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New Insights in Breast Cancer: Independent Conference Coverage of SABCS 2020
  • CME

Sara Hurvitz, MD, FACP
Joyce O'Shaughnessy, MD
Released: February 19, 2021

Advances in the Treatment of Hormone Receptor–Positive/HER2-Negative MBC

CONTESSA: Tesetaxel Plus Capecitabine vs Capecitabine in Hormone Receptor+/HER2- MBC With Prior Taxane

Joyce O’Shaughnessy, MD:
I had the opportunity to present the first data on the multicenter, open-label, randomized phase III CONTESSA trial of tesetaxel plus capecitabine vs capecitabine alone in patients with hormone receptor–positive/HER2-negative MBC who had received previous taxane therapy (N = 685).[23] Although patients were required to have received previous taxane therapy, there was no requirement for a minimum disease-free interval (eg, duration of at least 1 year) before entering the trial. Patients were randomized to single‑agent oral capecitabine at the FDA-approved dose (1250 mg/m2 twice daily, 14 days on/7 days off) vs a lower dose of capecitabine (825 mg/m2 twice daily, 14 days on/7 days off) plus oral tesetaxel given on Day 1 of a 3-week cycle. The primary endpoint was PFS by an independent radiology committee.


Joyce O’Shaughnessy, MD:
The primary endpoint of PFS was significantly positive, with an HR of 0.716 in favor of tesetaxel plus capecitabine (P = .003). The absolute improvement was 2.9 months.

CONTESSA: PFS by IRC Across Subgroups

Joyce O’Shaughnessy, MD:
The PFS benefit with tesetaxel plus capecitabine was seen in many subgroups, including patients younger than 65 years of age (P = .003), those with baseline Eastern Cooperative Oncology Group performance score of 0 (P = .002), and those with visceral or CNS disease (P = .004). In the 50% of patients who had not had CDK4/6 inhibitor therapy, the HR was 0.67 (P = .013), whereas in patients who had previous CDK4/6 inhibitors, the HR for PFS was 0.76 (P = .086). However, there is a lot of overlap in those confidence intervals. Patients with a shorter disease‑free interval following previous taxane therapy did just as well as those with a longer disease‑free interval following previous taxane therapy. That is encouraging, showing potential non–cross‑resistance of tesetaxel with other taxanes.

CONTESSA: Response

Joyce O’Shaughnessy, MD:
The ORR was also greater with the addition of tesetaxel, as was the disease control rate, which was defined the same way as the classical clinical benefit rate. We saw a 67% clinical benefit rate with the combination vs 50% with single-agent capecitabine (P < .0001).

CONTESSA: Adverse Events

Joyce O’Shaughnessy, MD:
Safety was acceptable. Eight percent of patients in the tesetaxel plus capecitabine arm had grade 2 alopecia and 28% had any alopecia (20% were grade 1). The main toxicity was neutropenia, including a grade 4 neutropenia rate of 38% with tesetaxel plus capecitabine. This was managed with dose reduction and/or utilization of filgrastim, per physician’s discretion, on non‑capecitabine days. The febrile neutropenia rate was 13% with the combination and some patients had grade 1/2 diarrhea or stomatitis, but that was a minority of patients.

CONTESSA: Adverse Events Leading to Discontinuation

Joyce O’Shaughnessy, MD:
Fortunately, neuropathy was quite uncommon with the tesetaxel, which is helpful for our patients who had preexisting neuropathy from their previous taxane. Only 4.2% of patients stopped tesetaxel plus capecitabine because of neutropenia or febrile neutropenia.

CONTESSA: Clinical Implications

Joyce O’Shaughnessy, MD:
These data demonstrate that the addition of a taxane—in this case an oral taxane—to capecitabine improves PFS for patients with hormone receptor–positive/HER2-negative MBC who have received previous taxane therapy. We knew this from previous phase III trials. However, pending approval of tesetaxel, we may then have an oral option for a taxane. I think taking two oral agents will be a welcome addition for patients who need a combination of cytotoxic agents, a strategy we generally do not pursue unless patients have a heavy tumor burden, virulent disease, and are very symptomatic. I think that tesetaxel will have some monotherapy use as well, and patients will be able to forego placement of a portacath and will have a low pill burden while retaining the benefits of taxane therapy in the metastatic setting.

Sara Hurvitz, MD, FACP:
It is exciting to see phase III results reported with oral tesetaxel with the possibility of having this agent available to our patients in the near future. Oral chemotherapy has obvious advantages to our patients and the lower rates of alopecia, in particular, are exciting. That said, I am not surprised to see better ORRs and PFS with doublet chemotherapy compared with single‑agent chemotherapy. This has been demonstrated in multiple clinical trials. However, the use of doublet chemotherapy has not been shown to improve OS in the long run compared with sequential single‑agent therapy. I hope that, in the future, we will see results from trials evaluating the use of tesetaxel as a single agent so that we will have the availability of single‑agent oral chemotherapy for our patients to be used in sequence.

MONALEESA-7: Ribociclib Plus Endocrine Therapy in Hormone Receptor+/HER2- Advanced Breast Cancer

Joyce O’Shaughnessy, MD:
MONALEESA‑7 is an international, double-blind, randomized phase III study comparing the CDK4/6 inhibitor ribociclib plus ET vs placebo plus ET in younger (< 59 years) pre/perimenopausal women with hormone receptor–positive/HER2-negative advanced breast cancer (N = 672).[24-26] In addition to ribociclib or placebo, all patients received ET with either an aromatase inhibitor or tamoxifen as well as goserelin for ovarian function suppression to essentially render them postmenopausal. The primary endpoint of PFS was met: The addition of ribociclib to ET significantly improved PFS by more than 10 months (HR: 0.55).[26] In addition, there was a significant improvement in OS for patients who received ribociclib plus ET (HR: 71; P = .00973).[25] The FDA did not approve the tamoxifen combination with ribociclib because of the possibility of prolonged QTc, which is associated with tamoxifen as well as ribociclib in a small proportion of patients. But they did approve the nonsteroidal aromatase inhibitor plus goserelin and ribociclib because of the improvement in both PFS and OS compared to goserelin plus an AI with placebo. At SABCS 2020, the investigators presented updated survival data for MONALEESA-7.

MONALEESA-7: Updated OS in ITT Population (Key Secondary Endpoint)

Joyce O’Shaughnessy, MD:
The statistically significant improvement in OS was maintained in the ribociclib arm, with a HR of 0.763 and a 10‑month improvement in median OS vs placebo. This was equivalent to a 24% reduction in the risk of death. Among patients who received the nonsteroidal aromatase inhibitor, adding ribociclib led to an 11‑month improvement in median OS compared with placebo (58.7 vs 47.7 months, respectively). That is very impressive and gratifying to see the addition of the CDK4/6 inhibitor translate into an OS benefit in this premenopausal population.

MONALEESA Biomarker Analysis: Intrinsic Breast Cancer Subtype and Efficacy With Ribociclib Plus ET in Hormone Receptor+/HER2- Advanced Breast Cancer

Joyce O’Shaughnessy, MD:
The MONALEESA investigators undertook a retrospective, exploratory analysis of the MONALEESA-2, -3, and -7 data to evaluate if there was any association of intrinsic breast cancer subtype with efficacy benefit in the ribociclib arms (n = 1106 tumor samples).[27] Prognostic relationships were evaluated by univariate and multivariable Cox proportion hazard models.

MONALEESA Biomarker Analysis: Selected Baseline Characteristics

Joyce O’Shaughnessy, MD:
The biomarker positive population was similar to the intention-to-treat population in key patient and tumor characteristics.

MONALEESA Biomarker Analysis: PFS by Intrinsic Subtype

Joyce O’Shaughnessy, MD:
The analysis revealed that patients with luminal A, luminal B, and HER2‑enriched subtypes all benefited greatly from ribociclib. Based on the enrollment criteria, all patients were hormone receptor positive/HER2 negative, but a subset of the patients had HER2‑enriched disease. These patients had an extraordinary PFS benefit, with an HR of 0.39 (P < .001). A small number of patients with basal‑like subtype did not benefit from ribociclib, as we would expect. These patients have the worst prognosis and are going to be more effectively treated with chemotherapy rather than ET. 

MONALEESA: Clinical Implications

Joyce O’Shaughnessy, MD:
To summarize, the MONALEESA-7 trial demonstrated a persistent survival improvement that is considerable with a nonsteroidal aromatase inhibitor plus goserelin and ribociclib in premenopausal women with hormone receptor–positive/HER2‑negative metastatic breast cancer. This OS improvement of 11 months is really holding up with the extended follow-up. To my mind, this is the “go-to” regimen for our premenopausal or perimenopausal patients who require first‑line metastatic therapy for hormone receptor–positive/HER2‑negative disease. Together with data from the MONALEESA‑2 (also first line with letrozole) and MONALEESA‑3 (first line or second line with fulvestrant) trials, we can be confident that even patients with grade 3, highly proliferative breast cancer will have a substantial benefit from ribociclib.[28,29]

Sara Hurvitz, MD, FACP:
I think these sustained OS benefits from the MONALEESA‑7 trial are very important, especially given that the initial reporting of survival from this study showed that the Kaplan-Meier curves separated relatively late in the trial. There was a lot of speculation around the time of that reporting that the curves may come together over time, so I am quite encouraged to see the curves remain separate and I believe that these data support the use of this agent as standard of care for premenopausal and perimenopausal women with advanced hormone receptor–positive/HER2-negative breast cancer.

I also think it is encouraging to see that ribociclib benefits patients with all intrinsic subtypes of breast cancer, with the exception of the basal‑like subtype, which, thankfully, tends to be rare and often, in my opinion, can be picked up by its high‑grade, more aggressive clinical behavior and often lower expression of hormone receptors.

BYLieve (Cohort B): Alpelisib Plus Letrozole in PIK3CA-Mutated Hormone Receptor+/HER2- Advanced Breast Cancer After CDK4/6i Plus AI

Joyce O’Shaughnessy, MD:
The open-label, multicohort, noncomparative phase II BYLieve trial evaluated alpelisib plus ET in patients with PIK3CA-mutated hormone receptor–positive, HER2-negative advanced breast cancer who had been immediately previously treated with a CDK4/6 inhibitor plus ET, systemic chemotherapy, or ET alone.[30] The primary endpoint was the proportion of each cohort alive without progressive disease at 6 months, and the endpoint was considered positive if the lower 95% CI was > 30%. At SABCS, Dr. Rugo and colleagues presented an update on cohort B, patients with previous CDK4/6 inhibitor plus fulvestrant who then received alpelisib plus letrozole (n = 126).

BYLieve (Cohort B): Efficacy

Joyce O’Shaughnessy, MD:
The results showed a clinical benefit rate of 32% in this cohort. At 6 months, 46% of patients were progression free, and this exceeded the 95% CI lower limit of 30% that they would accept for a positive trial. Thus, the primary endpoint was met for this cohort and that is quite gratifying. The median PFS was 5.7 months and the ORR was 15.7%.

These data show me that it is reasonable to consider letrozole plus alpelisib for patients whose disease is progressing on fulvestrant plus a CDK4/6 inhibitor, and we can expect that approximately one half of them will have substantial clinical benefit. These are very practical data to have for our daily practice.

BYLieve (Cohort B): Safety

Joyce O’Shaughnessy, MD:
The safety profile was manageable. Patients were eligible for this trial if they had a hemoglobin A1C ≤ 6.4% and fasting plasma glucose ≤ 140 mg/dL. That point is important, because patients with uncontrolled diabetes do not do well with alpelisib; they often develop serious hyperglycemia. Hyperglycemia was the most common reason for dose adjustment/interruption, but in this trial population, adding metformin works well. Other common causes of dose reduction were diarrhea and rash. The rash can be prevented with a nondrowsy antihistamine regimen. It must be administered prophylactically, as it does not work well once the patients get a rash. I recommend it twice daily and I rarely see significant rash that leads to interruption and dose reduction.

BYLieve: Clinical Implications

Sara Hurvitz, MD, FACP:
The BYLieve study is important because it augments the amount of data we have supporting the use of alpelisib in patients who received previous CDK4/6 inhibitors and/or first‑line fulvestrant. The SOLAR‑1 study of course excluded previous fulvestrant.[31] Some patients in this study had received an aromatase inhibitor in combination or as a single agent, and it is important to see the activity of alpelisib in this population.

I should point out that BYLieve was not randomized. However, it does support the activity of this agent in those with tumor PIK3CA mutations and in the context of those prior therapies.

SOLAR-1: Alpelisib Plus Fulvestrant vs Placebo Plus Fulvestrant in Hormone Receptor+/HER2- Advanced Breast Cancer

Joyce O’Shaughnessy, MD:
The randomized, double-blind phase III SOLAR-1 trial evaluated alpelisib plus fulvestrant vs placebo plus fulvestrant in patients with hormone receptor–positive/HER2-negative advanced breast cancer whose disease progressed with previous aromatase inhibitor therapy (N = 572).[31,32] The primary analysis previously demonstrated a significant improvement in PFS with alpelisib in patients with PIK3CA‑mutations.[31]

SOLAR-1 Biomarker Analysis: Methods

Joyce O’Shaughnessy, MD:
The current exploratory analysis of SOLAR-1 evaluated outcomes in patients with and without PIK3CA alterations as retrospectively detected in ctDNA and by NGS. This was interesting, as NGS of breast cancer tissue detected some alterations that were not picked up by the PCR assay in tumor tissue performed at study screening. Among 193 patients with detectable PIK3CA alterations on tissue, 87% were also detectable by PCR.

SOLAR-1 Biomarker Analysis: Discordance Between PIK3CA Detection in ctDNA vs Tumor Tissue

Joyce O’Shaughnessy, MD:
This NGS analysis revealed a discordance between detectable PIK3CA alterations in ctDNA vs tumor tissue and treatment outcomes in the trial. Patients without detectable PIK3CA alterations in ctDNA who did have detectable PIK3CA alterations in their breast cancer tissue had a very robust improvement in PFS with the alpelisib. The median PFS was approximately 22 months with alpelisib plus fulvestrant vs approximately 10 months in the placebo arm.

SOLAR-1 Biomarker Analysis: Clinical Implications

Joyce O’Shaughnessy, MD:
These data tell us that if patients do not have a PIK3CA mutation in their plasma ctDNA sample, it is important to go back and test their tumor tissue by NGS because 38% of those patients’ cancers could harbor a PIK3CA mutation. Those patients may benefit from alpelisib. Hence, it is reasonable to start with ctDNA, but do not stop there if it is negative.

Sara Hurvitz, MD, FACP:
I agree. The SOLAR‑1 data presented at SABCS underscores the importance of testing tumor tissue if ctDNA is negative. I was really interested to see that nearly 40% of patients who had negative plasma ctDNA were found to have a PIK3CA alteration by tumor testing. Hence, when we see a negative ctDNA result in the clinical setting, it is critical for us to then test the tumor tissue to ensure that we are not missing patients who may be eligible for this treatment.

E2112: Entinostat Plus ET vs Placebo Plus ET in Hormone Receptor+/HER2- Advanced Breast Cancer

Joyce O’Shaughnessy, MD:
The randomized phase III E2112 trial evaluated the histone deacetylase (HDAC) inhibitor entinostat vs placebo, both paired with exemestane, in patients with hormone receptor–positive/HER2‑negative advanced breast cancer who had received nonsteroidal aromatase inhibitor therapy and no more than 1 previous chemotherapy for metastatic disease (N = 600).[33] Approximately 35% of patients had received a previous CDK4/6 inhibitor. Unfortunately, the primary endpoints of PFS and OS were not met. Adding entinostat did not change the natural history of the metastatic disease in these patients following progression on a nonsteroidal aromatase inhibitor. These results were disappointing in the wake of the randomized phase II ENCORE301 trial, which had shown a survival advantage with entinostat plus exemestane in the same population.[34] Moreover, an earlier phase III trial in China had demonstrated a PFS benefit of adding another HDAC inhibitor, tucidinostat, to exemestane in a similar patient population.[35]

It is unclear why the E2112 trial was negative. I would like to see further clinical evaluation of HDAC inhibitors in HR+ MBC because in preclinical models HDAC inhibitors can resensitize breast cancer to ET.[36]

Sara Hurvitz, MD, FACP:
There was a lot of excitement when the phase II ENCORE301 trial was reported. But, of course, those results had to be confirmed in a larger phase III trial, which was the E2112 study. Unfortunately, this larger phase III study failed to demonstrate any benefit with the addition of entinostat to ET, and based on these data, I do not think we will see further development of entinostat in this setting.

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