Manali Bhave, MD

Results from TROPION-Breast01, EMBER, and OPERA were recently presented at ESMO Breast Cancer 2023. 

A number of exciting updates on systemic therapies for the treatment of hormone receptor (HR)-positive, HER2-negative breast cancer were presented at the European Society for Medical Oncology (ESMO) Breast Cancer 2023, including novel endocrine agents and antibody-drug conjugates (ADC). We have highlighted 3 key studies, including the phase III study of datopotamab deruxtecan (Dato-DXd), the new trophoblast cell surface antigen 2 (TROP2)-directed ADC; the phase I study of imlunestrant, a selective estrogen receptor degrader (SERD); and phase I/II data evaluating OP-1250, a small molecule oral complete estrogen receptor antagonist (CERAN) and SERD. 

TROPION-Breast01: Dato-DXd Improves Progression-Free Survival Compared With Systemic Chemotherapy

Study synopsis

Dato-DXd, an investigational TROP2 ADC, resulted in significantly improved progression-free survival (PFS) when compared with investigator’s choice chemotherapy (ICC) in individuals with inoperable or metastatic HR-positive, HER2-low or HER2-negative breast cancer, according to a randomized phase III trial. 

Participants in the study had progressed on or were not eligible for endocrine therapy and had received 1 or 2 prior lines of systemic chemotherapy. Patients were randomized to receive either 6 mg/kg of Dato-DXd once every 3 weeks (n=365; median age 56), or ICC with eribulin, vinorelbine, capecitabine, or gemcitabine (n=367; median age 54) until progression or unacceptable toxicity. Blinded independent review assessed PFS and overall survival. Among the results: 

• In the blinded independent review, PFS was 6.9 months for Dato-DXd and 4.9 months for ICC (HR 0.63 [95% CI: 0.52, 0.76]; p<0.0001)

• At 6 months, 53% of participants receiving Dato-DXd achieved PFS, compared with 39% in the systemic chemotherapy contingent

• In the Dato-DXd group, treatment-related adverse events led to dose reductions in 23% and discontinuation in 3% of patients

• In the systemic chemotherapy cohort, the dose reduction and discontinuation rates were 32% and 3%, respectively

• At the time data were reported at ESMO, overall survival data were not mature but trending favorably for Dato-DXd

The investigators concluded that Dato-DXd is a promising novel treatment option for individuals with inoperable or metastatic HR-positive, HER2-low or HER2-negative breast cancer who have received prior chemotherapy.

EMBER: Imlunestrant Alone or With a Kinase Inhibitor: Early Safety and Efficacy Results Are Encouraging

Study synopsis

The SERD imlunestrant—used either alone or combined with a kinase inhibitor—showed favorable efficacy in individuals with estrogen receptor (ER)-positive, HER2-negative advanced breast cancer, according to the first set of clinical data reported from the phase 1a/b EMBER study. 

Key eligibility criteria for phase 1b enrollment included prior sensitivity to endocrine therapy, ≤2 prior therapies, and a PIK3CA mutation (alpelisib arm only). Prior therapies included endocrine therapy (100%), CDK4/6 inhibitors (100%), hormonal therapy with fulvestrant (35%), and chemotherapy (17%). At baseline, 46% of patients had visceral disease and 46% had an ESR1 mutation. Participants received imlunestrant alone (n=114) or with the kinase inhibitors everolimus (n=42) or alpelisib (n=21). Investigators assessed each regimen’s safety profile, as well as the objective response rate and clinical benefit rate. 

The safety profile of each regimen was similar to those seen with everolimus and alpelisib alone. No cardiac or ocular toxicities were observed. Regarding grade ≥3 treatment-related adverse events: 

• The imlunestrant alone group experienced fatigue (2%) and neutropenia (2%)

• The imlunestrant + everolimus group experienced hypertriglyceridemia (5%) and aspartate aminotransferase increase (5%)

• The imlunestrant + alpelisib cohort experienced rash (43%) and hyperglycemia (10%).

• In the imlunestrant alone group, 2% of individuals had their doses reduced due to adverse events; none discontinued treatment

• In the imlunestrant + everolimus cohort, 12% of patients experienced dose reduction due to everolimus and 2% due to both medications; 2% discontinued treatment due to everolimus

• In the imlunestrant + alpelisib cohort, 24% of patients experienced dose reduction due to alpelisib and 14% due to both medications; 29% discontinued treatment due to alpelisib

Regarding efficacy:

• The objective response rates in the imlunestrant alone, imlunestrant + everolimus, and imlunestrant + alpelisib groups were 9%, 21%, and 50%, respectively

• The clinical benefit rates in the imlunestrant alone, imlunestrant + everolimus, and imlunestrant + alpelisib groups were 42%, 62%, and 62%, respectively

Investigators concluded that imlunestrant used alone or in combination with 1 of the 2 kinase inhibitors demonstrated robust efficacy in individuals with pretreated, ER-positive, HER2-negative advanced breast cancer. 

OPERA: OP-1250 Paired With a CDK4/6 Inhibitor: Anti-Tumor Activity With No Dose-Limiting Toxicities

Study synopsis

OP-1250, a CERAN and SERD, continues to show promising results when paired with a CDK4/6 inhibitor. The combination of OP-1250 and the CDK4/6 inhibitor palbociclib appears to be well tolerated and has a similar safety profile to each drug when used alone, according to a phase I/II study involving 20 individuals with pretreated ER-positive, HER2-negative breast cancer.

Participants had advanced or metastatic ER-positive, HER2-negative breast cancer that progressed on ≤1 lines of endocrine therapy. Fourteen participants had received prior CDK4/6 inhibitor therapy, including 11 who were previously treated with palbociclib. Patients received escalating doses of OP-1250 with 125 mg of palbociclib orally daily for 21 of 28 days. OP-1250 doses were 30 mg (n=3), 60 mg (n=3), 90 mg (n=3), and 120 mg (n=11). Investigators assessed pharmacokinetics, drug-drug interactions, safety, and efficacy. Among the results observed to date: 

• Grade 3 neutropenia occurred in 55% of participants

• There were no grade 4 treatment-related adverse events and no dose-limiting toxicities

• OP-1250 exposure yielded similar results to what was seen in the previous monotherapy study

• Palbociclib exposure was comparable to published monotherapy data when combined with OP-1250 for all dosages

• Investigators observed antitumor activity, including partial responses

Researchers concluded that OP-1250 does not affect the pharmacokinetics of palbociclib, and there do not appear to be drug-drug interactions. Tumor response to this combination was encouraging and requires continued investigation. 

Conclusions

These 3 studies presented at ESMO 2023 highlight exciting novel therapies for the treatment of HR-positive, HER2-low, and HER2-negative metastatic breast cancer. The EMBER and OPERA updates provide support for the safety and efficacy of these novel endocrine agents in combination with kinase inhibitors and CDK4/6 inhibitors, respectively, in patients with endocrine-sensitive disease, while the TROPION-01 study demonstrates the encouraging efficacy and safety of a second TROP-2-directed ADC in a more heavily pretreated population.

Results from TROPION-Breast01, EMBER, and OPERA were recently presented at ESMO Breast Cancer 2023. 

A number of exciting updates on systemic therapies for the treatment of hormone receptor (HR)-positive, HER2-negative breast cancer were presented at the European Society for Medical Oncology (ESMO) Breast Cancer 2023, including novel endocrine agents and antibody-drug conjugates (ADC). We have highlighted 3 key studies, including the phase III study of datopotamab deruxtecan (Dato-DXd), the new trophoblast cell surface antigen 2 (TROP2)-directed ADC; the phase I study of imlunestrant, a selective estrogen receptor degrader (SERD); and phase I/II data evaluating OP-1250, a small molecule oral complete estrogen receptor antagonist (CERAN) and SERD. 

TROPION-Breast01: Dato-DXd Improves Progression-Free Survival Compared With Systemic Chemotherapy

Study synopsis

Dato-DXd, an investigational TROP2 ADC, resulted in significantly improved progression-free survival (PFS) when compared with investigator’s choice chemotherapy (ICC) in individuals with inoperable or metastatic HR-positive, HER2-low or HER2-negative breast cancer, according to a randomized phase III trial. 

Participants in the study had progressed on or were not eligible for endocrine therapy and had received 1 or 2 prior lines of systemic chemotherapy. Patients were randomized to receive either 6 mg/kg of Dato-DXd once every 3 weeks (n=365; median age 56), or ICC with eribulin, vinorelbine, capecitabine, or gemcitabine (n=367; median age 54) until progression or unacceptable toxicity. Blinded independent review assessed PFS and overall survival. Among the results: 

• In the blinded independent review, PFS was 6.9 months for Dato-DXd and 4.9 months for ICC (HR 0.63 [95% CI: 0.52, 0.76]; p<0.0001)

• At 6 months, 53% of participants receiving Dato-DXd achieved PFS, compared with 39% in the systemic chemotherapy contingent

• In the Dato-DXd group, treatment-related adverse events led to dose reductions in 23% and discontinuation in 3% of patients

• In the systemic chemotherapy cohort, the dose reduction and discontinuation rates were 32% and 3%, respectively

• At the time data were reported at ESMO, overall survival data were not mature but trending favorably for Dato-DXd

The investigators concluded that Dato-DXd is a promising novel treatment option for individuals with inoperable or metastatic HR-positive, HER2-low or HER2-negative breast cancer who have received prior chemotherapy.

EMBER: Imlunestrant Alone or With a Kinase Inhibitor: Early Safety and Efficacy Results Are Encouraging

Study synopsis

The SERD imlunestrant—used either alone or combined with a kinase inhibitor—showed favorable efficacy in individuals with estrogen receptor (ER)-positive, HER2-negative advanced breast cancer, according to the first set of clinical data reported from the phase 1a/b EMBER study. 

Key eligibility criteria for phase 1b enrollment included prior sensitivity to endocrine therapy, ≤2 prior therapies, and a PIK3CA mutation (alpelisib arm only). Prior therapies included endocrine therapy (100%), CDK4/6 inhibitors (100%), hormonal therapy with fulvestrant (35%), and chemotherapy (17%). At baseline, 46% of patients had visceral disease and 46% had an ESR1 mutation. Participants received imlunestrant alone (n=114) or with the kinase inhibitors everolimus (n=42) or alpelisib (n=21). Investigators assessed each regimen’s safety profile, as well as the objective response rate and clinical benefit rate. 

The safety profile of each regimen was similar to those seen with everolimus and alpelisib alone. No cardiac or ocular toxicities were observed. Regarding grade ≥3 treatment-related adverse events: 

• The imlunestrant alone group experienced fatigue (2%) and neutropenia (2%)

• The imlunestrant + everolimus group experienced hypertriglyceridemia (5%) and aspartate aminotransferase increase (5%)

• The imlunestrant + alpelisib cohort experienced rash (43%) and hyperglycemia (10%).

• In the imlunestrant alone group, 2% of individuals had their doses reduced due to adverse events; none discontinued treatment

• In the imlunestrant + everolimus cohort, 12% of patients experienced dose reduction due to everolimus and 2% due to both medications; 2% discontinued treatment due to everolimus

• In the imlunestrant + alpelisib cohort, 24% of patients experienced dose reduction due to alpelisib and 14% due to both medications; 29% discontinued treatment due to alpelisib

Regarding efficacy:

• The objective response rates in the imlunestrant alone, imlunestrant + everolimus, and imlunestrant + alpelisib groups were 9%, 21%, and 50%, respectively

• The clinical benefit rates in the imlunestrant alone, imlunestrant + everolimus, and imlunestrant + alpelisib groups were 42%, 62%, and 62%, respectively

Investigators concluded that imlunestrant used alone or in combination with 1 of the 2 kinase inhibitors demonstrated robust efficacy in individuals with pretreated, ER-positive, HER2-negative advanced breast cancer. 

OPERA: OP-1250 Paired With a CDK4/6 Inhibitor: Anti-Tumor Activity With No Dose-Limiting Toxicities

Study synopsis

OP-1250, a CERAN and SERD, continues to show promising results when paired with a CDK4/6 inhibitor. The combination of OP-1250 and the CDK4/6 inhibitor palbociclib appears to be well tolerated and has a similar safety profile to each drug when used alone, according to a phase I/II study involving 20 individuals with pretreated ER-positive, HER2-negative breast cancer.

Participants had advanced or metastatic ER-positive, HER2-negative breast cancer that progressed on ≤1 lines of endocrine therapy. Fourteen participants had received prior CDK4/6 inhibitor therapy, including 11 who were previously treated with palbociclib. Patients received escalating doses of OP-1250 with 125 mg of palbociclib orally daily for 21 of 28 days. OP-1250 doses were 30 mg (n=3), 60 mg (n=3), 90 mg (n=3), and 120 mg (n=11). Investigators assessed pharmacokinetics, drug-drug interactions, safety, and efficacy. Among the results observed to date: 

• Grade 3 neutropenia occurred in 55% of participants

• There were no grade 4 treatment-related adverse events and no dose-limiting toxicities

• OP-1250 exposure yielded similar results to what was seen in the previous monotherapy study

• Palbociclib exposure was comparable to published monotherapy data when combined with OP-1250 for all dosages

• Investigators observed antitumor activity, including partial responses

Researchers concluded that OP-1250 does not affect the pharmacokinetics of palbociclib, and there do not appear to be drug-drug interactions. Tumor response to this combination was encouraging and requires continued investigation. 

Conclusions

These 3 studies presented at ESMO 2023 highlight exciting novel therapies for the treatment of HR-positive, HER2-low, and HER2-negative metastatic breast cancer. The EMBER and OPERA updates provide support for the safety and efficacy of these novel endocrine agents in combination with kinase inhibitors and CDK4/6 inhibitors, respectively, in patients with endocrine-sensitive disease, while the TROPION-01 study demonstrates the encouraging efficacy and safety of a second TROP-2-directed ADC in a more heavily pretreated population.

Results from TROPION-Breast01, EMBER, and OPERA were recently presented at ESMO Breast Cancer 2023. 

A number of exciting updates on systemic therapies for the treatment of hormone receptor (HR)-positive, HER2-negative breast cancer were presented at the European Society for Medical Oncology (ESMO) Breast Cancer 2023, including novel endocrine agents and antibody-drug conjugates (ADC). We have highlighted 3 key studies, including the phase III study of datopotamab deruxtecan (Dato-DXd), the new trophoblast cell surface antigen 2 (TROP2)-directed ADC; the phase I study of imlunestrant, a selective estrogen receptor degrader (SERD); and phase I/II data evaluating OP-1250, a small molecule oral complete estrogen receptor antagonist (CERAN) and SERD. 

TROPION-Breast01: Dato-DXd Improves Progression-Free Survival Compared With Systemic Chemotherapy

Study synopsis

Dato-DXd, an investigational TROP2 ADC, resulted in significantly improved progression-free survival (PFS) when compared with investigator’s choice chemotherapy (ICC) in individuals with inoperable or metastatic HR-positive, HER2-low or HER2-negative breast cancer, according to a randomized phase III trial. 

Participants in the study had progressed on or were not eligible for endocrine therapy and had received 1 or 2 prior lines of systemic chemotherapy. Patients were randomized to receive either 6 mg/kg of Dato-DXd once every 3 weeks (n=365; median age 56), or ICC with eribulin, vinorelbine, capecitabine, or gemcitabine (n=367; median age 54) until progression or unacceptable toxicity. Blinded independent review assessed PFS and overall survival. Among the results: 

• In the blinded independent review, PFS was 6.9 months for Dato-DXd and 4.9 months for ICC (HR 0.63 [95% CI: 0.52, 0.76]; p<0.0001)

• At 6 months, 53% of participants receiving Dato-DXd achieved PFS, compared with 39% in the systemic chemotherapy contingent

• In the Dato-DXd group, treatment-related adverse events led to dose reductions in 23% and discontinuation in 3% of patients

• In the systemic chemotherapy cohort, the dose reduction and discontinuation rates were 32% and 3%, respectively

• At the time data were reported at ESMO, overall survival data were not mature but trending favorably for Dato-DXd

The investigators concluded that Dato-DXd is a promising novel treatment option for individuals with inoperable or metastatic HR-positive, HER2-low or HER2-negative breast cancer who have received prior chemotherapy.

EMBER: Imlunestrant Alone or With a Kinase Inhibitor: Early Safety and Efficacy Results Are Encouraging

Study synopsis

The SERD imlunestrant—used either alone or combined with a kinase inhibitor—showed favorable efficacy in individuals with estrogen receptor (ER)-positive, HER2-negative advanced breast cancer, according to the first set of clinical data reported from the phase 1a/b EMBER study. 

Key eligibility criteria for phase 1b enrollment included prior sensitivity to endocrine therapy, ≤2 prior therapies, and a PIK3CA mutation (alpelisib arm only). Prior therapies included endocrine therapy (100%), CDK4/6 inhibitors (100%), hormonal therapy with fulvestrant (35%), and chemotherapy (17%). At baseline, 46% of patients had visceral disease and 46% had an ESR1 mutation. Participants received imlunestrant alone (n=114) or with the kinase inhibitors everolimus (n=42) or alpelisib (n=21). Investigators assessed each regimen’s safety profile, as well as the objective response rate and clinical benefit rate. 

The safety profile of each regimen was similar to those seen with everolimus and alpelisib alone. No cardiac or ocular toxicities were observed. Regarding grade ≥3 treatment-related adverse events: 

• The imlunestrant alone group experienced fatigue (2%) and neutropenia (2%)

• The imlunestrant + everolimus group experienced hypertriglyceridemia (5%) and aspartate aminotransferase increase (5%)

• The imlunestrant + alpelisib cohort experienced rash (43%) and hyperglycemia (10%).

• In the imlunestrant alone group, 2% of individuals had their doses reduced due to adverse events; none discontinued treatment

• In the imlunestrant + everolimus cohort, 12% of patients experienced dose reduction due to everolimus and 2% due to both medications; 2% discontinued treatment due to everolimus

• In the imlunestrant + alpelisib cohort, 24% of patients experienced dose reduction due to alpelisib and 14% due to both medications; 29% discontinued treatment due to alpelisib

Regarding efficacy:

• The objective response rates in the imlunestrant alone, imlunestrant + everolimus, and imlunestrant + alpelisib groups were 9%, 21%, and 50%, respectively

• The clinical benefit rates in the imlunestrant alone, imlunestrant + everolimus, and imlunestrant + alpelisib groups were 42%, 62%, and 62%, respectively

Investigators concluded that imlunestrant used alone or in combination with 1 of the 2 kinase inhibitors demonstrated robust efficacy in individuals with pretreated, ER-positive, HER2-negative advanced breast cancer. 

OPERA: OP-1250 Paired With a CDK4/6 Inhibitor: Anti-Tumor Activity With No Dose-Limiting Toxicities

Study synopsis

OP-1250, a CERAN and SERD, continues to show promising results when paired with a CDK4/6 inhibitor. The combination of OP-1250 and the CDK4/6 inhibitor palbociclib appears to be well tolerated and has a similar safety profile to each drug when used alone, according to a phase I/II study involving 20 individuals with pretreated ER-positive, HER2-negative breast cancer.

Participants had advanced or metastatic ER-positive, HER2-negative breast cancer that progressed on ≤1 lines of endocrine therapy. Fourteen participants had received prior CDK4/6 inhibitor therapy, including 11 who were previously treated with palbociclib. Patients received escalating doses of OP-1250 with 125 mg of palbociclib orally daily for 21 of 28 days. OP-1250 doses were 30 mg (n=3), 60 mg (n=3), 90 mg (n=3), and 120 mg (n=11). Investigators assessed pharmacokinetics, drug-drug interactions, safety, and efficacy. Among the results observed to date: 

• Grade 3 neutropenia occurred in 55% of participants

• There were no grade 4 treatment-related adverse events and no dose-limiting toxicities

• OP-1250 exposure yielded similar results to what was seen in the previous monotherapy study

• Palbociclib exposure was comparable to published monotherapy data when combined with OP-1250 for all dosages

• Investigators observed antitumor activity, including partial responses

Researchers concluded that OP-1250 does not affect the pharmacokinetics of palbociclib, and there do not appear to be drug-drug interactions. Tumor response to this combination was encouraging and requires continued investigation. 

Conclusions

These 3 studies presented at ESMO 2023 highlight exciting novel therapies for the treatment of HR-positive, HER2-low, and HER2-negative metastatic breast cancer. The EMBER and OPERA updates provide support for the safety and efficacy of these novel endocrine agents in combination with kinase inhibitors and CDK4/6 inhibitors, respectively, in patients with endocrine-sensitive disease, while the TROPION-01 study demonstrates the encouraging efficacy and safety of a second TROP-2-directed ADC in a more heavily pretreated population.