass/MDedge News

SOURCE: Kingston et al. SABCS. 2019 Abstract GS3-07.

SAN ANTONIO – For detection of genomic aberrations in patients with advanced breast cancer, sensitivity of circulating tumor DNA (ctDNA) testing is effectively equivalent to that of tumor tissue sequencing, based on results of the plasmaMATCH trial.

Will Pass/MDedge News

When plasma and tumor tissue samples were collected within 60 days of one another, sensitivity of ctDNA testing was 98% for digital droplet PCR (ddPCR) and 100% for targeted sequencing with Guardant360, reported lead author Belinda Kingston, MB, ChB, of The Institute of Cancer Research, London.

In addition to analyzing ctDNA accuracy, Dr. Kingston and colleagues explored characteristics of genomic alterations in relation to one another and to disease subtypes.

“We have defined the genomic landscape of advanced breast cancer using ctDNA analysis,” Dr. Kingston said during a presentation at the San Antonio Breast Cancer Symposium.

The open-label plasmaMATCH trial, conducted at multiple centers in the United Kingdom, involved more than 1,000 patients with advanced breast cancer. The present analysis included 1,025 patients who underwent ctDNA testing via ddPCR, which screened for alterations in PIK3CA, ESR1, AKT1, and ERBB2. Eight hundred patients also underwent ctDNA testing with Guardant360 targeted sequencing (a 73-gene panel), while 77 patients additionally had tumor tissue sequencing performed on a fresh or frozen sample of metastatic tissue (a 16-gene panel).

Results showed that individual gene level agreement between the two ctDNA techniques ranged from 96% to 99% with kappa scores of at least 0.89. As described above, sensitivity of these tests, compared with tumor tissue sequencing, approached 100%.

Following this overview of diagnostic accuracy, Dr. Kingston described a series of genomic trends, focusing first on targetable alterations.

Both ctDNA techniques revealed that ESR1 mutations were common in cases of hormone receptor (HR)-positive disease, including approximately 40% of patients with HER2-negative breast cancer and approximately 20% of patients with HER2-positive breast cancer. In contrast, ESR1 mutations were found in less than 1% of patients with HR-negative disease. Although ERBB2 amplification was predominantly found in patients with HER2-positive breast cancer, this alteration was found in 1%-2% of patients with HER2-negative disease.

For the remainder of the presentation, Dr. Kingston focused on ctDNA targeted sequencing data.

Within this cohort of 800 participants, 92.9% of patients had a ctDNA alteration. The mean number of pathogenic alterations was 2.7; Dr. Kingston noted that, on average, patients with HR-positive, HER2-negative disease had significantly more alterations than did those with triple-negative breast cancer (3.0 vs 1.8; P less than .0001).

“We found that specific genes are enriched in certain breast cancer subtypes,” Dr. Kingston said, pointing out the “notable” rate of ERBB2 mutations (14%) in HER2-amplified disease.

Among patients with HR-positive disease, those who were HER2-negative often had ESR1 and KRAS mutations, whereas those with HER2-positive disease often had ESR1 mutations but not KRAS mutations.

Heterogeneity analysis showed that alterations in certain genes were clonally dominant, including AKT1, PIK3CA, GATA3, and TP53, while others were more often subclonal, including ESR1, RB1, SMAD4, and KRAS.

A closer look at frequency of alterations showed that AKT1, CDH1, and GATA3 were typically found as the only gene alteration present; in contrast, ESR1 alterations were often accompanied by multiple other gene hits.

Returning to targetable genes, the investigators found that there was significant variation in clonal dominance of pathogenic mutations in ESR1 and PIK3CA. A deeper analysis revealed that PIK3CA mutations were often double mutations in HR-positive disease, and that subclonal second mutations were found at APOBEC mutagenesis sites.

Carlos Arteaga, MD, of the University of Texas Southwestern Medical Center, Dallas, commented on the findings after the presentation and asked Dr. Kingston about a potential blind spot in the data.

Will Pass/MDedge News

SOURCE: Kingston et al. SABCS. 2019 Abstract GS3-07.

SAN ANTONIO – For patients with newly diagnosed HER2-negative breast cancer who are BRCA carriers, neoadjuvant cisplatin does not offer a higher pathologic complete response (pCR) rate than standard doxorubicin/cyclophosphamide (AC), based on results from the phase 2 INFORM trial.

Will Pass/MDedge News

Findings from this trial and others suggest that BRCA deficiency may be a marker of sensitivity to DNA-damaging chemotherapy generally, instead of platinum agents specifically, reported lead author Nadine Tung, MD, of Beth Israel Deaconess Medical Center in Boston.

While single-agent platinum chemotherapy has shown significant clinical activity in the neoadjuvant and metastatic settings for BRCA-mutated triple-negative breast cancer (TNBC), prospective trials comparing platinum-based therapy with non–platinum-based therapy have been lacking, Dr. Tung said during a presentation at the San Antonio Breast Cancer Symposium.

“Almost no data exist for the response to platinum agents among BRCA carriers with hormone receptor–positive breast cancer,” Dr. Tung said.

The investigators aimed to address both of these knowledge gaps with a head-to-head trial. Although the investigators aimed for an accrual of 170 participants, all newly diagnosed patients, only 118 were enrolled, of whom 117 were included in the final analysis. All patients had HER2-negative breast cancer with at least one germline BRCA mutation. About two-thirds of patients (69%) were BRCA1 positive, about one-third (30%) were BRCA2 positive, and the small remainder (2%) had both mutations. Clinical stage proportions were as follows: I (19%), II (63%), and III (18%). Almost three-fourths of patients (70%) had TNBC, and 45% had nodal involvement upon enrollment.

Patients were randomized at a 1:1 ratio to receive either cisplatin (75 mg/m² every 3 weeks for four cycles) or standard AC (doxorubicin 60 mg/m² and cyclophosphamide 600 mg/m² every 2-3 weeks for four cycles). These treatments were followed by surgery. The primary endpoint was pCR . Secondary endpoints included residual cancer burden of 0-1 (RCB 0/1), 3-year disease-free survival, and toxicities.

Most patients completed the regimens as planned; however, seven patients received more than four cycles of chemotherapy while four patients completed fewer than four cycles. These 11 patients were categorized as not having a pathologic complete response.

Among the remaining patients, platinum-based chemotherapy was associated with an 18% pCR rate, compared with 26% for standard AC, which translated to a risk ratio of 0.70 that was not significant. Among patients with TNBC (n = 82), pCR rates followed a similar trend (22% vs. 28%), again without statistical significance. For patients with estrogen receptor–positive disease, the numerical disparity in pCR rate was greater (cisplatin at 6% vs. AC at 21%); however, once more, this difference was not statistically significant. Because of the small number of patients in this subgroup (n = 35), Dr. Tung advised that results be interpreted with caution.

Results for RCB 0/1 were similar to pCR. AC was associated with a higher rate of RCB 0-1 for all patients (46% vs. 33%), patients with TNBC (47% vs. 36%), and patients with hormone receptor–positive disease (42% vs. 25%). Across all patients and subtypes, these differences were not statistically significant.

Safety profiles were similar to previously published data for both regimens.

“In conclusion, contrary to our initial expectations, the pCR rate and RCB 0/1 rate is not significantly higher after cisplatin than after AC in BRCA carriers with early-stage breast cancer, whether triple-negative or estrogen receptor–positive HER2-negative disease,” Dr. Tung said. “Our statistician has concluded that there is no realistic scenario by which the pCR with cisplatin would have been significantly higher than with AC had this study met its accrual.”

“We believe the results of the INFORM trial are consistent with those of the GeparSixto and BrightTNess neoadjuvant trials,” Dr. Tung said. “One interpretation of the INFORM trial results, as well as these two trials, is that breast cancer in BRCA carriers is more sensitive than in noncarriers to DNA-damaging agents. … BRCA deficiency or homologous combination deficiency may simply be a marker of sensitivity to DNA-damaging chemotherapy rather than platinum agents specifically.”

The investigators disclosed relationships with Merck, AstraZeneca, Genentech, and others.

SOURCE: Tung N et al. SABCS 2019, Abstract GS6-03.

SAN ANTONIO – For patients with newly diagnosed HER2-negative breast cancer who are BRCA carriers, neoadjuvant cisplatin does not offer a higher pathologic complete response (pCR) rate than standard doxorubicin/cyclophosphamide (AC), based on results from the phase 2 INFORM trial.

Will Pass/MDedge News

Findings from this trial and others suggest that BRCA deficiency may be a marker of sensitivity to DNA-damaging chemotherapy generally, instead of platinum agents specifically, reported lead author Nadine Tung, MD, of Beth Israel Deaconess Medical Center in Boston.

While single-agent platinum chemotherapy has shown significant clinical activity in the neoadjuvant and metastatic settings for BRCA-mutated triple-negative breast cancer (TNBC), prospective trials comparing platinum-based therapy with non–platinum-based therapy have been lacking, Dr. Tung said during a presentation at the San Antonio Breast Cancer Symposium.

“Almost no data exist for the response to platinum agents among BRCA carriers with hormone receptor–positive breast cancer,” Dr. Tung said.

The investigators aimed to address both of these knowledge gaps with a head-to-head trial. Although the investigators aimed for an accrual of 170 participants, all newly diagnosed patients, only 118 were enrolled, of whom 117 were included in the final analysis. All patients had HER2-negative breast cancer with at least one germline BRCA mutation. About two-thirds of patients (69%) were BRCA1 positive, about one-third (30%) were BRCA2 positive, and the small remainder (2%) had both mutations. Clinical stage proportions were as follows: I (19%), II (63%), and III (18%). Almost three-fourths of patients (70%) had TNBC, and 45% had nodal involvement upon enrollment.

Patients were randomized at a 1:1 ratio to receive either cisplatin (75 mg/m² every 3 weeks for four cycles) or standard AC (doxorubicin 60 mg/m² and cyclophosphamide 600 mg/m² every 2-3 weeks for four cycles). These treatments were followed by surgery. The primary endpoint was pCR . Secondary endpoints included residual cancer burden of 0-1 (RCB 0/1), 3-year disease-free survival, and toxicities.

Most patients completed the regimens as planned; however, seven patients received more than four cycles of chemotherapy while four patients completed fewer than four cycles. These 11 patients were categorized as not having a pathologic complete response.

Among the remaining patients, platinum-based chemotherapy was associated with an 18% pCR rate, compared with 26% for standard AC, which translated to a risk ratio of 0.70 that was not significant. Among patients with TNBC (n = 82), pCR rates followed a similar trend (22% vs. 28%), again without statistical significance. For patients with estrogen receptor–positive disease, the numerical disparity in pCR rate was greater (cisplatin at 6% vs. AC at 21%); however, once more, this difference was not statistically significant. Because of the small number of patients in this subgroup (n = 35), Dr. Tung advised that results be interpreted with caution.

Results for RCB 0/1 were similar to pCR. AC was associated with a higher rate of RCB 0-1 for all patients (46% vs. 33%), patients with TNBC (47% vs. 36%), and patients with hormone receptor–positive disease (42% vs. 25%). Across all patients and subtypes, these differences were not statistically significant.

Safety profiles were similar to previously published data for both regimens.

“In conclusion, contrary to our initial expectations, the pCR rate and RCB 0/1 rate is not significantly higher after cisplatin than after AC in BRCA carriers with early-stage breast cancer, whether triple-negative or estrogen receptor–positive HER2-negative disease,” Dr. Tung said. “Our statistician has concluded that there is no realistic scenario by which the pCR with cisplatin would have been significantly higher than with AC had this study met its accrual.”

“We believe the results of the INFORM trial are consistent with those of the GeparSixto and BrightTNess neoadjuvant trials,” Dr. Tung said. “One interpretation of the INFORM trial results, as well as these two trials, is that breast cancer in BRCA carriers is more sensitive than in noncarriers to DNA-damaging agents. … BRCA deficiency or homologous combination deficiency may simply be a marker of sensitivity to DNA-damaging chemotherapy rather than platinum agents specifically.”

The investigators disclosed relationships with Merck, AstraZeneca, Genentech, and others.

SOURCE: Tung N et al. SABCS 2019, Abstract GS6-03.

SAN ANTONIO – For patients with newly diagnosed HER2-negative breast cancer who are BRCA carriers, neoadjuvant cisplatin does not offer a higher pathologic complete response (pCR) rate than standard doxorubicin/cyclophosphamide (AC), based on results from the phase 2 INFORM trial.

Will Pass/MDedge News

Findings from this trial and others suggest that BRCA deficiency may be a marker of sensitivity to DNA-damaging chemotherapy generally, instead of platinum agents specifically, reported lead author Nadine Tung, MD, of Beth Israel Deaconess Medical Center in Boston.

While single-agent platinum chemotherapy has shown significant clinical activity in the neoadjuvant and metastatic settings for BRCA-mutated triple-negative breast cancer (TNBC), prospective trials comparing platinum-based therapy with non–platinum-based therapy have been lacking, Dr. Tung said during a presentation at the San Antonio Breast Cancer Symposium.

“Almost no data exist for the response to platinum agents among BRCA carriers with hormone receptor–positive breast cancer,” Dr. Tung said.

The investigators aimed to address both of these knowledge gaps with a head-to-head trial. Although the investigators aimed for an accrual of 170 participants, all newly diagnosed patients, only 118 were enrolled, of whom 117 were included in the final analysis. All patients had HER2-negative breast cancer with at least one germline BRCA mutation. About two-thirds of patients (69%) were BRCA1 positive, about one-third (30%) were BRCA2 positive, and the small remainder (2%) had both mutations. Clinical stage proportions were as follows: I (19%), II (63%), and III (18%). Almost three-fourths of patients (70%) had TNBC, and 45% had nodal involvement upon enrollment.

Patients were randomized at a 1:1 ratio to receive either cisplatin (75 mg/m² every 3 weeks for four cycles) or standard AC (doxorubicin 60 mg/m² and cyclophosphamide 600 mg/m² every 2-3 weeks for four cycles). These treatments were followed by surgery. The primary endpoint was pCR . Secondary endpoints included residual cancer burden of 0-1 (RCB 0/1), 3-year disease-free survival, and toxicities.

Most patients completed the regimens as planned; however, seven patients received more than four cycles of chemotherapy while four patients completed fewer than four cycles. These 11 patients were categorized as not having a pathologic complete response.

Among the remaining patients, platinum-based chemotherapy was associated with an 18% pCR rate, compared with 26% for standard AC, which translated to a risk ratio of 0.70 that was not significant. Among patients with TNBC (n = 82), pCR rates followed a similar trend (22% vs. 28%), again without statistical significance. For patients with estrogen receptor–positive disease, the numerical disparity in pCR rate was greater (cisplatin at 6% vs. AC at 21%); however, once more, this difference was not statistically significant. Because of the small number of patients in this subgroup (n = 35), Dr. Tung advised that results be interpreted with caution.

Results for RCB 0/1 were similar to pCR. AC was associated with a higher rate of RCB 0-1 for all patients (46% vs. 33%), patients with TNBC (47% vs. 36%), and patients with hormone receptor–positive disease (42% vs. 25%). Across all patients and subtypes, these differences were not statistically significant.

Safety profiles were similar to previously published data for both regimens.

“In conclusion, contrary to our initial expectations, the pCR rate and RCB 0/1 rate is not significantly higher after cisplatin than after AC in BRCA carriers with early-stage breast cancer, whether triple-negative or estrogen receptor–positive HER2-negative disease,” Dr. Tung said. “Our statistician has concluded that there is no realistic scenario by which the pCR with cisplatin would have been significantly higher than with AC had this study met its accrual.”

“We believe the results of the INFORM trial are consistent with those of the GeparSixto and BrightTNess neoadjuvant trials,” Dr. Tung said. “One interpretation of the INFORM trial results, as well as these two trials, is that breast cancer in BRCA carriers is more sensitive than in noncarriers to DNA-damaging agents. … BRCA deficiency or homologous combination deficiency may simply be a marker of sensitivity to DNA-damaging chemotherapy rather than platinum agents specifically.”

The investigators disclosed relationships with Merck, AstraZeneca, Genentech, and others.

SOURCE: Tung N et al. SABCS 2019, Abstract GS6-03.

SAN ANTONIO – Maintenance therapy with the immune checkpoint inhibitor durvalumab (Imfinzi) did not improve outcomes compared with chemotherapy for patients with metastatic breast cancer, although there was a trend toward benefit for patients with triple-negative breast cancer and those whose tumors were positive for programmed death ligand 1 (PD-L1), a substudy of SAFIR-02 Breast.

Neil Osterweil/MDedge News

Median progression-free survival for 131 patients with metastatic or locally advanced, HER2-negative, hormone receptor–negative or endocrine-resistant breast cancer who received durvalumab maintenance following chemotherapy in the study was 2.7 months, compared with 4.4 months for 68 patients who received maintenance chemotherapy, reported Florence Dalenc, MD, of Institut Claudius Regaud, Toulouse, France.

“For hormone receptor–positive metastatic breast cancer, exploratory analyses suggest that anti-PD-L1 as a single agent is less effective than chemotherapy as maintenance,” she said at the San Antonio Breast Cancer Symposium.

The rationale for investigating an anti-PD-L1 agent for maintenance in patients with metastatic breast cancer is that the tumor is (presumably) not growing when immunotherapy is introduced and disease burden, a mechanism of immune suppression, has been reduced by chemotherapy. In addition, chemotherapy attracts tumor infiltrating lymphocytes (TILs) to the tumor bed, and response to chemotherapy may be a marker for immunogenic tumors, she said.

Durvalumab is a human immunoglobulin G1 kappa monoclonal antibody that blocks the interaction of the programmed death protein 1 with PD-L1. In the GeparNuevo trial, the addition of durvalumab to anthracycline-/taxane-based neoadjuvant chemotherapy increased the pathologic complete response (pCR) rate particularly in patients treated with durvalumab alone before the start of chemotherapy.

To see whether durvalumab could offer a benefit over chemotherapy in the maintenance setting, Dr. Dalenc and colleagues studied patients who were enrolled in SAFIR-02 Breast, which was designed to assess the efficacy of genomic analysis as a therapeutic decision tool in patients with metastatic breast cancer.

In the trial, patients with HER2-negative metastatic breast cancer who have a complete or partial response or stable disease following six to eight chemotherapy cycles (or 4 cycles if chemotherapy was stopped for toxicities) are randomized based on the presence or absence of targetable molecular alterations. Patients with identified alteration are then randomized to either targeted therapy matched to genomics, or to maintenance chemotherapy.

Patients without molecular alterations – the population included in the SAFIR02-IMMUNO substudy reported by Dr. Dalenc and colleagues – are stratified by one or two prior lines of chemotherapy and by response type, and then stratified on a 2:1 basis to maintenance with either durvalumab 10 mg/kg every 14 days or standard maintenance chemotherapy for up to 2 years.

In each arm, the median patient age was 56, and approximately 58% of patients had Eastern Cooperative Oncology Group (ECOG) performance status of 0. Approximately 43% of patients in each arm had three or more metastatic sites, and roughly half had liver metastases, while slightly more than one-fourth had metastases to lung.

As noted before, median PFS in the overall substudy population, the primary endpoint, was 4.6 months for patients on maintenance chemotherapy, compared with 2.7 months with durvalumab. This difference translated into an adjusted hazard ratio for progression with durvalumab of 1.40 (P = .047).

Also as noted, there were nonsignificant trends toward benefit with durvalumab among patients with triple-negative breast cancer or PD-L1-positive tumors. For all other subgroups, however, maintenance chemotherapy was favored, with significant benefit seen among patients with disease that progressed after second-line chemotherapy, patients with a clinical response at the time of re-randomization, those 50 years and older, patients with non-triple-negative disease, patients with liver metastases, and those whose tumors were negative for PD-L1.

Median overall survival (OS) was numerically longer with durvalumab (21.7 vs. 17.9 months), but this difference was not statistically significant.

In exploratory analyses, median OS for patients with triple-negative disease was 21 vs. 14 months, respectively, with an unadjusted hazard ratio favoring durvalumab of 0.54 (P = .0377). Among patients with PD-L1 positive tumors, the median OS was 26 months with durvalumab vs. 12 months with chemotherapy, with an unadjusted hazard ratio of 0.42, which just missed statistical significance (P = .0552).

Dr. Dalenc said that the study generates the hypothesis that single-agent durvalumab could improve outcomes in metastatic triple-negative breast cancer, but also raises questions about which disease parameters limit the response to anti-PD-L1 therapy.

The study was sponsored by UNICANCER with support from Fondation ARC and AstraZeneca. Dr. Dalenc reported research grants, travel, and/or advisory board activity for AstraZeneca and others.

SOURCE: Dalenc F et al. SABCS 2019. Abstract GS3-02.

SAN ANTONIO – Maintenance therapy with the immune checkpoint inhibitor durvalumab (Imfinzi) did not improve outcomes compared with chemotherapy for patients with metastatic breast cancer, although there was a trend toward benefit for patients with triple-negative breast cancer and those whose tumors were positive for programmed death ligand 1 (PD-L1), a substudy of SAFIR-02 Breast.

Neil Osterweil/MDedge News

Median progression-free survival for 131 patients with metastatic or locally advanced, HER2-negative, hormone receptor–negative or endocrine-resistant breast cancer who received durvalumab maintenance following chemotherapy in the study was 2.7 months, compared with 4.4 months for 68 patients who received maintenance chemotherapy, reported Florence Dalenc, MD, of Institut Claudius Regaud, Toulouse, France.

“For hormone receptor–positive metastatic breast cancer, exploratory analyses suggest that anti-PD-L1 as a single agent is less effective than chemotherapy as maintenance,” she said at the San Antonio Breast Cancer Symposium.

The rationale for investigating an anti-PD-L1 agent for maintenance in patients with metastatic breast cancer is that the tumor is (presumably) not growing when immunotherapy is introduced and disease burden, a mechanism of immune suppression, has been reduced by chemotherapy. In addition, chemotherapy attracts tumor infiltrating lymphocytes (TILs) to the tumor bed, and response to chemotherapy may be a marker for immunogenic tumors, she said.

Durvalumab is a human immunoglobulin G1 kappa monoclonal antibody that blocks the interaction of the programmed death protein 1 with PD-L1. In the GeparNuevo trial, the addition of durvalumab to anthracycline-/taxane-based neoadjuvant chemotherapy increased the pathologic complete response (pCR) rate particularly in patients treated with durvalumab alone before the start of chemotherapy.

To see whether durvalumab could offer a benefit over chemotherapy in the maintenance setting, Dr. Dalenc and colleagues studied patients who were enrolled in SAFIR-02 Breast, which was designed to assess the efficacy of genomic analysis as a therapeutic decision tool in patients with metastatic breast cancer.

In the trial, patients with HER2-negative metastatic breast cancer who have a complete or partial response or stable disease following six to eight chemotherapy cycles (or 4 cycles if chemotherapy was stopped for toxicities) are randomized based on the presence or absence of targetable molecular alterations. Patients with identified alteration are then randomized to either targeted therapy matched to genomics, or to maintenance chemotherapy.

Patients without molecular alterations – the population included in the SAFIR02-IMMUNO substudy reported by Dr. Dalenc and colleagues – are stratified by one or two prior lines of chemotherapy and by response type, and then stratified on a 2:1 basis to maintenance with either durvalumab 10 mg/kg every 14 days or standard maintenance chemotherapy for up to 2 years.

In each arm, the median patient age was 56, and approximately 58% of patients had Eastern Cooperative Oncology Group (ECOG) performance status of 0. Approximately 43% of patients in each arm had three or more metastatic sites, and roughly half had liver metastases, while slightly more than one-fourth had metastases to lung.

As noted before, median PFS in the overall substudy population, the primary endpoint, was 4.6 months for patients on maintenance chemotherapy, compared with 2.7 months with durvalumab. This difference translated into an adjusted hazard ratio for progression with durvalumab of 1.40 (P = .047).

Also as noted, there were nonsignificant trends toward benefit with durvalumab among patients with triple-negative breast cancer or PD-L1-positive tumors. For all other subgroups, however, maintenance chemotherapy was favored, with significant benefit seen among patients with disease that progressed after second-line chemotherapy, patients with a clinical response at the time of re-randomization, those 50 years and older, patients with non-triple-negative disease, patients with liver metastases, and those whose tumors were negative for PD-L1.

Median overall survival (OS) was numerically longer with durvalumab (21.7 vs. 17.9 months), but this difference was not statistically significant.

In exploratory analyses, median OS for patients with triple-negative disease was 21 vs. 14 months, respectively, with an unadjusted hazard ratio favoring durvalumab of 0.54 (P = .0377). Among patients with PD-L1 positive tumors, the median OS was 26 months with durvalumab vs. 12 months with chemotherapy, with an unadjusted hazard ratio of 0.42, which just missed statistical significance (P = .0552).

Dr. Dalenc said that the study generates the hypothesis that single-agent durvalumab could improve outcomes in metastatic triple-negative breast cancer, but also raises questions about which disease parameters limit the response to anti-PD-L1 therapy.

The study was sponsored by UNICANCER with support from Fondation ARC and AstraZeneca. Dr. Dalenc reported research grants, travel, and/or advisory board activity for AstraZeneca and others.

SOURCE: Dalenc F et al. SABCS 2019. Abstract GS3-02.

SAN ANTONIO – Maintenance therapy with the immune checkpoint inhibitor durvalumab (Imfinzi) did not improve outcomes compared with chemotherapy for patients with metastatic breast cancer, although there was a trend toward benefit for patients with triple-negative breast cancer and those whose tumors were positive for programmed death ligand 1 (PD-L1), a substudy of SAFIR-02 Breast.

Neil Osterweil/MDedge News

Median progression-free survival for 131 patients with metastatic or locally advanced, HER2-negative, hormone receptor–negative or endocrine-resistant breast cancer who received durvalumab maintenance following chemotherapy in the study was 2.7 months, compared with 4.4 months for 68 patients who received maintenance chemotherapy, reported Florence Dalenc, MD, of Institut Claudius Regaud, Toulouse, France.

“For hormone receptor–positive metastatic breast cancer, exploratory analyses suggest that anti-PD-L1 as a single agent is less effective than chemotherapy as maintenance,” she said at the San Antonio Breast Cancer Symposium.

The rationale for investigating an anti-PD-L1 agent for maintenance in patients with metastatic breast cancer is that the tumor is (presumably) not growing when immunotherapy is introduced and disease burden, a mechanism of immune suppression, has been reduced by chemotherapy. In addition, chemotherapy attracts tumor infiltrating lymphocytes (TILs) to the tumor bed, and response to chemotherapy may be a marker for immunogenic tumors, she said.

Durvalumab is a human immunoglobulin G1 kappa monoclonal antibody that blocks the interaction of the programmed death protein 1 with PD-L1. In the GeparNuevo trial, the addition of durvalumab to anthracycline-/taxane-based neoadjuvant chemotherapy increased the pathologic complete response (pCR) rate particularly in patients treated with durvalumab alone before the start of chemotherapy.

To see whether durvalumab could offer a benefit over chemotherapy in the maintenance setting, Dr. Dalenc and colleagues studied patients who were enrolled in SAFIR-02 Breast, which was designed to assess the efficacy of genomic analysis as a therapeutic decision tool in patients with metastatic breast cancer.

In the trial, patients with HER2-negative metastatic breast cancer who have a complete or partial response or stable disease following six to eight chemotherapy cycles (or 4 cycles if chemotherapy was stopped for toxicities) are randomized based on the presence or absence of targetable molecular alterations. Patients with identified alteration are then randomized to either targeted therapy matched to genomics, or to maintenance chemotherapy.

Patients without molecular alterations – the population included in the SAFIR02-IMMUNO substudy reported by Dr. Dalenc and colleagues – are stratified by one or two prior lines of chemotherapy and by response type, and then stratified on a 2:1 basis to maintenance with either durvalumab 10 mg/kg every 14 days or standard maintenance chemotherapy for up to 2 years.

In each arm, the median patient age was 56, and approximately 58% of patients had Eastern Cooperative Oncology Group (ECOG) performance status of 0. Approximately 43% of patients in each arm had three or more metastatic sites, and roughly half had liver metastases, while slightly more than one-fourth had metastases to lung.

As noted before, median PFS in the overall substudy population, the primary endpoint, was 4.6 months for patients on maintenance chemotherapy, compared with 2.7 months with durvalumab. This difference translated into an adjusted hazard ratio for progression with durvalumab of 1.40 (P = .047).

Also as noted, there were nonsignificant trends toward benefit with durvalumab among patients with triple-negative breast cancer or PD-L1-positive tumors. For all other subgroups, however, maintenance chemotherapy was favored, with significant benefit seen among patients with disease that progressed after second-line chemotherapy, patients with a clinical response at the time of re-randomization, those 50 years and older, patients with non-triple-negative disease, patients with liver metastases, and those whose tumors were negative for PD-L1.

Median overall survival (OS) was numerically longer with durvalumab (21.7 vs. 17.9 months), but this difference was not statistically significant.

In exploratory analyses, median OS for patients with triple-negative disease was 21 vs. 14 months, respectively, with an unadjusted hazard ratio favoring durvalumab of 0.54 (P = .0377). Among patients with PD-L1 positive tumors, the median OS was 26 months with durvalumab vs. 12 months with chemotherapy, with an unadjusted hazard ratio of 0.42, which just missed statistical significance (P = .0552).

Dr. Dalenc said that the study generates the hypothesis that single-agent durvalumab could improve outcomes in metastatic triple-negative breast cancer, but also raises questions about which disease parameters limit the response to anti-PD-L1 therapy.

The study was sponsored by UNICANCER with support from Fondation ARC and AstraZeneca. Dr. Dalenc reported research grants, travel, and/or advisory board activity for AstraZeneca and others.

SOURCE: Dalenc F et al. SABCS 2019. Abstract GS3-02.

SAN ANTONIO – An oral formulation of paclitaxel given with the P-glycoprotein pump inhibitor encequidar improved outcomes and reduced neuropathy risk, compared with intravenous paclitaxel, in women with metastatic breast cancer in a randomized, open-label, phase 3 study.

Sharon Worcester/MDedge News

The primary study endpoint of radiologically confirmed tumor response rate was 35.8% among 265 patients randomized to receive oral paclitaxel plus encequidar, compared with 23.4% among 137 who received intravenous paclitaxel – a statistically significant 12.4% difference, Gerardo Umanzor, MD, reported at the San Antonio Breast Cancer Symposium.

In the prespecified modified intent-to-treat (mITT) population of patients who had evaluable scans at baseline and who received at least seven doses of oral therapy or one dose of intravenous therapy, the corresponding confirmed tumor response rates were 40.4% and 25.5% (absolute improvement, 14.8%), said Dr. Umanzor, a medical oncologist with Liga Contra el Cancer in San Pedro Sulas, Honduras.

Tumor responses in all clinically important subgroups were consistent with the overall confirmed response profiles, he said, noting that the responses were durable, with ongoing analyses showing median response durations of 39.0 weeks versus 30.1 weeks with oral versus intravenous therapy.

Further, a higher percentage of oral versus intravenous paclitaxel recipients were receiving ongoing treatment at the time of the study endpoint (19% vs. 13%, respectively), he said.

Progression-free survival also showed a trend toward improved outcome with oral therapy in ongoing analyses in the mITT population (9.3 vs. 8.3 months, respectively), and an early analysis of overall survival also showed significant improvement (27.9 vs. 16.9 months; P = .035), he said.

Oral paclitaxel also was associated with a lower incidence of chemotherapy-induced peripheral neuropathy – a “highly debilitating side effect of IV paclitaxel,” he said, adding that “the difference between the arms is quite dramatic.”

The overall rates of neuropathy to week 23 were 17% versus 15% with oral versus intravenous therapy, and the rates of grade 3 neuropathy were 1% versus 8%, he said.

Alopecia incidence was reduced by about 50% with oral versus intravenous therapy, he added.

Toxicity was generally similar in the two groups, although the oral paclitaxel patients experienced higher rates of neutropenia and gastrointestinal effects. “These were low grade and manageable,” Dr. Umanzor said.

Study participants were patients with any type of metastatic breast cancer randomized 2:1 to receive a 15-mg tablet of encequidar followed by 205 mg/m² of oral paclitaxel (about 11 capsules, each containing 30 mg of solubilized paclitaxel) for 3 consecutive days each week for 3 weeks or intravenous paclitaxel at the labeled dose of 175 mg/m² over a 3-hour infusion every 3 weeks.

Confirmed tumor response rates were based on blinded assessment at two consecutive time points, 3-6 weeks apart, by study day 160.

The treatment groups were similar with respect to demographic characteristics and prior taxane therapy, he noted.

The findings have important implications, because while intravenous paclitaxel is an efficacious chemotherapeutic agent against metastatic breast cancer and multiple other cancers, it is associated in some patients with neuropathy.

“As an oncologist, it has been very frustrating to have an effective chemotherapy like paclitaxel, which a lot of patients cannot tolerate,” Dr. Umanzor said, noting that, in addition to eliminating the need for intravenous access and the risk of infusion hypersensitivity reactions, oral administration offers a number of potential benefits – particularly patient convenience.

Hypothesizing that the lower peak concentration of oral paclitaxel might result in lower systemic toxicity, Dr. Umanzor and colleagues developed the orally administered paclitaxel regimen used in this study to test that hypothesis. The paclitaxel was made bioavailable through combination with the encequidar, which promotes paclitaxel absorption into the blood stream, he explained, noting that the pharmacokinetic exposure matches that of intravenous paclitaxel when given at 80 mg/m², but with peak concentrations that are approximately one-tenth of those seen with intravenous therapy.

In a phase 2 study of 26 patients with heavily pretreated metastatic breast cancer, the oral therapy was associated with an encouraging 42.3% partial response rate and a 46.2% stable disease rate, he said.

The oral paclitaxel plus encequidar combination used in this pivotal study is the first orally administered taxane to demonstrate improved and durable overall confirmed response rates with minimal clinically meaningful neuropathy, compared with intravenous paclitaxel given every 3 weeks, he said.

“Oral paclitaxel and encequidar provides an important oral therapeutic option for patients with metastatic breast cancer, representing a meaningful improvement in the clinical profile of paclitaxel,” he said.

He further noted in a press release that “[t]his oral form of paclitaxel provides a new therapeutic option for patients, in particular, for those who cannot easily travel. While blood counts still need to be monitored, oral administration allows patients to remain home during therapy, and avoid spending significant time in the chemotherapy unit.”

The next step will be testing the tolerability of oral paclitaxel in patients at high risk of developing peripheral neuropathy, he said, adding that the findings could also open the door for assessing this approach with other taxanes.

During a press briefing on the findings at the symposium, several attendees voiced concerns about patient compliance given the large number of capsules required for oral dosing, but Dr. Umanzor said “there were no complaints at all and no issues with adherence.”

“Patients were so excited that they were getting an oral treatment, and we had very good compliance,” he said.

The study was funded by Athenex, the maker of the oral form of paclitaxel. Dr. Umanzor reported having no conflicts of interest.

SOURCE: Umanzor G et al. SABCS 2019, Abstract GS6-01.

SAN ANTONIO – An oral formulation of paclitaxel given with the P-glycoprotein pump inhibitor encequidar improved outcomes and reduced neuropathy risk, compared with intravenous paclitaxel, in women with metastatic breast cancer in a randomized, open-label, phase 3 study.

Sharon Worcester/MDedge News

The primary study endpoint of radiologically confirmed tumor response rate was 35.8% among 265 patients randomized to receive oral paclitaxel plus encequidar, compared with 23.4% among 137 who received intravenous paclitaxel – a statistically significant 12.4% difference, Gerardo Umanzor, MD, reported at the San Antonio Breast Cancer Symposium.

In the prespecified modified intent-to-treat (mITT) population of patients who had evaluable scans at baseline and who received at least seven doses of oral therapy or one dose of intravenous therapy, the corresponding confirmed tumor response rates were 40.4% and 25.5% (absolute improvement, 14.8%), said Dr. Umanzor, a medical oncologist with Liga Contra el Cancer in San Pedro Sulas, Honduras.

Tumor responses in all clinically important subgroups were consistent with the overall confirmed response profiles, he said, noting that the responses were durable, with ongoing analyses showing median response durations of 39.0 weeks versus 30.1 weeks with oral versus intravenous therapy.

Further, a higher percentage of oral versus intravenous paclitaxel recipients were receiving ongoing treatment at the time of the study endpoint (19% vs. 13%, respectively), he said.

Progression-free survival also showed a trend toward improved outcome with oral therapy in ongoing analyses in the mITT population (9.3 vs. 8.3 months, respectively), and an early analysis of overall survival also showed significant improvement (27.9 vs. 16.9 months; P = .035), he said.

Oral paclitaxel also was associated with a lower incidence of chemotherapy-induced peripheral neuropathy – a “highly debilitating side effect of IV paclitaxel,” he said, adding that “the difference between the arms is quite dramatic.”

The overall rates of neuropathy to week 23 were 17% versus 15% with oral versus intravenous therapy, and the rates of grade 3 neuropathy were 1% versus 8%, he said.

Alopecia incidence was reduced by about 50% with oral versus intravenous therapy, he added.

Toxicity was generally similar in the two groups, although the oral paclitaxel patients experienced higher rates of neutropenia and gastrointestinal effects. “These were low grade and manageable,” Dr. Umanzor said.

Study participants were patients with any type of metastatic breast cancer randomized 2:1 to receive a 15-mg tablet of encequidar followed by 205 mg/m² of oral paclitaxel (about 11 capsules, each containing 30 mg of solubilized paclitaxel) for 3 consecutive days each week for 3 weeks or intravenous paclitaxel at the labeled dose of 175 mg/m² over a 3-hour infusion every 3 weeks.

Confirmed tumor response rates were based on blinded assessment at two consecutive time points, 3-6 weeks apart, by study day 160.

The treatment groups were similar with respect to demographic characteristics and prior taxane therapy, he noted.

The findings have important implications, because while intravenous paclitaxel is an efficacious chemotherapeutic agent against metastatic breast cancer and multiple other cancers, it is associated in some patients with neuropathy.

“As an oncologist, it has been very frustrating to have an effective chemotherapy like paclitaxel, which a lot of patients cannot tolerate,” Dr. Umanzor said, noting that, in addition to eliminating the need for intravenous access and the risk of infusion hypersensitivity reactions, oral administration offers a number of potential benefits – particularly patient convenience.

Hypothesizing that the lower peak concentration of oral paclitaxel might result in lower systemic toxicity, Dr. Umanzor and colleagues developed the orally administered paclitaxel regimen used in this study to test that hypothesis. The paclitaxel was made bioavailable through combination with the encequidar, which promotes paclitaxel absorption into the blood stream, he explained, noting that the pharmacokinetic exposure matches that of intravenous paclitaxel when given at 80 mg/m², but with peak concentrations that are approximately one-tenth of those seen with intravenous therapy.

In a phase 2 study of 26 patients with heavily pretreated metastatic breast cancer, the oral therapy was associated with an encouraging 42.3% partial response rate and a 46.2% stable disease rate, he said.

The oral paclitaxel plus encequidar combination used in this pivotal study is the first orally administered taxane to demonstrate improved and durable overall confirmed response rates with minimal clinically meaningful neuropathy, compared with intravenous paclitaxel given every 3 weeks, he said.

“Oral paclitaxel and encequidar provides an important oral therapeutic option for patients with metastatic breast cancer, representing a meaningful improvement in the clinical profile of paclitaxel,” he said.

He further noted in a press release that “[t]his oral form of paclitaxel provides a new therapeutic option for patients, in particular, for those who cannot easily travel. While blood counts still need to be monitored, oral administration allows patients to remain home during therapy, and avoid spending significant time in the chemotherapy unit.”

The next step will be testing the tolerability of oral paclitaxel in patients at high risk of developing peripheral neuropathy, he said, adding that the findings could also open the door for assessing this approach with other taxanes.

During a press briefing on the findings at the symposium, several attendees voiced concerns about patient compliance given the large number of capsules required for oral dosing, but Dr. Umanzor said “there were no complaints at all and no issues with adherence.”

“Patients were so excited that they were getting an oral treatment, and we had very good compliance,” he said.

The study was funded by Athenex, the maker of the oral form of paclitaxel. Dr. Umanzor reported having no conflicts of interest.

SOURCE: Umanzor G et al. SABCS 2019, Abstract GS6-01.

SAN ANTONIO – An oral formulation of paclitaxel given with the P-glycoprotein pump inhibitor encequidar improved outcomes and reduced neuropathy risk, compared with intravenous paclitaxel, in women with metastatic breast cancer in a randomized, open-label, phase 3 study.

Sharon Worcester/MDedge News

The primary study endpoint of radiologically confirmed tumor response rate was 35.8% among 265 patients randomized to receive oral paclitaxel plus encequidar, compared with 23.4% among 137 who received intravenous paclitaxel – a statistically significant 12.4% difference, Gerardo Umanzor, MD, reported at the San Antonio Breast Cancer Symposium.

In the prespecified modified intent-to-treat (mITT) population of patients who had evaluable scans at baseline and who received at least seven doses of oral therapy or one dose of intravenous therapy, the corresponding confirmed tumor response rates were 40.4% and 25.5% (absolute improvement, 14.8%), said Dr. Umanzor, a medical oncologist with Liga Contra el Cancer in San Pedro Sulas, Honduras.

Tumor responses in all clinically important subgroups were consistent with the overall confirmed response profiles, he said, noting that the responses were durable, with ongoing analyses showing median response durations of 39.0 weeks versus 30.1 weeks with oral versus intravenous therapy.

Further, a higher percentage of oral versus intravenous paclitaxel recipients were receiving ongoing treatment at the time of the study endpoint (19% vs. 13%, respectively), he said.

Progression-free survival also showed a trend toward improved outcome with oral therapy in ongoing analyses in the mITT population (9.3 vs. 8.3 months, respectively), and an early analysis of overall survival also showed significant improvement (27.9 vs. 16.9 months; P = .035), he said.

Oral paclitaxel also was associated with a lower incidence of chemotherapy-induced peripheral neuropathy – a “highly debilitating side effect of IV paclitaxel,” he said, adding that “the difference between the arms is quite dramatic.”

The overall rates of neuropathy to week 23 were 17% versus 15% with oral versus intravenous therapy, and the rates of grade 3 neuropathy were 1% versus 8%, he said.

Alopecia incidence was reduced by about 50% with oral versus intravenous therapy, he added.

Toxicity was generally similar in the two groups, although the oral paclitaxel patients experienced higher rates of neutropenia and gastrointestinal effects. “These were low grade and manageable,” Dr. Umanzor said.

Study participants were patients with any type of metastatic breast cancer randomized 2:1 to receive a 15-mg tablet of encequidar followed by 205 mg/m² of oral paclitaxel (about 11 capsules, each containing 30 mg of solubilized paclitaxel) for 3 consecutive days each week for 3 weeks or intravenous paclitaxel at the labeled dose of 175 mg/m² over a 3-hour infusion every 3 weeks.

Confirmed tumor response rates were based on blinded assessment at two consecutive time points, 3-6 weeks apart, by study day 160.

The treatment groups were similar with respect to demographic characteristics and prior taxane therapy, he noted.

The findings have important implications, because while intravenous paclitaxel is an efficacious chemotherapeutic agent against metastatic breast cancer and multiple other cancers, it is associated in some patients with neuropathy.

“As an oncologist, it has been very frustrating to have an effective chemotherapy like paclitaxel, which a lot of patients cannot tolerate,” Dr. Umanzor said, noting that, in addition to eliminating the need for intravenous access and the risk of infusion hypersensitivity reactions, oral administration offers a number of potential benefits – particularly patient convenience.

Hypothesizing that the lower peak concentration of oral paclitaxel might result in lower systemic toxicity, Dr. Umanzor and colleagues developed the orally administered paclitaxel regimen used in this study to test that hypothesis. The paclitaxel was made bioavailable through combination with the encequidar, which promotes paclitaxel absorption into the blood stream, he explained, noting that the pharmacokinetic exposure matches that of intravenous paclitaxel when given at 80 mg/m², but with peak concentrations that are approximately one-tenth of those seen with intravenous therapy.

In a phase 2 study of 26 patients with heavily pretreated metastatic breast cancer, the oral therapy was associated with an encouraging 42.3% partial response rate and a 46.2% stable disease rate, he said.

The oral paclitaxel plus encequidar combination used in this pivotal study is the first orally administered taxane to demonstrate improved and durable overall confirmed response rates with minimal clinically meaningful neuropathy, compared with intravenous paclitaxel given every 3 weeks, he said.

“Oral paclitaxel and encequidar provides an important oral therapeutic option for patients with metastatic breast cancer, representing a meaningful improvement in the clinical profile of paclitaxel,” he said.

He further noted in a press release that “[t]his oral form of paclitaxel provides a new therapeutic option for patients, in particular, for those who cannot easily travel. While blood counts still need to be monitored, oral administration allows patients to remain home during therapy, and avoid spending significant time in the chemotherapy unit.”

The next step will be testing the tolerability of oral paclitaxel in patients at high risk of developing peripheral neuropathy, he said, adding that the findings could also open the door for assessing this approach with other taxanes.

During a press briefing on the findings at the symposium, several attendees voiced concerns about patient compliance given the large number of capsules required for oral dosing, but Dr. Umanzor said “there were no complaints at all and no issues with adherence.”

“Patients were so excited that they were getting an oral treatment, and we had very good compliance,” he said.

The study was funded by Athenex, the maker of the oral form of paclitaxel. Dr. Umanzor reported having no conflicts of interest.

SOURCE: Umanzor G et al. SABCS 2019, Abstract GS6-01.

SAN ANTONIO – For postmenopausal women with hormone receptor–positive, HER2-negative breast cancer that has progressed on aromatase inhibitor therapy, the combination of palbociclib with either exemestane or fulvestrant was not better than capecitabine at delaying progression or inducing clinical responses, results of the phase 3 PEARL trial showed.

At a median follow-up of 13.45 months there was no significant difference in progression-free survival (PFS) for patients treated with either fulvestrant (Faslodex) or exemestane (Aromasin) plus palbociclib (Ibrance) or with capecitabine (Xeloda) alone, nor was there a difference in PFS between patients with mutated or wild-type ESR1, reported Miguel Martin, MD, PhD, from the Gregorio Marañón Health Research Institute in Madrid.

“Palbociclib plus endocrine therapy is one of the standards of care today for patients with prior aromatase inhibitor [therapy] in the metastatic setting, and capecitabine as well is another option for this population, since it produces significant activity and a significant proportion of responses in patients with metastatic breast cancer. But we don’t know actually the relative efficacy of each therapy versus the other,” he said at the San Antonio Breast Cancer Symposium.

The phase 3 PEARL study was a head-to-head comparison of the two regimens in women with hormone receptor (HR)–positive, HER2-negative metastatic breast cancer that had progressed on aromatase inhibitors (AIs).

The study was originally designed to test the combination of palbociclib and exemestane versus capecitabine, and 296 patients were enrolled (cohort 1).

The study was modified in 2016, however, following evidence that mutations in ESR1 are a major mechanism of resistance to AIs in patients with metastatic disease, and that fulvestrant, a selective estrogen receptor down-regulator, did not appear to have cross-resistance to either tamoxifen or AIs, and may be active against tumors with ESR1 mutations. Therefore, a second cohort of 305 patients was enrolled to test palbociclib plus fulvestrant versus capecitabine.

Each cohort included patients with HR-positive, HER2-negative metastatic breast cancer that had recurred within 1 year of completed adjuvant therapy with nonsteroidal AIs, or progression within 1 month of completing adjuvant AIs for advanced disease. Patients could have received one prior line of chemotherapy for metastatic disease, but no prior capecitabine, exemestane (in cohort 1), or fulvestrant (in cohort 2)

In each cohort, patients were stratified by visceral or nonvisceral metastases, prior sensitivity to hormonal therapy (yes or no), and prior chemotherapy for metastatic breast cancer, and then randomized on a 1:1 basis to capecitabine 1,250 mg/m² (1,000 mg/m² for patients older than 70 years) twice daily 2 weeks on, 1 week off every 21 days; to palbociclib 125 mg 3 weeks on, 1 week off every 28 days plus exemestane 25 mg daily in cohort 1; or to fulvestrant 500 mg on days 1 and 15 of cycle 1 and then once every 28 days.

The trial did not meet its coprimary endpoints of superior PFS with palbociclib/fulvestrant regardless of ESR1 mutational status, or superior PFS with palbociclib and either partners in patients with ESR1 wild-type tumors.

In cohort 2, after a median follow-up of 13.47 months, the median PFS with palbociclib/fulvestrant was 7.5 months versus 10 months with capecitabine, with a nonsignificant hazard ratio.

Similarly, in cohort 1 (patients with wild-type ESR1), the median PFS at a median follow-up of 18.89 months was 8.0 months with palbociclib plus endocrine therapy versus 10.6 months with capecitabine.

For the secondary endpoint of PFS in the combined cohorts, the median overall PFS after a median 17.64 months of follow-up was 7.4 versus 9.4 months, respectively.

There were no significant differences by intrinsic breast cancer subtypes expect for nonluminal breast cancer, for which capecitabine had a significantly better benefit (P = .008 in cohort 2, and .002 for patients with ESR1 wild type).

Objective response rates in both cohorts trended in favor of capecitabine, but neither trend was statistically significant.

The palbociclib-containing regimens were, however, generally better tolerated than capecitabine, with a lower frequency of treatment discontinuations (3.7% with palbociclib plus endocrine therapy vs. 12.8% with capecitabine) and a smaller proportion of patients with serious adverse events (3.7% vs. 10.4%, respectively).

In the question and response following his presentation, perennial SABCS provocateur Steven “Vogl New York” Vogl, MD, of Montefiore Medical Center asked Dr. Martin: “Did you really give the capecitabine for a median of 18 months because that was the time to progression?”

Dr. Vogl commented that 18 months “is a very long time to keep a patient on drugs that make their palms sore, give them diarrhea, give them rashes, and sore mouths. So were the Spanish doctors particularly smart about reducing the doses?”

Dr. Martin replied that in his experience patients could be maintained on capecitabine for more than 4 years, with dose adjustments for those who develop palmar or plantar problems or other side effects, but “many patients prefer that to alopecia, to vomiting, to IV injections, so in my view capecitabine is a great drug for luminal metastatic breast cancer cases, and we can keep the drug going for many, many months in most patients.”

The study was funded by Pfizer. Dr. Martin disclosed speaker honoraria and consulting fees from Pfizer and others.

SOURCE: Martin M et al. SABCS 2019. Abstract GS2-07

SAN ANTONIO – For postmenopausal women with hormone receptor–positive, HER2-negative breast cancer that has progressed on aromatase inhibitor therapy, the combination of palbociclib with either exemestane or fulvestrant was not better than capecitabine at delaying progression or inducing clinical responses, results of the phase 3 PEARL trial showed.

At a median follow-up of 13.45 months there was no significant difference in progression-free survival (PFS) for patients treated with either fulvestrant (Faslodex) or exemestane (Aromasin) plus palbociclib (Ibrance) or with capecitabine (Xeloda) alone, nor was there a difference in PFS between patients with mutated or wild-type ESR1, reported Miguel Martin, MD, PhD, from the Gregorio Marañón Health Research Institute in Madrid.

“Palbociclib plus endocrine therapy is one of the standards of care today for patients with prior aromatase inhibitor [therapy] in the metastatic setting, and capecitabine as well is another option for this population, since it produces significant activity and a significant proportion of responses in patients with metastatic breast cancer. But we don’t know actually the relative efficacy of each therapy versus the other,” he said at the San Antonio Breast Cancer Symposium.

The phase 3 PEARL study was a head-to-head comparison of the two regimens in women with hormone receptor (HR)–positive, HER2-negative metastatic breast cancer that had progressed on aromatase inhibitors (AIs).

The study was originally designed to test the combination of palbociclib and exemestane versus capecitabine, and 296 patients were enrolled (cohort 1).

The study was modified in 2016, however, following evidence that mutations in ESR1 are a major mechanism of resistance to AIs in patients with metastatic disease, and that fulvestrant, a selective estrogen receptor down-regulator, did not appear to have cross-resistance to either tamoxifen or AIs, and may be active against tumors with ESR1 mutations. Therefore, a second cohort of 305 patients was enrolled to test palbociclib plus fulvestrant versus capecitabine.

Each cohort included patients with HR-positive, HER2-negative metastatic breast cancer that had recurred within 1 year of completed adjuvant therapy with nonsteroidal AIs, or progression within 1 month of completing adjuvant AIs for advanced disease. Patients could have received one prior line of chemotherapy for metastatic disease, but no prior capecitabine, exemestane (in cohort 1), or fulvestrant (in cohort 2)

In each cohort, patients were stratified by visceral or nonvisceral metastases, prior sensitivity to hormonal therapy (yes or no), and prior chemotherapy for metastatic breast cancer, and then randomized on a 1:1 basis to capecitabine 1,250 mg/m² (1,000 mg/m² for patients older than 70 years) twice daily 2 weeks on, 1 week off every 21 days; to palbociclib 125 mg 3 weeks on, 1 week off every 28 days plus exemestane 25 mg daily in cohort 1; or to fulvestrant 500 mg on days 1 and 15 of cycle 1 and then once every 28 days.

The trial did not meet its coprimary endpoints of superior PFS with palbociclib/fulvestrant regardless of ESR1 mutational status, or superior PFS with palbociclib and either partners in patients with ESR1 wild-type tumors.

In cohort 2, after a median follow-up of 13.47 months, the median PFS with palbociclib/fulvestrant was 7.5 months versus 10 months with capecitabine, with a nonsignificant hazard ratio.

Similarly, in cohort 1 (patients with wild-type ESR1), the median PFS at a median follow-up of 18.89 months was 8.0 months with palbociclib plus endocrine therapy versus 10.6 months with capecitabine.

For the secondary endpoint of PFS in the combined cohorts, the median overall PFS after a median 17.64 months of follow-up was 7.4 versus 9.4 months, respectively.

There were no significant differences by intrinsic breast cancer subtypes expect for nonluminal breast cancer, for which capecitabine had a significantly better benefit (P = .008 in cohort 2, and .002 for patients with ESR1 wild type).

Objective response rates in both cohorts trended in favor of capecitabine, but neither trend was statistically significant.

The palbociclib-containing regimens were, however, generally better tolerated than capecitabine, with a lower frequency of treatment discontinuations (3.7% with palbociclib plus endocrine therapy vs. 12.8% with capecitabine) and a smaller proportion of patients with serious adverse events (3.7% vs. 10.4%, respectively).

In the question and response following his presentation, perennial SABCS provocateur Steven “Vogl New York” Vogl, MD, of Montefiore Medical Center asked Dr. Martin: “Did you really give the capecitabine for a median of 18 months because that was the time to progression?”

Dr. Vogl commented that 18 months “is a very long time to keep a patient on drugs that make their palms sore, give them diarrhea, give them rashes, and sore mouths. So were the Spanish doctors particularly smart about reducing the doses?”

Dr. Martin replied that in his experience patients could be maintained on capecitabine for more than 4 years, with dose adjustments for those who develop palmar or plantar problems or other side effects, but “many patients prefer that to alopecia, to vomiting, to IV injections, so in my view capecitabine is a great drug for luminal metastatic breast cancer cases, and we can keep the drug going for many, many months in most patients.”

The study was funded by Pfizer. Dr. Martin disclosed speaker honoraria and consulting fees from Pfizer and others.

SOURCE: Martin M et al. SABCS 2019. Abstract GS2-07

SAN ANTONIO – For postmenopausal women with hormone receptor–positive, HER2-negative breast cancer that has progressed on aromatase inhibitor therapy, the combination of palbociclib with either exemestane or fulvestrant was not better than capecitabine at delaying progression or inducing clinical responses, results of the phase 3 PEARL trial showed.

At a median follow-up of 13.45 months there was no significant difference in progression-free survival (PFS) for patients treated with either fulvestrant (Faslodex) or exemestane (Aromasin) plus palbociclib (Ibrance) or with capecitabine (Xeloda) alone, nor was there a difference in PFS between patients with mutated or wild-type ESR1, reported Miguel Martin, MD, PhD, from the Gregorio Marañón Health Research Institute in Madrid.

“Palbociclib plus endocrine therapy is one of the standards of care today for patients with prior aromatase inhibitor [therapy] in the metastatic setting, and capecitabine as well is another option for this population, since it produces significant activity and a significant proportion of responses in patients with metastatic breast cancer. But we don’t know actually the relative efficacy of each therapy versus the other,” he said at the San Antonio Breast Cancer Symposium.

The phase 3 PEARL study was a head-to-head comparison of the two regimens in women with hormone receptor (HR)–positive, HER2-negative metastatic breast cancer that had progressed on aromatase inhibitors (AIs).

The study was originally designed to test the combination of palbociclib and exemestane versus capecitabine, and 296 patients were enrolled (cohort 1).

The study was modified in 2016, however, following evidence that mutations in ESR1 are a major mechanism of resistance to AIs in patients with metastatic disease, and that fulvestrant, a selective estrogen receptor down-regulator, did not appear to have cross-resistance to either tamoxifen or AIs, and may be active against tumors with ESR1 mutations. Therefore, a second cohort of 305 patients was enrolled to test palbociclib plus fulvestrant versus capecitabine.

Each cohort included patients with HR-positive, HER2-negative metastatic breast cancer that had recurred within 1 year of completed adjuvant therapy with nonsteroidal AIs, or progression within 1 month of completing adjuvant AIs for advanced disease. Patients could have received one prior line of chemotherapy for metastatic disease, but no prior capecitabine, exemestane (in cohort 1), or fulvestrant (in cohort 2)

In each cohort, patients were stratified by visceral or nonvisceral metastases, prior sensitivity to hormonal therapy (yes or no), and prior chemotherapy for metastatic breast cancer, and then randomized on a 1:1 basis to capecitabine 1,250 mg/m² (1,000 mg/m² for patients older than 70 years) twice daily 2 weeks on, 1 week off every 21 days; to palbociclib 125 mg 3 weeks on, 1 week off every 28 days plus exemestane 25 mg daily in cohort 1; or to fulvestrant 500 mg on days 1 and 15 of cycle 1 and then once every 28 days.

The trial did not meet its coprimary endpoints of superior PFS with palbociclib/fulvestrant regardless of ESR1 mutational status, or superior PFS with palbociclib and either partners in patients with ESR1 wild-type tumors.

In cohort 2, after a median follow-up of 13.47 months, the median PFS with palbociclib/fulvestrant was 7.5 months versus 10 months with capecitabine, with a nonsignificant hazard ratio.

Similarly, in cohort 1 (patients with wild-type ESR1), the median PFS at a median follow-up of 18.89 months was 8.0 months with palbociclib plus endocrine therapy versus 10.6 months with capecitabine.

For the secondary endpoint of PFS in the combined cohorts, the median overall PFS after a median 17.64 months of follow-up was 7.4 versus 9.4 months, respectively.

There were no significant differences by intrinsic breast cancer subtypes expect for nonluminal breast cancer, for which capecitabine had a significantly better benefit (P = .008 in cohort 2, and .002 for patients with ESR1 wild type).

Objective response rates in both cohorts trended in favor of capecitabine, but neither trend was statistically significant.

The palbociclib-containing regimens were, however, generally better tolerated than capecitabine, with a lower frequency of treatment discontinuations (3.7% with palbociclib plus endocrine therapy vs. 12.8% with capecitabine) and a smaller proportion of patients with serious adverse events (3.7% vs. 10.4%, respectively).

In the question and response following his presentation, perennial SABCS provocateur Steven “Vogl New York” Vogl, MD, of Montefiore Medical Center asked Dr. Martin: “Did you really give the capecitabine for a median of 18 months because that was the time to progression?”

Dr. Vogl commented that 18 months “is a very long time to keep a patient on drugs that make their palms sore, give them diarrhea, give them rashes, and sore mouths. So were the Spanish doctors particularly smart about reducing the doses?”

Dr. Martin replied that in his experience patients could be maintained on capecitabine for more than 4 years, with dose adjustments for those who develop palmar or plantar problems or other side effects, but “many patients prefer that to alopecia, to vomiting, to IV injections, so in my view capecitabine is a great drug for luminal metastatic breast cancer cases, and we can keep the drug going for many, many months in most patients.”

The study was funded by Pfizer. Dr. Martin disclosed speaker honoraria and consulting fees from Pfizer and others.

SOURCE: Martin M et al. SABCS 2019. Abstract GS2-07

SAN ANTONIO – In the neoadjuvant setting, weekly nab-paclitaxel outmatches a “two-out-of-three” regimen for patients with early-stage triple-negative breast cancer (TNBC), based on results from the phase 3 GeparX trial.

In contrast, neoadjuvant denosumab had no impact on pathologic complete response (pCR), according to lead author Jens-Uwe Blohmer, MD, of Charité University Medical Center in Berlin.

Will Pass/MDedge News

“The anti-cancer activity of RANK-ligand inhibition with denosumab is still under discussion,” Dr. Blohmer said while presenting findings at the San Antonio Breast Cancer Symposium. “The GeparSepto study demonstrated an increased pCR rate with weekly nab-paclitaxel but it remained unclear which schedule should be preferred for nab-paclitaxel in terms of toxicity and efficacy. And that is why the GeparX study addresses both questions in a two-by-two factorial design.”

GeparX involved 780 patients with early breast cancer who were stratified by subtype, stromal tumor-infiltrating lymphocytes (sTILs), and epirubicin/cyclophosphamide (EC) schedule. Following randomization, nab-paclitaxel was delivered at a dose of 125 mg/m² on a weekly basis or on days 1 and 8 on a 22-day cycle (two-out-of-three schedule) for 12 weeks, followed by an additional 12 weeks of EC (90/600 mg/m² every 2 weeks or 3 weeks). Each of these regimens was given with or without denosumab, which when delivered, was given at a dose of 120 mg every 4 weeks throughout the 24-week treatment period. Patients with HER2-positive breast cancer were also given trastuzumab plus pertuzumab, whereas women with TNBC received carboplatin plus taxane-based chemotherapy. All patients underwent surgery after treatment, at which point pCR rate, the primary endpoint, was determined. Of note, the prespecified significance level was higher than typical for oncology trials (alpha = .1).

At baseline, patient characteristics were comparable across the treatment arms. Median age was 49 years; 40% of patients had positive clinical nodal status; 83% of patients had Ki-67 expression greater than 20%; and 8% of patients had sTIL expression greater than 50%. The most common disease subtypes were triple-negative (40.6%) and HER2-positive/HR-positive (39.7%), followed by HER2-positive/HR-negative (19.6%).

Across subtypes, weekly nab-paclitaxel was associated with a significantly higher pCR rate than the two-out-of-three schedule (44.9% vs. 39%; P = .062). Denosumab had no such benefit; pCR rate with denosumab was 41.0%, versus 42.8% without denosumab, a slight difference that lacked statistical significance (P = .582).

A closer look at the nab-paclitaxel subtype data showed that patients with TNBC were deriving significant benefit from the weekly regimen instead of the two-out-of-three schedule (60.4% vs. 50.0%; P = .056), while patients with either of other two subtypes were not.

Although weekly dosing of nab-paclitaxel was superior from the standpoint of pCR, this efficacy advantage came with some trade-offs in tolerability. In the weekly group, 20.6% of patients discontinued nab-paclitaxel, compared with just 6.3% of patients in the two-out-of-three group. Discontinuations were most often due to adverse events, which occurred at a rate of 17.5% in the weekly arm, versus 3.7% among patients given the two-out-of-three regimen. Serious adverse events were also more common in the weekly cohort (31.5% vs. 24.4%).

Concluding his presentation, Dr. Blohmer summarized the key clinical finding.

“In triple-negative breast cancer, optimized neoadjuvant chemotherapy with nab-paclitaxel 125 mg/m² weekly plus carboplatin followed by EC achieves a remarkable pCR rate of at least 60%,” Dr. Blohmer said, adding that further translational research is ongoing.

Following the presentation, perennial symposium fixture Steven Vogl, MD, a practicing oncologist in New York, raised concerns about diminished quality of life that may result from the proposed nab-paclitaxel regimen.

“I really want to know how many patients had prolonged and significant neuropathy after they were finished,” Dr. Vogl said. “In the previous GBG trial, where 125 [mg/m²] of nab-paclitaxel was actually reduced from 150 [mg/m²], some of us thought that was too much neuropathy to give to our patients, because the ones who survived were moderately miserable. Survival and moderately miserable isn’t good enough. How many people had prolonged neuropathy?”

Dr. Blohmer acknowledged this concern.

“It is an excellent question, like I expected,” Dr. Blohmer said. “[Neuropathy] was one of our secondary study endpoints, but we haven’t yet the results. ... We will present our data later, at least, during our full publication.”

The study was funded by Amgen and Celgene. The investigators reported additional relationships with AstraZeneca, Pfizer, Pharma Mar, Daiichi Sankyo, and others.

SOURCE: Blohmer et al. SABCS. 2019 Dec 12. Abstract GS3-01.

SAN ANTONIO – In the neoadjuvant setting, weekly nab-paclitaxel outmatches a “two-out-of-three” regimen for patients with early-stage triple-negative breast cancer (TNBC), based on results from the phase 3 GeparX trial.

In contrast, neoadjuvant denosumab had no impact on pathologic complete response (pCR), according to lead author Jens-Uwe Blohmer, MD, of Charité University Medical Center in Berlin.

Will Pass/MDedge News

“The anti-cancer activity of RANK-ligand inhibition with denosumab is still under discussion,” Dr. Blohmer said while presenting findings at the San Antonio Breast Cancer Symposium. “The GeparSepto study demonstrated an increased pCR rate with weekly nab-paclitaxel but it remained unclear which schedule should be preferred for nab-paclitaxel in terms of toxicity and efficacy. And that is why the GeparX study addresses both questions in a two-by-two factorial design.”

GeparX involved 780 patients with early breast cancer who were stratified by subtype, stromal tumor-infiltrating lymphocytes (sTILs), and epirubicin/cyclophosphamide (EC) schedule. Following randomization, nab-paclitaxel was delivered at a dose of 125 mg/m² on a weekly basis or on days 1 and 8 on a 22-day cycle (two-out-of-three schedule) for 12 weeks, followed by an additional 12 weeks of EC (90/600 mg/m² every 2 weeks or 3 weeks). Each of these regimens was given with or without denosumab, which when delivered, was given at a dose of 120 mg every 4 weeks throughout the 24-week treatment period. Patients with HER2-positive breast cancer were also given trastuzumab plus pertuzumab, whereas women with TNBC received carboplatin plus taxane-based chemotherapy. All patients underwent surgery after treatment, at which point pCR rate, the primary endpoint, was determined. Of note, the prespecified significance level was higher than typical for oncology trials (alpha = .1).

At baseline, patient characteristics were comparable across the treatment arms. Median age was 49 years; 40% of patients had positive clinical nodal status; 83% of patients had Ki-67 expression greater than 20%; and 8% of patients had sTIL expression greater than 50%. The most common disease subtypes were triple-negative (40.6%) and HER2-positive/HR-positive (39.7%), followed by HER2-positive/HR-negative (19.6%).

Across subtypes, weekly nab-paclitaxel was associated with a significantly higher pCR rate than the two-out-of-three schedule (44.9% vs. 39%; P = .062). Denosumab had no such benefit; pCR rate with denosumab was 41.0%, versus 42.8% without denosumab, a slight difference that lacked statistical significance (P = .582).

A closer look at the nab-paclitaxel subtype data showed that patients with TNBC were deriving significant benefit from the weekly regimen instead of the two-out-of-three schedule (60.4% vs. 50.0%; P = .056), while patients with either of other two subtypes were not.

Although weekly dosing of nab-paclitaxel was superior from the standpoint of pCR, this efficacy advantage came with some trade-offs in tolerability. In the weekly group, 20.6% of patients discontinued nab-paclitaxel, compared with just 6.3% of patients in the two-out-of-three group. Discontinuations were most often due to adverse events, which occurred at a rate of 17.5% in the weekly arm, versus 3.7% among patients given the two-out-of-three regimen. Serious adverse events were also more common in the weekly cohort (31.5% vs. 24.4%).

Concluding his presentation, Dr. Blohmer summarized the key clinical finding.

“In triple-negative breast cancer, optimized neoadjuvant chemotherapy with nab-paclitaxel 125 mg/m² weekly plus carboplatin followed by EC achieves a remarkable pCR rate of at least 60%,” Dr. Blohmer said, adding that further translational research is ongoing.

Following the presentation, perennial symposium fixture Steven Vogl, MD, a practicing oncologist in New York, raised concerns about diminished quality of life that may result from the proposed nab-paclitaxel regimen.

“I really want to know how many patients had prolonged and significant neuropathy after they were finished,” Dr. Vogl said. “In the previous GBG trial, where 125 [mg/m²] of nab-paclitaxel was actually reduced from 150 [mg/m²], some of us thought that was too much neuropathy to give to our patients, because the ones who survived were moderately miserable. Survival and moderately miserable isn’t good enough. How many people had prolonged neuropathy?”

Dr. Blohmer acknowledged this concern.

“It is an excellent question, like I expected,” Dr. Blohmer said. “[Neuropathy] was one of our secondary study endpoints, but we haven’t yet the results. ... We will present our data later, at least, during our full publication.”

The study was funded by Amgen and Celgene. The investigators reported additional relationships with AstraZeneca, Pfizer, Pharma Mar, Daiichi Sankyo, and others.

SOURCE: Blohmer et al. SABCS. 2019 Dec 12. Abstract GS3-01.

SAN ANTONIO – In the neoadjuvant setting, weekly nab-paclitaxel outmatches a “two-out-of-three” regimen for patients with early-stage triple-negative breast cancer (TNBC), based on results from the phase 3 GeparX trial.

In contrast, neoadjuvant denosumab had no impact on pathologic complete response (pCR), according to lead author Jens-Uwe Blohmer, MD, of Charité University Medical Center in Berlin.

Will Pass/MDedge News

“The anti-cancer activity of RANK-ligand inhibition with denosumab is still under discussion,” Dr. Blohmer said while presenting findings at the San Antonio Breast Cancer Symposium. “The GeparSepto study demonstrated an increased pCR rate with weekly nab-paclitaxel but it remained unclear which schedule should be preferred for nab-paclitaxel in terms of toxicity and efficacy. And that is why the GeparX study addresses both questions in a two-by-two factorial design.”

GeparX involved 780 patients with early breast cancer who were stratified by subtype, stromal tumor-infiltrating lymphocytes (sTILs), and epirubicin/cyclophosphamide (EC) schedule. Following randomization, nab-paclitaxel was delivered at a dose of 125 mg/m² on a weekly basis or on days 1 and 8 on a 22-day cycle (two-out-of-three schedule) for 12 weeks, followed by an additional 12 weeks of EC (90/600 mg/m² every 2 weeks or 3 weeks). Each of these regimens was given with or without denosumab, which when delivered, was given at a dose of 120 mg every 4 weeks throughout the 24-week treatment period. Patients with HER2-positive breast cancer were also given trastuzumab plus pertuzumab, whereas women with TNBC received carboplatin plus taxane-based chemotherapy. All patients underwent surgery after treatment, at which point pCR rate, the primary endpoint, was determined. Of note, the prespecified significance level was higher than typical for oncology trials (alpha = .1).

At baseline, patient characteristics were comparable across the treatment arms. Median age was 49 years; 40% of patients had positive clinical nodal status; 83% of patients had Ki-67 expression greater than 20%; and 8% of patients had sTIL expression greater than 50%. The most common disease subtypes were triple-negative (40.6%) and HER2-positive/HR-positive (39.7%), followed by HER2-positive/HR-negative (19.6%).

Across subtypes, weekly nab-paclitaxel was associated with a significantly higher pCR rate than the two-out-of-three schedule (44.9% vs. 39%; P = .062). Denosumab had no such benefit; pCR rate with denosumab was 41.0%, versus 42.8% without denosumab, a slight difference that lacked statistical significance (P = .582).

A closer look at the nab-paclitaxel subtype data showed that patients with TNBC were deriving significant benefit from the weekly regimen instead of the two-out-of-three schedule (60.4% vs. 50.0%; P = .056), while patients with either of other two subtypes were not.

Although weekly dosing of nab-paclitaxel was superior from the standpoint of pCR, this efficacy advantage came with some trade-offs in tolerability. In the weekly group, 20.6% of patients discontinued nab-paclitaxel, compared with just 6.3% of patients in the two-out-of-three group. Discontinuations were most often due to adverse events, which occurred at a rate of 17.5% in the weekly arm, versus 3.7% among patients given the two-out-of-three regimen. Serious adverse events were also more common in the weekly cohort (31.5% vs. 24.4%).

Concluding his presentation, Dr. Blohmer summarized the key clinical finding.

“In triple-negative breast cancer, optimized neoadjuvant chemotherapy with nab-paclitaxel 125 mg/m² weekly plus carboplatin followed by EC achieves a remarkable pCR rate of at least 60%,” Dr. Blohmer said, adding that further translational research is ongoing.

Following the presentation, perennial symposium fixture Steven Vogl, MD, a practicing oncologist in New York, raised concerns about diminished quality of life that may result from the proposed nab-paclitaxel regimen.

“I really want to know how many patients had prolonged and significant neuropathy after they were finished,” Dr. Vogl said. “In the previous GBG trial, where 125 [mg/m²] of nab-paclitaxel was actually reduced from 150 [mg/m²], some of us thought that was too much neuropathy to give to our patients, because the ones who survived were moderately miserable. Survival and moderately miserable isn’t good enough. How many people had prolonged neuropathy?”

Dr. Blohmer acknowledged this concern.

“It is an excellent question, like I expected,” Dr. Blohmer said. “[Neuropathy] was one of our secondary study endpoints, but we haven’t yet the results. ... We will present our data later, at least, during our full publication.”

The study was funded by Amgen and Celgene. The investigators reported additional relationships with AstraZeneca, Pfizer, Pharma Mar, Daiichi Sankyo, and others.

SOURCE: Blohmer et al. SABCS. 2019 Dec 12. Abstract GS3-01.

SAN ANTONIO – Adding atezolizumab, an anti–programmed death-ligand 1 (PD-L1) monoclonal antibody, to neoadjuvant chemotherapy failed to significantly improve pathologic complete response (pCR) rates in women with triple-negative breast cancer in the randomized NeoTRIPaPDL1 trial.

Sharon Worcester/MDedge News

A slight improvement in pCR rates, which is a secondary study endpoint, was seen in the subgroup of PD-L1-positive women, but the difference in that group also failed to reach statistical significance, Luca Gianni, MD, said at the San Antonio Breast Cancer Symposium where he reported these initial results from the open-label multicenter trial.

“In the intent-to-treat analysis, the rate of pathological complete response was 43.5% with atezolizumab, and 40.8% without atezolizumab, for a net difference of 2.63% and an odds ratio of 1.11,” said Dr. Gianni, president of the Fondazione Michelangelo in Milan.

Among patients whose tumors tested positive for PD-L1, the pCR rates were 51.9 and 48.0% with atezolizumab versus without, but this difference was also not significant.

On multivariate analysis accounting for treatment group, PD-L1 expression, and disease stage, the only variable significantly associated with the pCR rate was PD-L1 positivity, and this association was similar in both treatment groups, he noted (odds ratio, 2.08).

“The same trend toward a numerically higher rate of clinical overall response with atezolizumab was observed on clinical grounds, but again, at 76.1% vs. 68.3% – not statistically significant,” he said.

The complete response rates with atezolizumab versus without were 29% vs. 26.1% and the partial response rates were 47.1% vs. 42.3%, respectively; 3.6% vs. 4.9% of patients in the groups had stable disease, and 5.8% vs. 8.4% had progressive disease.

The NeoTRIPaPDL1 study enrolled 280 adult women with HER2-negative, estrogen receptor– and progesterone receptor–negative early high-risk or locally advanced unilateral triple-negative breast cancer (TNBC). Participants were randomized to receive neoadjuvant carboplatin AUC 2 and intravenous abraxane at a dose of 125 mg/m² on days 1 and 8 either with or without 1,200 mg of IV atezolizumab on day 1. Both regimens were given every 3 weeks for eight cycles, followed by surgery and four cycles of an investigator-selected anthracycline regimen.

The primary study endpoint is event-free survival at 5 years after randomization of the last patient, but this initial report from the trial focused on pCR, Dr. Gianni said.

Tolerability of treatment was similar with both regimens, except for an increase in abnormal liver transaminases “that tended to be significantly more frequent with atezolizumab administration,” he said, noting that the “toxicity was very short lived and didn’t limit the possibility of administering the drug.”

“Immune-mediated adverse events and infusion reactions clustered around the atezolizumab arm, as expected, and mostly consisted of infusion reactions and hypothyroidism,” he added.

Infusion reactions occurred in 8.0% and 5.7% of patients in the atezolizumab versus no atezolizumab groups, and grade 3 or greater infusion reactions occurred in 1.4% versus 0.7%. Hypothyroidism occurred in 5.8% and 1.4%, respectively, with no grade 3 or greater events.

“All other toxicities were either mild or very rare,” he noted.

TNBC is an aggressive subtype of breast cancer with poor prognosis. Progression to distant metastases is often rapid, as is development of resistance chemotherapy, Dr. Gianni explained, adding that chemotherapy is currently the only treatment for early-stage TNBC.

Chemotherapy works in some patients, but relapse and resistance are common even after good initial responses; therefore, he and his colleagues examined the effects of immune checkpoint inhibition added to neoadjuvant chemotherapy, reasoning that the combination might boost the antitumor immune response.

Atezolizumab in combination with nab-paclitaxel is now approved by the Food and Drug Administration for the treatment of some patients with locally advanced or metastatic TNBC. The approval was based on findings from the IMpassion130 study showing a significant progression-free and overall survival benefit with atezolizumab when added to nab-paclitaxel in PD-L1-positive metastatic TNBC.

In a press statement, Dr. Gianni noted that the pCR findings he reported from the NeoTRIPaPDL1 study “may indicate that there is no therapeutic benefit to adding atezolizumab to neoadjuvant chemotherapy compared to chemotherapy alone, or may simply mean that any beneficial effects of the combination will be seen in the long term.”

“Pathologic complete response does not provide information about the quality of response, which is why we did not use it as the primary endpoint for this study. Further analyses may reveal differences in the quality of response between the treatment groups,” he added, noting that the study is limited in that reported results apply only to the initial effects of the combination treatment and do not account for effects of therapies administered after surgery.

Follow-up for the primary endpoint of event-free survival and other efficacy endpoints in the NeoTRIPaPDL1 trial is ongoing, and molecular studies are also underway, Dr. Gianni said.

Biological samples collected from patients before, during, and after neoadjuvant treatment are being examined for lymphocyte infiltration, DNA mutations, and/or levels of circulating tumor DNA, and may reveal differences between the treatment groups, he explained.

This study was sponsored by Roche and Celgene. Dr. Gianni has been an advisor and/or consultant for numerous pharmaceutical companies. He has received support for research from Daiichi Sankyo, Zymeworks, and Revolution Medicines and is a coinventor on a patent for PD-L1 expression in anti-HER2 therapy.

[email protected]

SOURCE: Gianni L et al. SABCS 2019. Abstract GS3-04.

SAN ANTONIO – Adding atezolizumab, an anti–programmed death-ligand 1 (PD-L1) monoclonal antibody, to neoadjuvant chemotherapy failed to significantly improve pathologic complete response (pCR) rates in women with triple-negative breast cancer in the randomized NeoTRIPaPDL1 trial.

Sharon Worcester/MDedge News

A slight improvement in pCR rates, which is a secondary study endpoint, was seen in the subgroup of PD-L1-positive women, but the difference in that group also failed to reach statistical significance, Luca Gianni, MD, said at the San Antonio Breast Cancer Symposium where he reported these initial results from the open-label multicenter trial.

“In the intent-to-treat analysis, the rate of pathological complete response was 43.5% with atezolizumab, and 40.8% without atezolizumab, for a net difference of 2.63% and an odds ratio of 1.11,” said Dr. Gianni, president of the Fondazione Michelangelo in Milan.

Among patients whose tumors tested positive for PD-L1, the pCR rates were 51.9 and 48.0% with atezolizumab versus without, but this difference was also not significant.

On multivariate analysis accounting for treatment group, PD-L1 expression, and disease stage, the only variable significantly associated with the pCR rate was PD-L1 positivity, and this association was similar in both treatment groups, he noted (odds ratio, 2.08).

“The same trend toward a numerically higher rate of clinical overall response with atezolizumab was observed on clinical grounds, but again, at 76.1% vs. 68.3% – not statistically significant,” he said.

The complete response rates with atezolizumab versus without were 29% vs. 26.1% and the partial response rates were 47.1% vs. 42.3%, respectively; 3.6% vs. 4.9% of patients in the groups had stable disease, and 5.8% vs. 8.4% had progressive disease.

The NeoTRIPaPDL1 study enrolled 280 adult women with HER2-negative, estrogen receptor– and progesterone receptor–negative early high-risk or locally advanced unilateral triple-negative breast cancer (TNBC). Participants were randomized to receive neoadjuvant carboplatin AUC 2 and intravenous abraxane at a dose of 125 mg/m² on days 1 and 8 either with or without 1,200 mg of IV atezolizumab on day 1. Both regimens were given every 3 weeks for eight cycles, followed by surgery and four cycles of an investigator-selected anthracycline regimen.

The primary study endpoint is event-free survival at 5 years after randomization of the last patient, but this initial report from the trial focused on pCR, Dr. Gianni said.

Tolerability of treatment was similar with both regimens, except for an increase in abnormal liver transaminases “that tended to be significantly more frequent with atezolizumab administration,” he said, noting that the “toxicity was very short lived and didn’t limit the possibility of administering the drug.”

“Immune-mediated adverse events and infusion reactions clustered around the atezolizumab arm, as expected, and mostly consisted of infusion reactions and hypothyroidism,” he added.

Infusion reactions occurred in 8.0% and 5.7% of patients in the atezolizumab versus no atezolizumab groups, and grade 3 or greater infusion reactions occurred in 1.4% versus 0.7%. Hypothyroidism occurred in 5.8% and 1.4%, respectively, with no grade 3 or greater events.

“All other toxicities were either mild or very rare,” he noted.

TNBC is an aggressive subtype of breast cancer with poor prognosis. Progression to distant metastases is often rapid, as is development of resistance chemotherapy, Dr. Gianni explained, adding that chemotherapy is currently the only treatment for early-stage TNBC.

Chemotherapy works in some patients, but relapse and resistance are common even after good initial responses; therefore, he and his colleagues examined the effects of immune checkpoint inhibition added to neoadjuvant chemotherapy, reasoning that the combination might boost the antitumor immune response.

Atezolizumab in combination with nab-paclitaxel is now approved by the Food and Drug Administration for the treatment of some patients with locally advanced or metastatic TNBC. The approval was based on findings from the IMpassion130 study showing a significant progression-free and overall survival benefit with atezolizumab when added to nab-paclitaxel in PD-L1-positive metastatic TNBC.

In a press statement, Dr. Gianni noted that the pCR findings he reported from the NeoTRIPaPDL1 study “may indicate that there is no therapeutic benefit to adding atezolizumab to neoadjuvant chemotherapy compared to chemotherapy alone, or may simply mean that any beneficial effects of the combination will be seen in the long term.”

“Pathologic complete response does not provide information about the quality of response, which is why we did not use it as the primary endpoint for this study. Further analyses may reveal differences in the quality of response between the treatment groups,” he added, noting that the study is limited in that reported results apply only to the initial effects of the combination treatment and do not account for effects of therapies administered after surgery.

Follow-up for the primary endpoint of event-free survival and other efficacy endpoints in the NeoTRIPaPDL1 trial is ongoing, and molecular studies are also underway, Dr. Gianni said.

Biological samples collected from patients before, during, and after neoadjuvant treatment are being examined for lymphocyte infiltration, DNA mutations, and/or levels of circulating tumor DNA, and may reveal differences between the treatment groups, he explained.

This study was sponsored by Roche and Celgene. Dr. Gianni has been an advisor and/or consultant for numerous pharmaceutical companies. He has received support for research from Daiichi Sankyo, Zymeworks, and Revolution Medicines and is a coinventor on a patent for PD-L1 expression in anti-HER2 therapy.

[email protected]

SOURCE: Gianni L et al. SABCS 2019. Abstract GS3-04.

SAN ANTONIO – Adding atezolizumab, an anti–programmed death-ligand 1 (PD-L1) monoclonal antibody, to neoadjuvant chemotherapy failed to significantly improve pathologic complete response (pCR) rates in women with triple-negative breast cancer in the randomized NeoTRIPaPDL1 trial.

Sharon Worcester/MDedge News

A slight improvement in pCR rates, which is a secondary study endpoint, was seen in the subgroup of PD-L1-positive women, but the difference in that group also failed to reach statistical significance, Luca Gianni, MD, said at the San Antonio Breast Cancer Symposium where he reported these initial results from the open-label multicenter trial.

“In the intent-to-treat analysis, the rate of pathological complete response was 43.5% with atezolizumab, and 40.8% without atezolizumab, for a net difference of 2.63% and an odds ratio of 1.11,” said Dr. Gianni, president of the Fondazione Michelangelo in Milan.

Among patients whose tumors tested positive for PD-L1, the pCR rates were 51.9 and 48.0% with atezolizumab versus without, but this difference was also not significant.

On multivariate analysis accounting for treatment group, PD-L1 expression, and disease stage, the only variable significantly associated with the pCR rate was PD-L1 positivity, and this association was similar in both treatment groups, he noted (odds ratio, 2.08).

“The same trend toward a numerically higher rate of clinical overall response with atezolizumab was observed on clinical grounds, but again, at 76.1% vs. 68.3% – not statistically significant,” he said.

The complete response rates with atezolizumab versus without were 29% vs. 26.1% and the partial response rates were 47.1% vs. 42.3%, respectively; 3.6% vs. 4.9% of patients in the groups had stable disease, and 5.8% vs. 8.4% had progressive disease.

The NeoTRIPaPDL1 study enrolled 280 adult women with HER2-negative, estrogen receptor– and progesterone receptor–negative early high-risk or locally advanced unilateral triple-negative breast cancer (TNBC). Participants were randomized to receive neoadjuvant carboplatin AUC 2 and intravenous abraxane at a dose of 125 mg/m² on days 1 and 8 either with or without 1,200 mg of IV atezolizumab on day 1. Both regimens were given every 3 weeks for eight cycles, followed by surgery and four cycles of an investigator-selected anthracycline regimen.

The primary study endpoint is event-free survival at 5 years after randomization of the last patient, but this initial report from the trial focused on pCR, Dr. Gianni said.

Tolerability of treatment was similar with both regimens, except for an increase in abnormal liver transaminases “that tended to be significantly more frequent with atezolizumab administration,” he said, noting that the “toxicity was very short lived and didn’t limit the possibility of administering the drug.”

“Immune-mediated adverse events and infusion reactions clustered around the atezolizumab arm, as expected, and mostly consisted of infusion reactions and hypothyroidism,” he added.

Infusion reactions occurred in 8.0% and 5.7% of patients in the atezolizumab versus no atezolizumab groups, and grade 3 or greater infusion reactions occurred in 1.4% versus 0.7%. Hypothyroidism occurred in 5.8% and 1.4%, respectively, with no grade 3 or greater events.

“All other toxicities were either mild or very rare,” he noted.

TNBC is an aggressive subtype of breast cancer with poor prognosis. Progression to distant metastases is often rapid, as is development of resistance chemotherapy, Dr. Gianni explained, adding that chemotherapy is currently the only treatment for early-stage TNBC.

Chemotherapy works in some patients, but relapse and resistance are common even after good initial responses; therefore, he and his colleagues examined the effects of immune checkpoint inhibition added to neoadjuvant chemotherapy, reasoning that the combination might boost the antitumor immune response.

Atezolizumab in combination with nab-paclitaxel is now approved by the Food and Drug Administration for the treatment of some patients with locally advanced or metastatic TNBC. The approval was based on findings from the IMpassion130 study showing a significant progression-free and overall survival benefit with atezolizumab when added to nab-paclitaxel in PD-L1-positive metastatic TNBC.

In a press statement, Dr. Gianni noted that the pCR findings he reported from the NeoTRIPaPDL1 study “may indicate that there is no therapeutic benefit to adding atezolizumab to neoadjuvant chemotherapy compared to chemotherapy alone, or may simply mean that any beneficial effects of the combination will be seen in the long term.”

“Pathologic complete response does not provide information about the quality of response, which is why we did not use it as the primary endpoint for this study. Further analyses may reveal differences in the quality of response between the treatment groups,” he added, noting that the study is limited in that reported results apply only to the initial effects of the combination treatment and do not account for effects of therapies administered after surgery.

Follow-up for the primary endpoint of event-free survival and other efficacy endpoints in the NeoTRIPaPDL1 trial is ongoing, and molecular studies are also underway, Dr. Gianni said.

Biological samples collected from patients before, during, and after neoadjuvant treatment are being examined for lymphocyte infiltration, DNA mutations, and/or levels of circulating tumor DNA, and may reveal differences between the treatment groups, he explained.

This study was sponsored by Roche and Celgene. Dr. Gianni has been an advisor and/or consultant for numerous pharmaceutical companies. He has received support for research from Daiichi Sankyo, Zymeworks, and Revolution Medicines and is a coinventor on a patent for PD-L1 expression in anti-HER2 therapy.

[email protected]

SOURCE: Gianni L et al. SABCS 2019. Abstract GS3-04.

SAN ANTONIO – The presence of circulating tumor DNA (ctDNA) and to a lesser degree circulating tumor cells (CTCs) following neoadjuvant chemotherapy for triple-negative breast cancer (TNBC) augurs poor prognosis, but it’s still unclear how this information can inform therapy.

Neil Osterweil/MDedge News

An analysis of plasma samples from 142 women enrolled in a trial that compared outcomes of genomically directed therapy with those of physician’s choice of a regimen for treatment of TNBC showed that, at a median follow-up of 17.2 months, detection of ctDNA was significantly associated with worse distant disease-free survival and the risk of relapse was especially high for patients with both detectable ctDNA and CTCs, reported Milan Radovich, PhD, from Indiana University in Indianapolis.

“Patients with TNBC at high clinical risk of relapse due to incomplete response to neoadjuvant chemotherapy can be further risk-stratified based on the presence of [minimal residual disease] as determined by ctDNA,” he said at the San Antonio Breast Cancer Symposium.

As previously reported, the presence of detectable ctDNA after surgery for breast cancer is a significant predictor of inferior disease-free survival (DFS), but the findings, while clinically valid, are not yet applicable to clinical care, Dr. Radovich acknowledged in a briefing shortly before his presentation of the data in a general session.

As part of the BRE12-158 trial, Dr. Radovich and colleagues conducted a prospective analysis of patients with early-stage TNBC who had significant residual disease at the time of surgery, despite having undergone neoadjuvant chemotherapy. The tumors were genomically sequenced and the patients were then randomized to receive either genomocially directed therapy or the treating physician’s choice of a regimen.

Of 177 evaluable patients, a total of 142 had successful ctDNA results and 123 had successful CTC testing. The ctDNA samples were sequenced using a liquid assay for 70 oncogenes commonly mutated in cancer. CTCs were isolated from peripheral blood with a positive-selection microfluidic device. CTC-positivity was defined at detection of one or more cells.

The investigators found that ctDNA was significantly associated with distant DFS, with a median of 32.5 months for ctDNA-positive patients versus median not reached for ctDNA-negative patients. The respective 2-year distant DFS rates were 56% and 81%, respectively. The hazard ratio for worse distant DFS among ctDNA-positive patients was 2.99 (P = .0055).

Similarly, DFS was significantly inferior among ctDNA-positive patients, with a median of 22.8 months versus not reached for ctDNA-negative patients, and median 2-year DFS rates of 50% and 76%. The HR for worse survival in ctDNA-positive patients was 2.67 (P = .0069).

Overall survival (OS) was also worse for ctDNA-positive patients; although the median OS was not reached in either positive or negative patients, the 2-year OS rates were 57% among ctDNA-positive patients and 80% among negative patients. The HR for death among the ctDNA-positive patients was 4.16 (P = .0024).

CTC detection, in contrast, showed a trend toward a significant association with clinical outcomes, but neither distant DFS, DFS, nor OS measures achieved statistical significance.

However, when ctDNA and CTC were combined, the results showed significantly inferior distant DFS for patients positive for both markers, compared with that of patients who were ctDNA positive but CTC negative (median, 32.5 months vs. not reached; 2 year distant DFS, 52% vs. 89%; HR, 5.29; P = .0095).

Similarly, this group of patients had worse DFS (median, 20.8 months vs. not reached; 2-year DFS, 43% vs. 80%; HR, 3.15; P = .0370) and worse OS (median, OS not reached in either group; 2-year OS, 51% vs. 76%; HR, 8.60; P = .0074).

To take advantage of these data, the investigators are preparing to launch a phase 2 trial (BRE18-334) in which patients with residual disease are randomized by ctDNA status (positive or negative) to either genetically directed therapy or therapy with no genomic target. The patients randomized to genomically directed therapy will be treated according to mutation category.

For example, capecitabine will given plus either a PARP (poly [ADP-ribose] polymerase) inhibitor for patients with mutations in DNA repair pathways, atezolizumab (Tecentriq) for patients with mutations in the immunotherapy pathway, ipatasertib for mutations in the P13K/AKT/mTOR pathway, or a PARP inhibitor plus atezolizumab for patients with mutations in the both DNA repair immunotherapy pathways.

At the briefing, moderator Virginia Kaklamani, MD, DSc, from University of Texas Health San Antonio, commented that the results of the study can inform clinical research, but “we don’t have predictive data as to how we’re going to act on this and improve patient outcomes. What we need is exactly the trial that the investigators have designed to see whether these results can then further help us in treating our patients and improving their outcomes.”

Neil Osterweil/MDedge News

“Should we be doing this on Monday in clinic, and the answer is no,” Dr. Radovich agreed. “What we don’t know is if having this information is really going to improve outcomes.”

In an interview, senior author Bryan P. Schneider, MD from Indiana University School of Medicine put it this way: “I’ve always believed that you don’t order a test until you know what to do with it,” he said.

The study was funded by the Vera Bradley Foundation for Breast Cancer and the Indiana University Grand Challenge Precision Health Initiative. Dr. Radovich and Dr. Schneider reported no relevant disclosures. Dr. Kaklamani disclosed speakers bureau activities and consulting for multiple companies, as well as research funding from Eiasi.

SOURCE: Radovich M. SABCS 2019, Abstract GS5-02.

SAN ANTONIO – The presence of circulating tumor DNA (ctDNA) and to a lesser degree circulating tumor cells (CTCs) following neoadjuvant chemotherapy for triple-negative breast cancer (TNBC) augurs poor prognosis, but it’s still unclear how this information can inform therapy.

Neil Osterweil/MDedge News

An analysis of plasma samples from 142 women enrolled in a trial that compared outcomes of genomically directed therapy with those of physician’s choice of a regimen for treatment of TNBC showed that, at a median follow-up of 17.2 months, detection of ctDNA was significantly associated with worse distant disease-free survival and the risk of relapse was especially high for patients with both detectable ctDNA and CTCs, reported Milan Radovich, PhD, from Indiana University in Indianapolis.

“Patients with TNBC at high clinical risk of relapse due to incomplete response to neoadjuvant chemotherapy can be further risk-stratified based on the presence of [minimal residual disease] as determined by ctDNA,” he said at the San Antonio Breast Cancer Symposium.

As previously reported, the presence of detectable ctDNA after surgery for breast cancer is a significant predictor of inferior disease-free survival (DFS), but the findings, while clinically valid, are not yet applicable to clinical care, Dr. Radovich acknowledged in a briefing shortly before his presentation of the data in a general session.

As part of the BRE12-158 trial, Dr. Radovich and colleagues conducted a prospective analysis of patients with early-stage TNBC who had significant residual disease at the time of surgery, despite having undergone neoadjuvant chemotherapy. The tumors were genomically sequenced and the patients were then randomized to receive either genomocially directed therapy or the treating physician’s choice of a regimen.

Of 177 evaluable patients, a total of 142 had successful ctDNA results and 123 had successful CTC testing. The ctDNA samples were sequenced using a liquid assay for 70 oncogenes commonly mutated in cancer. CTCs were isolated from peripheral blood with a positive-selection microfluidic device. CTC-positivity was defined at detection of one or more cells.

The investigators found that ctDNA was significantly associated with distant DFS, with a median of 32.5 months for ctDNA-positive patients versus median not reached for ctDNA-negative patients. The respective 2-year distant DFS rates were 56% and 81%, respectively. The hazard ratio for worse distant DFS among ctDNA-positive patients was 2.99 (P = .0055).

Similarly, DFS was significantly inferior among ctDNA-positive patients, with a median of 22.8 months versus not reached for ctDNA-negative patients, and median 2-year DFS rates of 50% and 76%. The HR for worse survival in ctDNA-positive patients was 2.67 (P = .0069).

Overall survival (OS) was also worse for ctDNA-positive patients; although the median OS was not reached in either positive or negative patients, the 2-year OS rates were 57% among ctDNA-positive patients and 80% among negative patients. The HR for death among the ctDNA-positive patients was 4.16 (P = .0024).

CTC detection, in contrast, showed a trend toward a significant association with clinical outcomes, but neither distant DFS, DFS, nor OS measures achieved statistical significance.

However, when ctDNA and CTC were combined, the results showed significantly inferior distant DFS for patients positive for both markers, compared with that of patients who were ctDNA positive but CTC negative (median, 32.5 months vs. not reached; 2 year distant DFS, 52% vs. 89%; HR, 5.29; P = .0095).

Similarly, this group of patients had worse DFS (median, 20.8 months vs. not reached; 2-year DFS, 43% vs. 80%; HR, 3.15; P = .0370) and worse OS (median, OS not reached in either group; 2-year OS, 51% vs. 76%; HR, 8.60; P = .0074).

To take advantage of these data, the investigators are preparing to launch a phase 2 trial (BRE18-334) in which patients with residual disease are randomized by ctDNA status (positive or negative) to either genetically directed therapy or therapy with no genomic target. The patients randomized to genomically directed therapy will be treated according to mutation category.

For example, capecitabine will given plus either a PARP (poly [ADP-ribose] polymerase) inhibitor for patients with mutations in DNA repair pathways, atezolizumab (Tecentriq) for patients with mutations in the immunotherapy pathway, ipatasertib for mutations in the P13K/AKT/mTOR pathway, or a PARP inhibitor plus atezolizumab for patients with mutations in the both DNA repair immunotherapy pathways.

At the briefing, moderator Virginia Kaklamani, MD, DSc, from University of Texas Health San Antonio, commented that the results of the study can inform clinical research, but “we don’t have predictive data as to how we’re going to act on this and improve patient outcomes. What we need is exactly the trial that the investigators have designed to see whether these results can then further help us in treating our patients and improving their outcomes.”

Neil Osterweil/MDedge News

“Should we be doing this on Monday in clinic, and the answer is no,” Dr. Radovich agreed. “What we don’t know is if having this information is really going to improve outcomes.”

In an interview, senior author Bryan P. Schneider, MD from Indiana University School of Medicine put it this way: “I’ve always believed that you don’t order a test until you know what to do with it,” he said.

The study was funded by the Vera Bradley Foundation for Breast Cancer and the Indiana University Grand Challenge Precision Health Initiative. Dr. Radovich and Dr. Schneider reported no relevant disclosures. Dr. Kaklamani disclosed speakers bureau activities and consulting for multiple companies, as well as research funding from Eiasi.

SOURCE: Radovich M. SABCS 2019, Abstract GS5-02.

SAN ANTONIO – The presence of circulating tumor DNA (ctDNA) and to a lesser degree circulating tumor cells (CTCs) following neoadjuvant chemotherapy for triple-negative breast cancer (TNBC) augurs poor prognosis, but it’s still unclear how this information can inform therapy.

Neil Osterweil/MDedge News

An analysis of plasma samples from 142 women enrolled in a trial that compared outcomes of genomically directed therapy with those of physician’s choice of a regimen for treatment of TNBC showed that, at a median follow-up of 17.2 months, detection of ctDNA was significantly associated with worse distant disease-free survival and the risk of relapse was especially high for patients with both detectable ctDNA and CTCs, reported Milan Radovich, PhD, from Indiana University in Indianapolis.

“Patients with TNBC at high clinical risk of relapse due to incomplete response to neoadjuvant chemotherapy can be further risk-stratified based on the presence of [minimal residual disease] as determined by ctDNA,” he said at the San Antonio Breast Cancer Symposium.

As previously reported, the presence of detectable ctDNA after surgery for breast cancer is a significant predictor of inferior disease-free survival (DFS), but the findings, while clinically valid, are not yet applicable to clinical care, Dr. Radovich acknowledged in a briefing shortly before his presentation of the data in a general session.

As part of the BRE12-158 trial, Dr. Radovich and colleagues conducted a prospective analysis of patients with early-stage TNBC who had significant residual disease at the time of surgery, despite having undergone neoadjuvant chemotherapy. The tumors were genomically sequenced and the patients were then randomized to receive either genomocially directed therapy or the treating physician’s choice of a regimen.

Of 177 evaluable patients, a total of 142 had successful ctDNA results and 123 had successful CTC testing. The ctDNA samples were sequenced using a liquid assay for 70 oncogenes commonly mutated in cancer. CTCs were isolated from peripheral blood with a positive-selection microfluidic device. CTC-positivity was defined at detection of one or more cells.

The investigators found that ctDNA was significantly associated with distant DFS, with a median of 32.5 months for ctDNA-positive patients versus median not reached for ctDNA-negative patients. The respective 2-year distant DFS rates were 56% and 81%, respectively. The hazard ratio for worse distant DFS among ctDNA-positive patients was 2.99 (P = .0055).

Similarly, DFS was significantly inferior among ctDNA-positive patients, with a median of 22.8 months versus not reached for ctDNA-negative patients, and median 2-year DFS rates of 50% and 76%. The HR for worse survival in ctDNA-positive patients was 2.67 (P = .0069).

Overall survival (OS) was also worse for ctDNA-positive patients; although the median OS was not reached in either positive or negative patients, the 2-year OS rates were 57% among ctDNA-positive patients and 80% among negative patients. The HR for death among the ctDNA-positive patients was 4.16 (P = .0024).

CTC detection, in contrast, showed a trend toward a significant association with clinical outcomes, but neither distant DFS, DFS, nor OS measures achieved statistical significance.

However, when ctDNA and CTC were combined, the results showed significantly inferior distant DFS for patients positive for both markers, compared with that of patients who were ctDNA positive but CTC negative (median, 32.5 months vs. not reached; 2 year distant DFS, 52% vs. 89%; HR, 5.29; P = .0095).

Similarly, this group of patients had worse DFS (median, 20.8 months vs. not reached; 2-year DFS, 43% vs. 80%; HR, 3.15; P = .0370) and worse OS (median, OS not reached in either group; 2-year OS, 51% vs. 76%; HR, 8.60; P = .0074).

To take advantage of these data, the investigators are preparing to launch a phase 2 trial (BRE18-334) in which patients with residual disease are randomized by ctDNA status (positive or negative) to either genetically directed therapy or therapy with no genomic target. The patients randomized to genomically directed therapy will be treated according to mutation category.

For example, capecitabine will given plus either a PARP (poly [ADP-ribose] polymerase) inhibitor for patients with mutations in DNA repair pathways, atezolizumab (Tecentriq) for patients with mutations in the immunotherapy pathway, ipatasertib for mutations in the P13K/AKT/mTOR pathway, or a PARP inhibitor plus atezolizumab for patients with mutations in the both DNA repair immunotherapy pathways.

At the briefing, moderator Virginia Kaklamani, MD, DSc, from University of Texas Health San Antonio, commented that the results of the study can inform clinical research, but “we don’t have predictive data as to how we’re going to act on this and improve patient outcomes. What we need is exactly the trial that the investigators have designed to see whether these results can then further help us in treating our patients and improving their outcomes.”

Neil Osterweil/MDedge News

“Should we be doing this on Monday in clinic, and the answer is no,” Dr. Radovich agreed. “What we don’t know is if having this information is really going to improve outcomes.”

In an interview, senior author Bryan P. Schneider, MD from Indiana University School of Medicine put it this way: “I’ve always believed that you don’t order a test until you know what to do with it,” he said.

The study was funded by the Vera Bradley Foundation for Breast Cancer and the Indiana University Grand Challenge Precision Health Initiative. Dr. Radovich and Dr. Schneider reported no relevant disclosures. Dr. Kaklamani disclosed speakers bureau activities and consulting for multiple companies, as well as research funding from Eiasi.

SOURCE: Radovich M. SABCS 2019, Abstract GS5-02.

SAN ANTONIO – The Clinical Treatment Score post 5 years (CTS5) has been validated for the prediction of late distant recurrences in a large contemporary cohort of breast cancer patients drawn from the landmark TAILORx study – but only provided they’re over age 50 at the time of their initial breast cancer diagnosis, Ivana Sestak, PhD, reported at the San Antonio Breast Cancer Symposium.

Bruce Jancin/MDedge News

“The CTS5 was much less prognostic in younger patients, and we did not observe good discrimination for the CTS5 in this cohort,” she said. “Further evaluation in premenopausal cohorts is needed before CTS5 can be applied to younger patients.”

She and her coworkers developed the CTS5 as a simple, expeditious tool to identify women at high risk of late distance recurrence of estrogen receptor–positive breast cancer after successfully completing 5 years of endocrine therapy. It’s designed to serve as an aid to physicians and patients in clinical decision making: Women who are CTS5 high risk are likely to benefit from extended endocrine therapy beyond the 5-year mark, while those at low risk are not.

“Trials so far have shown only a modest risk reduction of around 5% with extended endocrine therapy. This may be partly due to the fact that none of these trials had specifically selected patients who were at high risk of developing a late recurrence. It is therefore crucial that we identify those patients who are at high risk of late recurrence, as they will benefit most from extended endocrine therapy,” explained Dr. Sestak, a medical statistician at Queen Mary University, London.

The CTS5 calculator is freely available online at www.cts5-calculator.com. Clinicians simply plug in readily available information on four specific variables for their patients who have completed 5 years of endocrine therapy free of distant recurrence: age at breast cancer diagnosis, tumor size in millimeters, tumor grade, and number of involved nodes. The calculator promptly spits out a CTS5 score and the associated risk of distant recurrence during years 5-10 after initial diagnosis. That risk is categorized as low if it’s 5% or less in years 5-10, and high if it’s greater than 10%.

The CTS5 was developed and validated using long-term follow-up data on more than 11,000 postmenopausal breast cancer patients in the ATAC and BIG1-98 randomized trials. The CTS5 performed well in those tests. But those studies were completed more than a decade ago and were limited to postmenopausal patients. Dr. Sestak and coinvestigators wanted to assess the tool’s discriminatory powers in a contemporary population of breast cancer patients that included large numbers of premenopausal women. So they tapped into the National Cancer Institute–sponsored TAILORx study, which included 7,353 breast cancer patients who were distant recurrence free after 5 years. All had early-stage, hormone receptor–positive, HER2-negative, and axillary node–negative breast cancer. And all underwent baseline testing using Genomic Health’s Oncotype DX Breast Recurrence Score to assess expression of 21 genes associated with breast cancer recurrence.

The CTS5 proved to be highly prognostic in the overall TAILORx population. But upon drilling down further, Dr. Sestak and coworkers determined that CTS5 had only marginal prognostic value in the 2,259 women age 50 years or younger. Indeed, not a single patient in that age group was categorized as CTS5 high risk, and the actual distant recurrence rates during years 5-9 weren’t significantly different between the low- and intermediate-risk CTS5 groups.

In contrast, CTS5 performed well as a prognosticator in the 2,257 TAILORx participants over age 50 who received both chemotherapy and endocrine therapy during their first 5 years following diagnosis. For a fast and simple test with zero cost, it displayed impressive discriminatory power: The 63.8% of women classified as CTS5 low risk had a 2.6% distant recurrence rate – and thus constituted a group who could reasonably avoid extended endocrine therapy – while the 3.5% who were CTS5 high risk had a 9.5% event rate, and the intermediate-risk group had a 7.3% event rate. The prognostic power of CTS5 in the 2,837 women aged over 50 years who received only hormonal therapy was less robust, albeit still statistically significant.

In women classified as being at low risk of recurrence based upon an Oncotype DX score of 0-10, the CTS5 was not a significant prognosticator for the prediction of late distant recurrences. However, in those who were at intermediate or high risk as determined by a score of 11-100 on the Oncotype test, CTS5 was highly prognostic.

A significant limitation of this CTS5 validation study in the TAILORx population was that only a median 2.86 years of follow-up data after the 5-year mark was available – not sufficient time for a large number of distant recurrences. The rate was 3.1% in women treated with only endocrine therapy who had an Oncotype DX score of 0-25, and 3.8% in those with a score of 11-100 who received both chemotherapy and endocrine therapy.

Dr. Sestak shrugged off the less than stellar performance of the CTS5 in women aged age 50 years or younger in the TAILORx analysis.

“We developed the CTS5 specifically in postmenopausal women, so we’re not really surprised that it’s less prognostic in young women,” she said.

Her group next plans to evaluate the CTS5 in another large premenopausal cohort of breast cancer patients.

“If it’s not prognostic there, then we’ll have to adjust the algorithm and recalibrate it specifically for younger patients,” according to Dr. Sestak.

The TAILORx validation study was supported by Breast Cancer Now, Cancer Research UK, Exact Sciences, and the University of London. Dr. Sestak reported having received honoraria from Myriad Genetics, Nanostring Technology, and Pfizer Oncology.

SOURCE: Sestak I et al. SABCS 2019, Abstract GS4-03.

SAN ANTONIO – The Clinical Treatment Score post 5 years (CTS5) has been validated for the prediction of late distant recurrences in a large contemporary cohort of breast cancer patients drawn from the landmark TAILORx study – but only provided they’re over age 50 at the time of their initial breast cancer diagnosis, Ivana Sestak, PhD, reported at the San Antonio Breast Cancer Symposium.

Bruce Jancin/MDedge News

“The CTS5 was much less prognostic in younger patients, and we did not observe good discrimination for the CTS5 in this cohort,” she said. “Further evaluation in premenopausal cohorts is needed before CTS5 can be applied to younger patients.”

She and her coworkers developed the CTS5 as a simple, expeditious tool to identify women at high risk of late distance recurrence of estrogen receptor–positive breast cancer after successfully completing 5 years of endocrine therapy. It’s designed to serve as an aid to physicians and patients in clinical decision making: Women who are CTS5 high risk are likely to benefit from extended endocrine therapy beyond the 5-year mark, while those at low risk are not.

“Trials so far have shown only a modest risk reduction of around 5% with extended endocrine therapy. This may be partly due to the fact that none of these trials had specifically selected patients who were at high risk of developing a late recurrence. It is therefore crucial that we identify those patients who are at high risk of late recurrence, as they will benefit most from extended endocrine therapy,” explained Dr. Sestak, a medical statistician at Queen Mary University, London.

The CTS5 calculator is freely available online at www.cts5-calculator.com. Clinicians simply plug in readily available information on four specific variables for their patients who have completed 5 years of endocrine therapy free of distant recurrence: age at breast cancer diagnosis, tumor size in millimeters, tumor grade, and number of involved nodes. The calculator promptly spits out a CTS5 score and the associated risk of distant recurrence during years 5-10 after initial diagnosis. That risk is categorized as low if it’s 5% or less in years 5-10, and high if it’s greater than 10%.

The CTS5 was developed and validated using long-term follow-up data on more than 11,000 postmenopausal breast cancer patients in the ATAC and BIG1-98 randomized trials. The CTS5 performed well in those tests. But those studies were completed more than a decade ago and were limited to postmenopausal patients. Dr. Sestak and coinvestigators wanted to assess the tool’s discriminatory powers in a contemporary population of breast cancer patients that included large numbers of premenopausal women. So they tapped into the National Cancer Institute–sponsored TAILORx study, which included 7,353 breast cancer patients who were distant recurrence free after 5 years. All had early-stage, hormone receptor–positive, HER2-negative, and axillary node–negative breast cancer. And all underwent baseline testing using Genomic Health’s Oncotype DX Breast Recurrence Score to assess expression of 21 genes associated with breast cancer recurrence.

The CTS5 proved to be highly prognostic in the overall TAILORx population. But upon drilling down further, Dr. Sestak and coworkers determined that CTS5 had only marginal prognostic value in the 2,259 women age 50 years or younger. Indeed, not a single patient in that age group was categorized as CTS5 high risk, and the actual distant recurrence rates during years 5-9 weren’t significantly different between the low- and intermediate-risk CTS5 groups.

In contrast, CTS5 performed well as a prognosticator in the 2,257 TAILORx participants over age 50 who received both chemotherapy and endocrine therapy during their first 5 years following diagnosis. For a fast and simple test with zero cost, it displayed impressive discriminatory power: The 63.8% of women classified as CTS5 low risk had a 2.6% distant recurrence rate – and thus constituted a group who could reasonably avoid extended endocrine therapy – while the 3.5% who were CTS5 high risk had a 9.5% event rate, and the intermediate-risk group had a 7.3% event rate. The prognostic power of CTS5 in the 2,837 women aged over 50 years who received only hormonal therapy was less robust, albeit still statistically significant.

In women classified as being at low risk of recurrence based upon an Oncotype DX score of 0-10, the CTS5 was not a significant prognosticator for the prediction of late distant recurrences. However, in those who were at intermediate or high risk as determined by a score of 11-100 on the Oncotype test, CTS5 was highly prognostic.

A significant limitation of this CTS5 validation study in the TAILORx population was that only a median 2.86 years of follow-up data after the 5-year mark was available – not sufficient time for a large number of distant recurrences. The rate was 3.1% in women treated with only endocrine therapy who had an Oncotype DX score of 0-25, and 3.8% in those with a score of 11-100 who received both chemotherapy and endocrine therapy.

Dr. Sestak shrugged off the less than stellar performance of the CTS5 in women aged age 50 years or younger in the TAILORx analysis.

“We developed the CTS5 specifically in postmenopausal women, so we’re not really surprised that it’s less prognostic in young women,” she said.

Her group next plans to evaluate the CTS5 in another large premenopausal cohort of breast cancer patients.

“If it’s not prognostic there, then we’ll have to adjust the algorithm and recalibrate it specifically for younger patients,” according to Dr. Sestak.

The TAILORx validation study was supported by Breast Cancer Now, Cancer Research UK, Exact Sciences, and the University of London. Dr. Sestak reported having received honoraria from Myriad Genetics, Nanostring Technology, and Pfizer Oncology.

SOURCE: Sestak I et al. SABCS 2019, Abstract GS4-03.

SAN ANTONIO – The Clinical Treatment Score post 5 years (CTS5) has been validated for the prediction of late distant recurrences in a large contemporary cohort of breast cancer patients drawn from the landmark TAILORx study – but only provided they’re over age 50 at the time of their initial breast cancer diagnosis, Ivana Sestak, PhD, reported at the San Antonio Breast Cancer Symposium.

Bruce Jancin/MDedge News

“The CTS5 was much less prognostic in younger patients, and we did not observe good discrimination for the CTS5 in this cohort,” she said. “Further evaluation in premenopausal cohorts is needed before CTS5 can be applied to younger patients.”

She and her coworkers developed the CTS5 as a simple, expeditious tool to identify women at high risk of late distance recurrence of estrogen receptor–positive breast cancer after successfully completing 5 years of endocrine therapy. It’s designed to serve as an aid to physicians and patients in clinical decision making: Women who are CTS5 high risk are likely to benefit from extended endocrine therapy beyond the 5-year mark, while those at low risk are not.

“Trials so far have shown only a modest risk reduction of around 5% with extended endocrine therapy. This may be partly due to the fact that none of these trials had specifically selected patients who were at high risk of developing a late recurrence. It is therefore crucial that we identify those patients who are at high risk of late recurrence, as they will benefit most from extended endocrine therapy,” explained Dr. Sestak, a medical statistician at Queen Mary University, London.

The CTS5 calculator is freely available online at www.cts5-calculator.com. Clinicians simply plug in readily available information on four specific variables for their patients who have completed 5 years of endocrine therapy free of distant recurrence: age at breast cancer diagnosis, tumor size in millimeters, tumor grade, and number of involved nodes. The calculator promptly spits out a CTS5 score and the associated risk of distant recurrence during years 5-10 after initial diagnosis. That risk is categorized as low if it’s 5% or less in years 5-10, and high if it’s greater than 10%.

The CTS5 was developed and validated using long-term follow-up data on more than 11,000 postmenopausal breast cancer patients in the ATAC and BIG1-98 randomized trials. The CTS5 performed well in those tests. But those studies were completed more than a decade ago and were limited to postmenopausal patients. Dr. Sestak and coinvestigators wanted to assess the tool’s discriminatory powers in a contemporary population of breast cancer patients that included large numbers of premenopausal women. So they tapped into the National Cancer Institute–sponsored TAILORx study, which included 7,353 breast cancer patients who were distant recurrence free after 5 years. All had early-stage, hormone receptor–positive, HER2-negative, and axillary node–negative breast cancer. And all underwent baseline testing using Genomic Health’s Oncotype DX Breast Recurrence Score to assess expression of 21 genes associated with breast cancer recurrence.

The CTS5 proved to be highly prognostic in the overall TAILORx population. But upon drilling down further, Dr. Sestak and coworkers determined that CTS5 had only marginal prognostic value in the 2,259 women age 50 years or younger. Indeed, not a single patient in that age group was categorized as CTS5 high risk, and the actual distant recurrence rates during years 5-9 weren’t significantly different between the low- and intermediate-risk CTS5 groups.

In contrast, CTS5 performed well as a prognosticator in the 2,257 TAILORx participants over age 50 who received both chemotherapy and endocrine therapy during their first 5 years following diagnosis. For a fast and simple test with zero cost, it displayed impressive discriminatory power: The 63.8% of women classified as CTS5 low risk had a 2.6% distant recurrence rate – and thus constituted a group who could reasonably avoid extended endocrine therapy – while the 3.5% who were CTS5 high risk had a 9.5% event rate, and the intermediate-risk group had a 7.3% event rate. The prognostic power of CTS5 in the 2,837 women aged over 50 years who received only hormonal therapy was less robust, albeit still statistically significant.

In women classified as being at low risk of recurrence based upon an Oncotype DX score of 0-10, the CTS5 was not a significant prognosticator for the prediction of late distant recurrences. However, in those who were at intermediate or high risk as determined by a score of 11-100 on the Oncotype test, CTS5 was highly prognostic.

A significant limitation of this CTS5 validation study in the TAILORx population was that only a median 2.86 years of follow-up data after the 5-year mark was available – not sufficient time for a large number of distant recurrences. The rate was 3.1% in women treated with only endocrine therapy who had an Oncotype DX score of 0-25, and 3.8% in those with a score of 11-100 who received both chemotherapy and endocrine therapy.

Dr. Sestak shrugged off the less than stellar performance of the CTS5 in women aged age 50 years or younger in the TAILORx analysis.

“We developed the CTS5 specifically in postmenopausal women, so we’re not really surprised that it’s less prognostic in young women,” she said.

Her group next plans to evaluate the CTS5 in another large premenopausal cohort of breast cancer patients.

“If it’s not prognostic there, then we’ll have to adjust the algorithm and recalibrate it specifically for younger patients,” according to Dr. Sestak.

The TAILORx validation study was supported by Breast Cancer Now, Cancer Research UK, Exact Sciences, and the University of London. Dr. Sestak reported having received honoraria from Myriad Genetics, Nanostring Technology, and Pfizer Oncology.

SOURCE: Sestak I et al. SABCS 2019, Abstract GS4-03.