This video features Melissa McShane, MD presenting on MBC. This presentation was given at our January 19th 21st Annual Highlights of the 2022 San Antonio Breast Cancer Symposium in 2023.
Hello. My name is melissa Mcshane and I'm an assistant professor in the department of hematology oncology here at Fox Chase Cancer Center. I'm going to review a few pertinent presentations from the SAN Antonio breast cancer symposium in regards to hormone receptor positive her two negative metastatic breast cancer. I have no disclosures. Here is my agenda. I will be reviewing five presentations including the Emerald trial serena to their attack capital A 291 and tropic so to the first presentation that I will review is the Emerald trial. This is a phase three trial of Ellis Restaurant versus Standard of Care endocrine therapy in patients with er positive her two negative metastatic breast cancer. This presentation reviewed the updated results by duration of Prior CTK 46 inhibitor use in the metastatic setting. This was presented by Dr Kaku Mani. The investigators sought to examine the impact of the duration of Prior CTK 46 inhibitor use on PFS and share updated safety results. A brief review of the study design Some notable inclusion criteria included. All patients had to have received a C. D. K 46 inhibitor and equal to or less than one line of chemotherapy was allowed patients were randomized to Ellis Restaurant 400 mg daily versus investigator's choice of standard of care, full veteran or an AI the primary endpoints were PFS. In all patients and P. F. S and E. S. R. One mutant patients. Dr Ramani noted that since the length of duration of C. D. K 46 inhibitor is one of the parameters used to determine endocrine sensitivity. They conducted a post talk analysis of ellis Estrin versus standard of care hormonal therapy based on the duration of prior C K 46 inhibitor. In the metastatic setting they divided CTK 46 inhibitor used into at least six months, at least 12 months and at least 18 months. The results show that the longer the duration of CDK- 46 inhibitor therapy, the greater the benefit from later lines of endocrine therapy reflecting a more endocrine sensitive to the observation was more pronounced in the Alice Estrin arm. PFS rates at different pre specified time points demonstrate a consistent benefit of Alice's restaurant over standard of care and at 18 months nearly five fold increase in PFS rate for else Estrin over standard of care. As shown in these Kaplan meier curves the longer the duration of prior CTK 46 inhibitor therapy, the longer the median PFS on L. Session or substandard of care, hormonal therapy, the benefit of Alice's restaurant over standard of care is more pronounced in tumors harboring an E. S. R one mutation, 71.6% of patients had at least 12 months of a C D K 46 inhibitor and those that had at least 12 months achieved a median PFS of 8.61 months on L. C. Restaurant versus 1.91 months on standard of care PFS rates at pre specified landmark time points also demonstrated a consistent benefit of Alice's restaurant over standard of care, there were no patients with an E. S. R. One mutated tumor on standard of care who were progression free at 18 months versus 30% on the al Sesto arm who were progression free at this time. Point Updated safety data were consistent with previously reported results. Most adverse events were Grade one and 2 and there were no great for treatment related adverse events, adverse events reported. These were their conclusions. The longer the duration of Prior CTK 46 inhibitor, the longer PFS on ellis Estrin. As compared to standard of care. This was even more pronounced in patients with an E. S. R. One mutated mutated and there were no new safety signals, mostly just low grade nausea. Their final conclusion was that Alice Estrin can become an important oral endocrine monotherapy agent in 2nd and 3rd line as an alternative to combination therapies that can be associated with challenging safety profiles. The next presentation I will review is the results from the randomized multi dose phase two serena trout which looked at camas, Estrin and next generation oral surgery versus full restaurant in postmenopausal. Women with advanced er positive, her two negative breast cancer. This was presented by dr Oliveira. For those who are not familiar with campus Estrin. This is an next generation oral selective estrogen receptor. Degrade er serena one demonstrated the safety tolerable itty and preliminary clinical efficacy at a range of doses serena two was designed to explore efficacy and safety of a range of doses administered once daily as monotherapy. In comparison to full veteran, the current surge standard of care. This is an overview of the study serena to is randomized open label multi center phase two that included postmenopausal women with er positive her two negative advanced breast cancer who are candidates for a full restaurant monotherapy. Key inclusion exclusion criteria included recurrence or progression on at least one line of endocrine therapy. No prior full veteran or oral surgeon in advanced breast cancer patients were stratified by prior use of CDK 46 inhibitor, liver and lung mets and then randomized to receive chemo session at three different doses or full veteran camas, Estrin 300 mg arm was closed in december 2020. Primary endpoint was PFS. Serena two was designed to compare each of the cameras Estrin doses with full veteran. It was not powered to compare the clams Estrin doses with each other. These are the baseline patient characteristics. A few things to be aware of, 50% of included patients had received prior CTK 46 inhibitor E. S. R one mutations were present in 36% of patients overall this proportion was slightly higher in the full restaurant arm. 20% of patients have received previous chemotherapy. In looking at the primary endpoint PFS by investigator assessment system produced a statistically significant and clinically meaningful improvement in PFS for both 75 100 50 mg doses over full restaurant median PFS of 7.2 months for the 75 mg dose ng and 7.7 months for the 150 mg dose ng. As compared to the 3.7 months in the full restaurant. In the cell population of patients with detectable es are one mutation at baseline chemise Estrin. At both doses, improved PFS over full restaurant median PFS was 6.3 months for the 75 mg dose ng 9.2 months for the 150 mg dose ng versus 2.2 months for the full restaurant dozing for for western. Among patients with no ES are one mutation detected at baseline. The magnitude of benefit was smaller but has a ratio still favored Caymus Estrin and 0.78 at the 75 mg dosing and 0.76 at 150 mg dosing when they looked at PFS by er driven disease which is um They defined this by those patients who had previously received 12 months of endocrine therapy and a C. D. K 46 inhibitor. The median PFS was 7.4 months for the 75 mg dose ng. 12 months for the 150 mg dose ng as compared to 3.2 months with full veteran with respective hazard ratios of 0.53 and 0.58. This subgroup of patients with er driven disease made up 71.3% of the overall population. Treatment related adverse events of grade three or higher and treatment related adverse events leading to discontinuation were infrequent across all treatment arms treatment emergent adverse events that occurred in more than 10% of patients in the kims Estrin arms worth a top CIA, Sinus bradycardia, fatigue, anemia xenia and are thrilled to the vast majority of the top CIA and sinus bradycardia were grade one events. Here are their conclusions commis Estrin at both 75 mg and 100 50 mg doses improves. PFS over full Restaurant benefit was seen in the pre specified subgroups including those with the S. R. One mutated disease and evidence of er driven disease. In the phase three trial they will be using the 75 mg dose ng. The next presentation of review is the phase two expansion fair attack of a Phase one. To study of a RV 471. A pro tech estrogen receptor degrade er in advanced er positive Her two negative breast cancer. This was presented by DR Shot A. R. V. 471 is a selective protein degradation er that can degrade both wild type and mutant estrogen receptors. A RV 471 directly binds both the E. R. And the E. Three ubiquity in legs to initiate ubiquity nation and subsequent protas Amiel degradation of estrogen receptors. This differs from surge such as restaurant which causes a degradation secondary to er confirmation all changes or immobilization. A. R. 47 ones distinct mechanism of action may provide more robust er degradation that may translate to stronger anti tumor effects. The primary objective of their attack is to evaluate the anti tumor activity of orally administered. A RV 471 Key eligibility criteria included one or more endocrine regimens. One or more of those had to be for greater than or equal to six months prior C. K. 46 inhibitor therapy and up to one prior chemo regimen. In the advanced setting, Patients were assigned to 200 or 500 mg once daily dosing groups. Primary endpoint was clinical benefit rate here. The patient characteristics 58% of patients had an E. S. R. One mutation positive. The population was heavily pre treated with a median three prior lines of therapy. In the metastatic setting 100% have received C. D. K. 46 per inclusion criteria, 90% had prior ai 70% had prior full restaurant and 45% had chemotherapy in the metastatic setting. The most common adverse events in both cohorts was nausea fatigue, arthur raja, hot flush and increased A. S. T. Except for one grade three fatigue. All were grade one or two. The overall clinical benefit rate was 37% which was notable given the heavily pre treated population. The clinical benefit rate was similar in the 200 mg and 500 mg cohorts. At 37.1 and 38.9%. They also looked at the clinical benefit rate in the sub population of patients with an E. S. R. One mutation positive. It was 47.4% in the 200 mg cohort and 54.5% in the 500 mg cohort. This is notable given that E. S. R. One mutant tumors can be resistant to endocrine therapies including full restaurant progression free survival was evaluated in the overall population and the S. R. One mutation mutation positive population for both doses combined, shown in purple. The 200 mg cohort is in blue. The 500 mg Cohort began enrollment after the 200 mg cohort. So the data was not mature at the time of the data cut, median PFS was 3.5 months in the 200 mg cohort and 3.7 months in the overall population. In the mutant es are one population. The median PFS was 5.5 months in the 200 mg cohort and 5.7 months in the total es are one mutation subgroup. Their conclusions included. The R. V. 471 showed clinical activity in the bear attack expansion cohorts of heavily pre treated patients with er positive. Her two negative advanced breast cancer. A. R. A. R. V. 471 had a manageable a profile. Most adverse events were grade one or two and R. V. 471 200 mg daily dosing was selected as the phase three monotherapy dose based on comparable efficacy favorable tolerable itty and robust er degradation. The next presentation I will review are the results from the phase three Kappa Tell oh 291 trial, assertive and full restaurant for patients with aromatase inhibitor resistant hormone receptor positive, her two negative advanced breast cancer. This was presented by DR Turner A. K. T. Pathway activation occurs in many hormone receptor positive her two negative advanced breast cancers through alteration in PIK three C A A. K. T and P. 10. But these may occurring cancers without these genetic alterations. A Katie signaling is also implicated in the development of resistance to endocrine therapy is a potent selective inhibitor of all three A. K. T. I. So forms here is the study overview. All patients had to have progressed on previous aromatase inhibitor therapy up to two lines of endocrine therapy and one line of chemotherapy for advanced breast cancer was allowed Prior CTK 46 inhibitors was allowed at least 51% was required, Patients were randomized to full veteran and assertive were full veteran and placebo with the randomization stratified by the presence of liver mets prior CK 46 inhibitor use and region Of note cap of assertive is given 400 mg b. i. d. for four days on followed by three days off. There were two co primary endpoints PFS by investigator assessment. Both overall and by a Katie pathway altered. They had to require one or more qualified pick three C. A. A. K. T. One or P 10 alterations. Key secondary endpoints included overall survival and objective response rate. Baseline characteristics were well balanced, both overall and the A. K. T. Pathway altered tumors. Overall the median age was 59 77% of patients were postmenopausal and 37% of patients had primary endocrine resistance. Prior treatments were also well balanced between the groups. 69% of patients had a prior CTK46 inhibitor A. K. T. Pathway alterations were assessed in tissue that was collected prior to randomization. Overall 41% of patients had an A. K. T. Pathway alteration and these were well balanced. As expected. The majority were picked three C. A mutations also 15% had an unknown result predominantly because there was insufficient DNA for sequencing after extraction. In looking at the results. First we had the investigators SPFs. In the overall population median PFS was 3.6 months with Silvestro and placebo which increased to 7.2 months with cup of assertive And full restaurant with a hazard. With an adjusted hazard ratio of 0.60. Here's the investigator assessed PFS in the A. K. T. Pathway alter population which was 3.1 months with full vista and placebo which increased to 7.3 months with Sylvester and plus capital assertive with an adjusted hazard ratio. 0.50 dr. Turner also reported an exploratory analysis of investigator assessed PFS in the non altered populations including unknowns. The hazard ratio here was 0.70. Now, if excluding the unknowns, the hazard ratio increased to 0.79. He reported that the two had very had largely very similar curves. Here's the force plot of the pre specified subgroup analysis. Across all subgroups, there was consistent efficacy. They highlighted those with or without liver metastases and those with or without priorities of C. K 46 inhibitors had similar benefit favoring captive assertive and full restaurant. Any serious adverse event occurred in 16.1% of those on top of assertive and 8% on placebo. Any adverse event leading to death was 1.1% or four patients on top of assertive and 0.3% or one patient on placebo did not review this during the presentation, but per the footnote, no grade five events were classified as related to cap of assertive or placebo by the local investigator, Adverse events leading to discontinuation were 13% on capital, assertive and 2.3% on Placebo. Most common adverse events in cap of assertive included diarrhea, mostly grade one or two and there were 9.3% of grade three diarrhea. There were 38% of patients overall with rash and hyperglycemia and Stamatis were low on top of assertive with 2.3%. Grade three hyperglycemia and 2.0%. Grade three sta mastitis. Their conclusions were that type of a start plus full restaurant provides a statistically significant and clinically meaningful improvement in PFS in both the overall and a Katie pathway alter population. Overall survival. Follow up is ongoing. Lastly, I will briefly review the presentation on the tropics. So to study of patients with hormone receptor positive, her two negative metastatic breast cancer. This presentation reviewed the efficacy analysis by Trop two expression of icam versus treatment of physicians choice. This was presented by DR Rogo. Here is the study design eligible patients had to have at least one endocrine therapy taxing and c D k 46 inhibitor in any setting, at least two or more at least two, but no more than four lines of chemotherapy for metastatic disease patients were randomized 1212 Saskatoon Vatican or treatment of physicians choice which included capeside bean mineral being Jim city being or rebellion. Primary endpoint was PFS. This is an exploratory analysis to evaluate the potential impact of trop two expression on efficacy outcomes in tropics to trip to was not required to determine patient eligibility for this trial and was not a stratification factor. A total of 85% of patients had samples of valuable for Trump to expression and expression was found in 95% of patients. PFS for a trope to age. Score cut off of 100 is dictated here for less than 100 sub for those who had less than 100 this subgroup, The median PFS was 5.3 months for society as a mob and four months for treatment of physicians choice if over 100 for the median progression free survival was 6.4 months and 4.1 months in treatment of physicians choice. This PFS status suggests benefit from Saskatchewan over TPC regardless of trope to score. Similar results were seen with trope to score cut off of 10. So this is the less than or equal to less than or equal to 10 subgroup versus the 10 to 100 subgroup, although there are small sample sizes so needs to be careful when interpreting the data. Overall survival outcomes also favored massachusetts over TPC regardless of trope to score. Again, looking at the cut off of less than 100 versus over 100. And in both groups, Sassa choose a map had a longer median Os as compared to treatment of physicians choice. Os benefit was also seen in those with a very low trope to score 10 or less, although just like PFS sample sizes for this subgroup or small and results should be interpreted with caution. In conclusion, PFS and Os benefit of Sassafras mob over treatment of physicians choice was observed across all trope. Two subgroups of safety profile was not impacted by trop two expression and trope to testing is not required for treatment. Finally, I will review my summary or take home points from my presentations in Emerald. The majority of benefit of ellis Estrin over for veteran is in E. S. R. One mutated. And if the FDA approves ellis Estrin it is unclear if it will require PSR one mutation to be used for it to be used. The benefit clearly improves with history of longer C. D K 46 inhibitor duration. As we saw from their presentation in serena two cameras Estrin provided a PFS benefit over full restaurant. This was most profound and E. S. R. One mutated and er driven disease subgroups. The Phase three trials for chemistry are currently ongoing and being recruited A R. V 471 pro tech. It's a new class of drug with a new mechanism of action. So I think the studies show that it has definitely has to anti tumor activity but ongoing studies are required to see where it will actually fit in in this er resistant sub um E. R resistant population of metastatic breast cancer cap of assertive and full veteran are potential targeted combination therapy and Ai resistant disease as shown by the capital a trial. But the big question is how will this compare to Al Pelous IB and where will it work in the current scheme of a Katie pathway altered tumors And lastly sassy Govt can improves PFS and Os over treatment and physician's choice regardless of trop two expression. So trope to testing is definitely not required for sausages, um, abuse. Thank you for listening. And I will take any questions during the Q and a session.
