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Current Sequencing Approaches in HR+ mBC

Insights From: Debu Tripathy, MD, MD Anderson Cancer Center; Sara Hurvitz, MD, UCLA Jonsson Comprehensive Cancer Center; Hatem Soliman, MD, H. Lee Moffitt Cancer Center & Research Institute
Published: Tuesday, Aug 14, 2018



Transcript: 

Sara Hurvitz, MD: We are beginning to learn more and more about primary and secondary resistance mechanisms. For example, we now know that patients who’ve been treated for a long time with aromatase inhibitors, about 30% of them will develop an ESR1 mutation, which will render their disease resistant to aromatase inhibitors, but generally allows the patient’s disease to still be sensitive to fulvestrant.

Patients with de novo metastatic disease have much lower rates of ESR1 mutations. Other mutations and pathways—including the PI3-kinase pathway, for example, PIK3CA mutations—also can render patient’s resistant to therapy. Not necessarily to CDK4/6 inhibitors, but to hormone therapy per se. So, a number of inhibitors are being developed to target these pathways and help us circumvent these pathways as mechanism of resistance.

Hatem Soliman, MD: Sequencing strategies that we would need to consider still rely heavily on understanding the patient’s natural history, what therapies they have been exposed to ,and if they have been treated in the adjuvant setting or not, what therapies did they get in the adjuvant setting? An example would be if you have a woman who presented with non-metastatic disease, was treated with an aromatase inhibitor, and was fine for 3 years during her initial therapy but then relapsed while she was on the aromatase inhibitor, you would not want to start her on an aromatase inhibitor in that setting. And you would sequence her with fulvestrant in the first-line setting, preferentially with a CDK4/6 inhibitor in that scenario.

However, if the woman successfully completed multiple years of aromatase inhibitor therapy, stopped it, went for 2 to 3 years without any issues and then relapsed off of the aromatase inhibitor, you could argue that that woman still could be potentially sensitive to the aromatase inhibitor. And especially if she does not want to take injections monthly or have to come back as frequently for treatment, an aromatase inhibitor may still be a reasonable option in some of those patients. For a de novo patient who has not been treated and who presents to you with metastatic disease up front, especially if they’re bone-only, I would say the discussion needs to center around overall survival and the potential benefit  of starting with fulvestrant in that subgroup of patients versus using an aromatase inhibitor. And if the patient is agreeable, starting off with fulvestrant in that setting may be the most appropriate way to give her the best length of time during the first-line treatment in order to improve her quality of life and management of her disease.

Debu Tripathy, MD: The issue of a CDK inhibitor, I think, reflects back to what the NCCN guidelines are. I typically use a CDK inhibitor in my practice in first-line therapy, and if someone hasn’t received it in first-line therapy, then I use it in second-line therapy with whatever endocrine partner I’m giving.

But it’s important to recognize that there is not yet a survival advantage that has been demonstrated. It’s also important to recognize that these trials were not designed to detect a survival benefit because one would have to have a much, much larger study. And it’s always more difficult to show a survival benefit in first-line therapy because these patients are going to be on so many subsequent therapies and generally do have a much longer lifespan than, say, patients who get treated in later lines. So, I don’t know that we’ll ever detect a survival advantage. But the NCCN guidelines do leave the CDK issue as optional.

Now in my practice, I do tend to use CDK inhibitors. I think that that delay of progression is important. I think it may even delay when patients have to move on to chemotherapy. Some of those studies that are looking at quality of life have also shown that decrease in quality of life is delayed with the addition of a CDK inhibitor. So, it does seem to help with quality of life. For all of those reasons, I do tend to use CDK inhibitors in frontline therapy, whether I’m using fulvestrant or an aromatase inhibitor.

Hatem Soliman, MD: Abemaciclib monotherapy data right now primarily are generated through the MONARCH 1 trial. So, MONARCH 1 was a small phase II, single-arm trial that treated women who were heavily pretreated with both endocrine therapies and chemotherapies as well, who are hormone receptor–positive, HER2-negative, and who are treated with the higher dose of abemaciclib, 200 mg by mouth twice daily. And the trial showed a very remarkable rate of response and clinical benefit rate that was in excess of 40% and overall survival that was over 20 months. And that data led to the FDA approval for single-agent monotherapy with abemaciclib in women who have seen prior endocrine lines of therapy and also chemotherapy. But the data did not include patients who were exposed to a CDK4/6 inhibitor previously. All the patients on MONARCH 1 were CDK4/6-naïve, and so, as that pool of patients shrinks over time as more people get CDK4/6 in the earlier lines of therapy or potentially even in the adjuvant setting, that population is not going to reflect what was enrolled on MONARCH 1. So, additional trials and data will need to be generated to see if it retains that same level of activity in CDK4/6-exposed patients over time.

Transcript Edited for Clarity
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Transcript: 

Sara Hurvitz, MD: We are beginning to learn more and more about primary and secondary resistance mechanisms. For example, we now know that patients who’ve been treated for a long time with aromatase inhibitors, about 30% of them will develop an ESR1 mutation, which will render their disease resistant to aromatase inhibitors, but generally allows the patient’s disease to still be sensitive to fulvestrant.

Patients with de novo metastatic disease have much lower rates of ESR1 mutations. Other mutations and pathways—including the PI3-kinase pathway, for example, PIK3CA mutations—also can render patient’s resistant to therapy. Not necessarily to CDK4/6 inhibitors, but to hormone therapy per se. So, a number of inhibitors are being developed to target these pathways and help us circumvent these pathways as mechanism of resistance.

Hatem Soliman, MD: Sequencing strategies that we would need to consider still rely heavily on understanding the patient’s natural history, what therapies they have been exposed to ,and if they have been treated in the adjuvant setting or not, what therapies did they get in the adjuvant setting? An example would be if you have a woman who presented with non-metastatic disease, was treated with an aromatase inhibitor, and was fine for 3 years during her initial therapy but then relapsed while she was on the aromatase inhibitor, you would not want to start her on an aromatase inhibitor in that setting. And you would sequence her with fulvestrant in the first-line setting, preferentially with a CDK4/6 inhibitor in that scenario.

However, if the woman successfully completed multiple years of aromatase inhibitor therapy, stopped it, went for 2 to 3 years without any issues and then relapsed off of the aromatase inhibitor, you could argue that that woman still could be potentially sensitive to the aromatase inhibitor. And especially if she does not want to take injections monthly or have to come back as frequently for treatment, an aromatase inhibitor may still be a reasonable option in some of those patients. For a de novo patient who has not been treated and who presents to you with metastatic disease up front, especially if they’re bone-only, I would say the discussion needs to center around overall survival and the potential benefit  of starting with fulvestrant in that subgroup of patients versus using an aromatase inhibitor. And if the patient is agreeable, starting off with fulvestrant in that setting may be the most appropriate way to give her the best length of time during the first-line treatment in order to improve her quality of life and management of her disease.

Debu Tripathy, MD: The issue of a CDK inhibitor, I think, reflects back to what the NCCN guidelines are. I typically use a CDK inhibitor in my practice in first-line therapy, and if someone hasn’t received it in first-line therapy, then I use it in second-line therapy with whatever endocrine partner I’m giving.

But it’s important to recognize that there is not yet a survival advantage that has been demonstrated. It’s also important to recognize that these trials were not designed to detect a survival benefit because one would have to have a much, much larger study. And it’s always more difficult to show a survival benefit in first-line therapy because these patients are going to be on so many subsequent therapies and generally do have a much longer lifespan than, say, patients who get treated in later lines. So, I don’t know that we’ll ever detect a survival advantage. But the NCCN guidelines do leave the CDK issue as optional.

Now in my practice, I do tend to use CDK inhibitors. I think that that delay of progression is important. I think it may even delay when patients have to move on to chemotherapy. Some of those studies that are looking at quality of life have also shown that decrease in quality of life is delayed with the addition of a CDK inhibitor. So, it does seem to help with quality of life. For all of those reasons, I do tend to use CDK inhibitors in frontline therapy, whether I’m using fulvestrant or an aromatase inhibitor.

Hatem Soliman, MD: Abemaciclib monotherapy data right now primarily are generated through the MONARCH 1 trial. So, MONARCH 1 was a small phase II, single-arm trial that treated women who were heavily pretreated with both endocrine therapies and chemotherapies as well, who are hormone receptor–positive, HER2-negative, and who are treated with the higher dose of abemaciclib, 200 mg by mouth twice daily. And the trial showed a very remarkable rate of response and clinical benefit rate that was in excess of 40% and overall survival that was over 20 months. And that data led to the FDA approval for single-agent monotherapy with abemaciclib in women who have seen prior endocrine lines of therapy and also chemotherapy. But the data did not include patients who were exposed to a CDK4/6 inhibitor previously. All the patients on MONARCH 1 were CDK4/6-naïve, and so, as that pool of patients shrinks over time as more people get CDK4/6 in the earlier lines of therapy or potentially even in the adjuvant setting, that population is not going to reflect what was enrolled on MONARCH 1. So, additional trials and data will need to be generated to see if it retains that same level of activity in CDK4/6-exposed patients over time.

Transcript Edited for Clarity
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