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Key Studies in Breast and Gynecologic Cancers: Independent Conference Coverage of the 2020 ASCO Virtual Scientific Meeting

Sara Hurvitz, MD, FACP
Bradley J. Monk, MD, FACS, FACOG
Released: September 9, 2020

Breast Cancer

ECOG-ACRIN 2108: Early Local Therapy for Metastatic Breast Cancer With an Intact Primary Tumor: Background

Sara Hurvitz, MD, FACP:
ECOG-ACRIN 2108 is a phase III trial evaluating whether or not early locoregional therapy for patients with de novo metastatic breast cancer and an intact primary tumor improves survival after systemic therapy compared with continued systemic therapy followed by locoregional therapy as needed for palliation (Capsule Summary).[1] This trial is addressing a very important clinical question. In the United States, 5% to 10% of patients who present with a new primary tumor will have de novo metastatic breast cancer. That percentage is even higher in other countries, where resource restrictions mean that screening mammography is not routinely performed. The question is raised whether the patient should be placed on systemic therapy and only use radiation or surgery in the case where palliation is needed, or whether there is a survival benefit by using locoregional therapy and systemic therapy upfront regardless of whether or not palliation is needed.

Previous trials addressing this question have delivered controversial or conflicting results.[2,3] One or two studies showed that early locoregional therapy may reduce the risk of death from breast cancer, but other studies have not shown this benefit. None of the previous studies has found a quality-of-life benefit from the early use of locoregional therapy. These conflicting results may have arisen due to differences in the trial designs, powering of the studies, and inclusion of certain patient populations.

Early Local Therapy for Metastatic Breast Cancer: Study Design

Sara Hurvitz, MD, FACP:
The ECOG 2108 trial randomized 258 patients with de novo metastatic breast cancer, an intact primary tumor, and no progression of distant disease after optimal systemic therapy to receive early locoregional treatment for the intact primary tumor or continued systemic therapy with locoregional therapy as needed for palliation. The primary endpoint was OS, and the study was powered to detect a 19% difference in 3-year OS at 85% power. Secondary endpoints included time to locoregional progression, health-related quality of life, circulating tumor cell burden, and collection of biologic samples.

Early Local Therapy for Metastatic Breast Cancer: Baseline Characteristics

Sara Hurvitz, MD, FACP:
It should be noted that fewer than 10% of patients in each treatment arm had TNBC. Approximately one third had HER2-positive disease and the remainder were hormone receptor positive/HER2 negative.

Early Local Therapy for Metastatic Breast Cancer: OS (Primary Endpoint)

Sara Hurvitz, MD, FACP:
This study found no OS benefit with the use of early local therapy. The OS curves for the 2 treatment arms were completely overlapping, with a median OS of 54 months. The 3-year OS was 68.4% in patients who received early local therapy and 67.9% in those who did not (HR: 1.09; 90% CI: 0.80-1.49; log-rank P = .63).

PFS results were similar to trends seen in the OS analysis. There was also no difference in PFS between the arms, with overlapping curves (P = .40).

Early Local Therapy for Metastatic Breast Cancer: OS by Tumor Subtype

Sara Hurvitz, MD, FACP:
When analyzed by tumor subtype, patients with HER2-positive disease or hormone receptor–positive/HER2‑negative disease showed no difference in OS with early local therapy. For the few patients who had TNBC, the use of early local therapy appeared to worsen survival (HR: 3.50; 95% CI: 1.16-10.57), although the small numbers make it difficult to assess reliability.

Early Local Therapy for Metastatic Breast Cancer: Locoregional Progression

Sara Hurvitz, MD, FACP:
Early local therapy did improve the rate of locoregional progression, with a 3-year cumulative rate of 10.2% compared with 25.6% with systemic therapy alone (HR: 0.37; 95% CI: 0.19-0.73). This is consistent with what has been shown in other trials and makes sense, because removing the primary tumor will reduce locoregional progression, but this did not result in an improvement in PFS or OS.

Early Local Therapy for Metastatic Breast Cancer: Health-Related Quality of Life

Sara Hurvitz, MD, FACP:
Similar to other studies, early locoregional therapy did not improve health-related quality of life as assessed by the FACT-B trial outcome index. At 18 months after randomization, the quality-of-life results were significantly lower in early local therapy arm, but at all other time points, no significant differences were identified between arms.

Early Local Therapy for Metastatic Breast Cancer: Conclusions

Sara Hurvitz, MD, FACP:
In conclusion, this study did not support the use of surgery and postoperative radiotherapy in patients with intact primary tumors and de novo metastatic breast cancer. This trial did not show a benefit in survival, even when broken down by tumor subtype, for early locoregional therapy. Surgery also did not show a benefit in quality of life, although there was a lower rate of early locoregional progression.

This study did not address some other questions, such as whether early locoregional therapy would benefit patients with solitary or limited bone metastases or with other sites of oligometastatic disease along with the use of stereotactic body radiation therapy. Although these questions still need to be addressed, the data from this trial confirm that, from a clinical standpoint, use of early locoregional therapy should not be standard of care for patients who have de novo metastatic breast cancer, especially at multiple sites.

It is important to point out that there was a very long median OS in this study, with a median OS of almost 5 years, underscoring the efficacy of systemic therapy now available for our patients with metastatic disease. Based on this trial and other collective data, I think we should be reserving locoregional therapy for those patients who need it for palliation.

HER2CLIMB: Tucatinib Plus Trastuzumab and Capecitabine in Previously Treated HER2-Positive MBC With Brain Metastases

Sara Hurvitz, MD, FACP:
The HER2CLIMB trial evaluated a HER2-selective tyrosine kinase inhibitor, tucatinib, in combination with trastuzumab and capecitabine vs trastuzumab and capecitabine alone in patients who had previously treated HER2-positive metastatic breast cancer (Capsule Summary).[4,5] A unique feature of this clinical trial is that patients who had either previously treated, stable brain metastases, or active brain metastases were allowed to be enrolled, and approximately one half of the patients enrolled on the study did have either a history of brain metastases or active brain metastases.

The results from this study were presented and published at the end of 2019 and were very impressive.[6] They showed an improvement in PFS not only in the intent to treat population but also in the patients who had central nervous system (CNS) metastases, as well as a significant benefit in terms of OS. These results led to the FDA approval of tucatinib in combination with trastuzumab and capecitabine in the United States in 2020.

Approximately 50% of patients with HER2-positive metastatic breast cancer will develop CNS metastases at some point during their disease course, making these data very clinically relevant. At ASCO, Lin and colleagues[4] presented an exploratory analysis of intracranial efficacy from the HER2CLIMB trial, focusing on outcomes in patients with CNS metastases.

HER2CLIMB: Study Design

Sara Hurvitz, MD, FACP:
In the full trial, 612 patients with previously treated HER2-positive metastatic breast cancer were randomized 2:1 to receive tucatinib 300 mg twice daily or placebo, plus trastuzumab 6 mg/kg every 3 weeks and capecitabine 1000 mg/m2 twice daily for the first 2 weeks of each cycle. Presence of brain metastases was one of the stratification factors.

HER2CLIMB Intracranial Activity: Brain Metastasis Status

Sara Hurvitz, MD, FACP:
In total, 291 patients had brain metastases, of whom 174 had active brain metastases and 117 were previously treated and had no evidence of progression of the CNS metastases at the time of study entry. Of the patients with active brain metastases, 66 were untreated and 108 were treated but progressing.

The endpoints for this exploratory analysis include OS and CNS-PFS in all patients with brain metastases, intracranial ORR and duration of response in patients with measurable intracranial disease, and time to second progression or death in patients with isolated CNS progression after CNS-directed local therapy.

HER2CLIMB Intracranial Activity: Baseline Characteristics in Patients With Brain Metastases

Sara Hurvitz, MD, FACP:
Since patients were stratified by presence of brain metastases, the 2 treatment arms were well balanced for this subpopulation; 198 patients received tucatinib and 93 received placebo.

HER2CLIMB Intracranial Activity: CNS-PFS in All Patients With Brain Metastases

Sara Hurvitz, MD, FACP:
The 1‑year CNS-PFS was 40.2% in the tucatinib arm and 0% in the placebo arm, underscoring the benefit of tucatinib, which can penetrate the blood–brain barrier and show activity in the CNS. The median CNS-PFS was 9.9 months in the tucatinib arm and 4.2 months in the placebo arm (HR: 0.32; 95% CI: 0.22-0.48; P < .00001). That translates to a 68% reduction in risk of CNS progression or death with tucatinib.

HER2CLIMB Intracranial Activity: OS in All Patients With Brain Metastases

Sara Hurvitz, MD, FACP:
The 1-year OS rate was 70.1% in the tucatinib arm and 46.7% in the placebo arm among patients with brain metastases. Median OS was 18.1 months with the addition of tucatinib and 12 months in patients who received placebo (HR: 0.58; 95% CI: 0.40-0.85; P = .005), again highlighting the importance of the CNS activity with tucatinib and how it relates to OS benefit for patients with this type of disease.

HER2CLIMB Intracranial Activity: CNS-PFS and OS With Active Brain Metastases

Sara Hurvitz, MD, FACP:
When we focus on those patients who had active CNS metastases at study entry, both CNS-PFS and OS were significantly improved with tucatinib. Patients who received tucatinib had a 64% reduction in risk of CNS progression and 51% reduction in risk of death. Clearly this drug is having a significant impact on patients whose disease was either untreated or progressing in the brain at the time of study entry.

HER2CLIMB Intracranial Activity: CNS-PFS and OS With Stable Brain Metastases

Sara Hurvitz, MD, FACP:
Similarly, patients with stable brain metastases also had significant improvements in CNS-PFS with tucatinib (HR: 0.31; 95% CI: 0.14-0.67; P = .002) and a numerical although not significant increase in OS (HR: 0.88; 95% CI: 0.45-1.70; P = .70).

HER2CLIMB Intracranial Activity: ORR in Patients With Active Brain Metastases and Baseline CNS Lesions

Sara Hurvitz, MD, FACP:
Twenty-six patients who received tucatinib achieved a confirmed CR or PR, with an intracranial ORR of 47%, compared with 20% with placebo. The median duration of intracranial response was 6.8 months with tucatinib vs 3 months with placebo.

HER2CLIMB Intracranial Activity: Outcomes With Isolated CNS Progression and Ongoing Assigned Study Treatment

Sara Hurvitz, MD, FACP:
Tucatinib also significantly prolonged the time to second progression or death from randomization (median of 15.9 months with tucatinib plus trastuzumab/capecitabine vs 9.7 months with placebo plus trastuzumab/capecitabine) and from first CNS progression (median of 7.6 months with tucatinib plus trastuzumab/capecitabine vs 3.1 months with tucatinib plus trastuzumab/capecitabine).

Several patients remained on treatment at the time of the study presentation.

HER2CLIMB Intracranial Activity: Conclusions

Sara Hurvitz, MD, FACP:
To sum up, patients with both active and stable CNS metastases benefited from the addition of tucatinib to trastuzumab/capecitabine, underscoring the activity of this agent in a subset of patients who are very high-risk for poor long-term outcomes.

I think these data are practice changing. Tucatinib is approved in the United States in combination with capecitabine and trastuzumab and I feel that these data support using tucatinib in patients who have CNS metastases. However, it is also important to remember that this triplet regimen is quite active even in patients without brain metastases and showed an OS benefit in the overall population as well.[6] This triplet is a very efficacious regimen in all patients with HER2-positive metastatic breast cancer. The adverse events associated with tucatinib are slightly higher than other regimens, with slightly greater risk of diarrhea and hand‑foot syndrome. However, it is fairly selective for HER2, has less inhibitory activity against EGFR, and is generally well tolerated.

I am also looking forward to seeing this treatment evaluated in earlier lines of therapy, such as adjuvant and newly diagnosed metastatic settings, to see if brain metastases can be prevented with the inclusion of tucatinib in an earlier treatment setting.

KEYNOTE-355: Pembrolizumab Plus Chemotherapy for Previously Untreated Advanced Triple-Negative Breast Cancer

Sara Hurvitz, MD, FACP:
The phase III KEYNOTE‑355 clinical trial evaluated pembrolizumab in combination with chemotherapy vs placebo plus chemotherapy as first‑line treatment for metastatic TNBC (Capsule Summary).[7] Pembrolizumab monotherapy has shown efficacy in smaller clinical trials in the metastatic TNBC setting, with a manageable toxicity profile. Activity has been seen in both treatment‑naive and previously treated patients, with some patients having very durable long‑term responses.[8-10]

In the phase III KEYNOTE-522 trial, the addition of  pembrolizumab to standard neoadjuvant chemotherapy led to an improved pathologic CR rate for patients with early TNBC regardless of PD-L1 expression.[11] These data contrast with the data from the phase III Impassion130 trial with atezolizumab in combination with taxane chemotherapy as first‑line therapy for metastatic TNBC, which showed statistically significant improvement in OS outcomes for those patients whose immune cells (IC) have PD-L1 expression, but not for the intention-to-treat patient population.[12] Based on data from the IMpassion130 trial, atezolizumab is now FDA approved in combination with paclitaxel protein-bound for the treatment of PD-L1–positive (IC ≥ 1%) TNBC in the metastatic setting.

The KEYNOTE‑355 trial is looking at the use of pembrolizumab combined with chemotherapy in the first‑line metastatic setting regardless of PD-L1 expression.

KEYNOTE-355: Study Design

Sara Hurvitz, MD, FACP:
Patients with previously untreated metastatic TNBC were randomized 2:1 to receive pembrolizumab 200 mg IV every 3 weeks with chemotherapy or placebo plus chemotherapy. In contrast to the IMpassion130 trial, patients were allowed to choose with their investigator whether to pair the pembrolizumab with nab‑paclitaxel, paclitaxel, or gemcitabine, so not all patients received taxane chemotherapy. The primary endpoints were PFS and OS in the intention-to-treat population and in patients with PD-L1 CPS ≥ 10 or ≥ 1.

KEYNOTE-355: Baseline Characteristics

Sara Hurvitz, MD, FACP:
In total 847 patients were randomized; 566 received pembrolizumab and 281 received placebo. Approximately 75% in each treatment arm had PD-L1 CPS ≥ 1 and 36% to 39% had PD-L1 CPS ≥ 10. Just more than one half of patients received gemcitabine/carboplatin‑based therapy, with the remainder receiving taxane chemotherapy.

KEYNOTE-355: PFS in PD-L1 CPS ≥ 10 Population

Sara Hurvitz, MD, FACP:
In this trial, PFS significantly improved with pembrolizumab regardless of PD-L1 expression, but the largest PFS improvement was seen in those patients with a CPS of ≥ 10, where the median PFS was 9.7 months with the pembrolizumab combination compared with 5.6 months in the control arm (HR: 0.65; 95% CI: 0.49-0.86; P = .0012).

KEYNOTE-355: PFS in PD-L1 CPS ≥ 10 Population According to Patient Subsets

Sara Hurvitz, MD, FACP:
Within the population of patients with PD-L1 CPS ≥ 10, we can see that the addition of pembrolizumab is favored for all analyzed patient subsets, regardless of age, world region, performance status, or selected chemotherapy.

KEYNOTE-355: PFS in PD-L1 CPS ≥ 1 Population

Sara Hurvitz, MD, FACP:
The investigators also assessed whether the addition of pembrolizumab is beneficial in patients with a lower, but still positive, CPS score. Among patients with a CPS of ≥ 1, we see a 2‑month improvement in median PFS with pembrolizumab compared with the control arm (7.6 vs 5.6 months, respectively).

The absolute delta is a little smaller in this patient subset, but there still appears to be a benefit with pembrolizumab (HR: 0.75; 95% CI: 0.61-0.90; P = .0014), although the prespecified boundary for statistical significance was not met.

KEYNOTE-355: PFS in PD-L1 CPS ≥ 1 Population According to Patient Subsets

Sara Hurvitz, MD, FACP:
Again, a subgroup analysis among the patients with a PD-L1 CPS ≥ 1 showed that the majority of patient groups do appear to benefit from the addition of pembrolizumab to chemotherapy.

KEYNOTE-355: PFS in Intention-to-Treat Population

Sara Hurvitz, MD, FACP:
PFS results were also similar in the intent to treat population, where there was again approximately a 2‑month improvement in median PFS in favor of the pembrolizumab arm (HR: 0.82; 95% CI: 0.69-0.97).

In this patient population, the median PFS was 7.5 months with the addition of pembrolizumab to chemotherapy or 5.6 months for placebo plus chemotherapy.

KEYNOTE-355: Treatment-Related Adverse Events

Sara Hurvitz, MD, FACP:
Adverse events were slightly higher in the patients receiving pembrolizumab, but these treatment regimens were fairly well tolerated. The treatment‑related adverse events observed were consistent with previous reports, with slightly greater rates of neutropenia and anemia associated with pembrolizumab compared with the control arm.

KEYNOTE-355: Immune-Related Adverse Events

Sara Hurvitz, MD, FACP:
As expected, pembrolizumab treatment was also associated with more immune‑related adverse events, but most were low grade. There was a higher rate of hyperthyroidism, which is expected with immune checkpoint inhibition, as well as a slightly higher rate of pneumonitis, with 2.5% of patients having any grade of pneumonitis with pembrolizumab, compared with none with placebo.

KEYNOTE-355: Conclusions

Sara Hurvitz, MD, FACP:
In conclusion, first-line pembrolizumab/chemotherapy significantly improved PFS compared with either a taxane or gemcitabine/carboplatin chemotherapy regimen alone in patients with metastatic TNBC. This improvement appeared to be independent of PD-L1 expression, although the largest improvement in PFS was seen in those patients who had a CPS ≥ 10.

The safety outcomes were very consistent with previous data, and I believe we may see this combination available soon for patients in the metastatic TNBC setting.

BYLieve: Alpelisib Plus Fulvestrant in Hormone Receptor–Positive/HER2-Negative Advanced Breast Cancer After CDK4/6 Inhibitor Plus AI

Sara Hurvitz, MD, FACP:
The phase II BYLieve trial evaluated alpelisib + endocrine therapy (ET) in patients with PIK3CA-mutated hormone receptor–positive, HER2-negative advanced breast cancer previously treated with CDK4/6 inhibitor plus ET, systemic chemotherapy, or ET alone (Capsule Summary).[13] PIK3CA mutations are found in approximately 40% of patients with hormone receptor–positive, HER2-negative advanced breast cancer. These mutations are associated with a negative prognosis and potentially mediate resistance to ET.[14-18]

Alpelisib is a PI3Kα selective inhibitor currently approved by FDA in combination with fulvestrant for treatment of postmenopausal women and men with PIK3CA-mutated hormone receptor–positive, HER2-negative advanced breast cancer whose disease has progressed on or after previous ET. Alpelisib plus fulvestrant is also a treatment option for patients with PIK3CA-mutated hormone receptor–positive, HER2-negative advanced breast cancer who have progressed on standard-of-care first-line treatment with CDK4/6i plus ET.

An interim analysis of BYLieve reported an ORR of 15.2% to 27.3% at ASCO 2019,[19] and these data presented at ASCO 2020 focused on the efficacy and safety of alpelisib plus fulvestrant in a cohort with hormone receptor–positive, HER2-negative advanced breast cancer who received an CDK4/6 inhibitor plus an AI as immediate previous treatment.

BYLieve: Study Design

Sara Hurvitz, MD, FACP:
The BYLieve trial is an international, open-label, multicohort, noncomparative phase II study assessing alpelisib plus ET in patients with PIK3CA-mutated hormone receptor–positive, HER2-negative advanced breast cancer previously treated with CDK4/6 inhibitor plus ET, systemic chemotherapy, or ET alone. This analysis focused on patients in cohort A of the trial, and assessed the efficacy and safety of alpelisib plus fulvestrant in patients who previously progressed on CDK4/6 inhibitor plus an AI (n = 127).[13] 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%. Secondary endpoints included PFS, PFS2, ORR, clinical benefit rate, duration of response, OS, and safety.

BYLieve: Baseline Characteristics

Sara Hurvitz, MD, FACP:
Patients in cohort A were all women, with a median age of 58 years. Approximately 70% of patients had received 1 previous line of therapy for metastatic disease, approximately 18% had received ≥ 2 previous lines of therapy, and 12% had received no previous therapy for metastatic disease but received CDK4/6 inhibitor–based therapy in the adjuvant setting. Approximately 77% of patients received 1 previous line of ET and 11% received 2 previous lines of ET for metastatic disease. Approximately 20% of patients had primary endocrine resistance and almost 60% developed secondary endocrine resistance. 

BYLieve: Patients Without Progressive Disease at 6 Months (Primary Endpoint)

Sara Hurvitz, MD, FACP:
In this analysis, the primary endpoint was met for patients in cohort A of the BYLieve trial. The rate of patients alive without progressive disease at 6 months was 50.4% (95% CI: 41.2% to 59.6%), with the lower bound of 95% CI > 30%.

The median PFS (secondary endpoint) was 7.3 months. In comparison, the unadjusted median PFS in real-world patients with PIK3CA-mutated hormone receptor–positive, HER2-negative advanced breast cancer previously treated with a CDK4/6 inhibitor in the United States (n = 95) was 3.6 months.

The ORR for patients in cohort A with centrally confirmed PIK3CA mutations was 17.4% and 21% for those with measurable disease at baseline, but no patients achieved CR and approximately 11% had progressive disease as best response.

BYLieve: Adverse Events

Sara Hurvitz, MD, FACP:
As with any agent, there toxicities that we do have to be mindful of with alpelisib. Approximately 67% of patients experienced grade ≥ 3 AEs with this combination. Specifically, 28.3% experienced grade 3/4 hyperglycemia and almost 10% reported grade 3/4 rash. Overall, 65% had an AE leading to dose adjustments or interruption and 21% had an AE leading to treatment discontinuation.

BYLieve: Other Safety Outcomes

Sara Hurvitz, MD, FACP:
There has been some recent data on use of prophylactic antihistamine to prevent rash during treatment with alpelisib. In this trial, 10 of 127 patients received antihistamines before developing a rash or had no rash events. Of these patients, 70% did not develop rash compared with 53% of those who did not receive prophylactic antihistamines.

Based on these and other data, it is reasonable to use prophylactic antihistamines when alpelisib is prescribed prior to starting the first dose of alpelisib.

BYLieve: Conclusions

Sara Hurvitz, MD, FACP:
In this analysis of the BYLieve trial, alpelisib plus fulvestrant demonstrated clinically meaningful efficacy in patients with PIK3CA-mutated hormone receptor–positive, HER2-negative advanced breast cancer who progressed after CDK4/6 inhibitor plus an AI. No new or unexpected safety signals were observed with this combination. Furthermore, efficacy and safety results from this analysis were comparable, or perhaps a little lower than those reported for SOLAR-1, in which patients who had progressed on a previous AI were randomized to receive fulvestrant alone or fulvestrant with alpelisib.[20,21]

I think the benefit of therapy that we see after previous CDK4/6 inhibitor therapy are a bit less, in general, than what we see in a treatment-naive population, but I think these data are much better than we would expect with fulvestrant monotherapy in a patient with a PI3-kinase mutation.

When considering therapy with alpelisib, I think considering prophylaxis with an antihistamine is a reasonable approach. It is also important to monitor for other toxicities, particularly hyperglycemia. Clinicians should obtain baseline A1C and a fasting glucose levels before initiating therapy with alpelisib and then recheck fasting glucose levels 1 week later followed by monthly assessment if levels remain stable. A1C levels should be monitored every 3 months, and if a patient does develop hyperglycemia, metformin should be initiated early.

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