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ESMO Breast Cancer Virtual Meeting

Fabrice André, MD, PhD, professor of Medical Oncology at the Institut Gustave Roussy in Villejuif, France, discusses strategies to improve outcomes in patients with breast cancer.

At the 2020 ESMO Breast Cancer Virtual Meeting, André spoke to 4 research priorities in the field of breast cancer.

One of these priorities is to improve patient outcomes as they pertain to overall survival and disease-free survival, explains André.

One strategy to move toward improving these outcomes is to develop a biological model of each patient’s disease to determine the molecular mechanisms that contribute to their progression, says André.

Additionally, developing novel biotechnologies to identify new agents could translate into improved outcomes, says André.

For example, using new biotechnologies to create improved linkers for antibody-drug conjugates is being done currently in breast cancer, concludes André.

Fabrice André, MD, PhD, discusses strategies to improve outcomes in patients with breast cancer.

Dr. Andre on Strategies to Improve Outcomes in Breast Cancer

Guy Jerusalem, MD, PhD, professor of oncology, Liège University, head of Medical Oncology, and director of the breast clinic, University Hospital of Liège, discusses the utility of fam-trastuzumab deruxtecan-nxki (Enhertu; DS-8201) in HER2-positive breast cancer.

Trastuzumab deruxtecan is a novel antibody-drug conjugate consisting of a HER2-directed monoclonal antibody and a topoisomerase I inhibitor payload, says Jerusalem.

The phase 2 DESTINY-Breast01 trial demonstrated an objective response rate of 60.3% including a 4.3% complete response rate and a 56% partial response rate in patients with metastatic HER2-positive breast cancer, says Jerusalem.

Moreover, these patients were heavily pretreated, having received multiple prior lines of therapy, explains Jerusalem.

As such, on December 20, 2019, trastuzumab deruxtecan was granted an accelerated approval by the FDA for the treatment of adult patients with unresectable or metastatic HER2-positive breast cancer who have received 2 or more prior anti—HER2-based regimens in the metastatic setting.

Guy Jerusalem, MD, PhD, discusses the utility of fam-trastuzumab deruxtecan-nxki in HER2-positive breast cancer.



Dr. Jerusalem on Trastuzumab Deruxtecan in HER2+ Breast Cancer

The PARP inhibitor veliparib increased progression-free survival (PFS) in women with hormone receptor (HR)-positive breast cancer and triple-negative breast cancer (TNBC) who harbored a germline 

 mutation when co-administered with carboplatin and paclitaxel, according to findings from the phase 3 BROCADE3 trial (NCT02163694), presented during the 2020 ESMO Breast Cancer Virtual Meeting.

“In both subgroups, the benefit of veliparib was durable with an increased probability of remaining progression free at 2 and 3 years compared with placebo,” said Jean-Pierre Ayoub, MD, lead author of the BROCADE3 study and an assistant professor in the Department of Medicine at the University of Montreal in Montreal, France.

In the HR-positive subset of patients treated with veliparib, carboplatin, and paclitaxel (n = 174), the 2 year and 3 year PFS by investigator assessment was 27.5% and 17.5%, respectively. Among the 92 HR-positive patients randomized to carboplatin and paclitaxel, the 2 year PFS was 15.3% and the 3 year PFS was 8.6%. The median PFS was 13.0 months with the 3 drug approach versus 12.5 months with carboplatin and paclitaxel alone (HR, 0.69; 95% CI, 0.52-0.93; 2-sided 

The tri-modality also led to a superior survival benefit in patients with TNBC. The 2 year, investigator-assessed PFS was 40.4% compared with 25.0% with carboplatin and paclitaxel. The 3 year PFS also favored veliparib, carboplatin, and paclitaxel: “It’s impressive to see [that] at 3 years in the veliparib arm, 35.3% of patients in this poor prognostic, triple-negative subgroup are progression-free compared [with] 13.0% in the placebo arm,” Ayoub said.

In this subgroup, the median PFS was 16.6 months (95% CI, 12.3-22.7) in the veliparib, carboplatin, and paclitaxel arm and 14.1 months (95% CI, 11.0-15.8) with chemotherapy (HR, 0.72; 95% CI, 0.52-1.00; 2-sided

These subgroup specific findings build on the survival benefit observed in the intent-to-treat population, where the investigator-assessed median PFS was 14.5 months with the veliparib-containing regimen and 12.6 months with chemotherapy (HR, 0.705; 95% CI, 0.566-0.877; 

Overall survival (OS) in the BROCADE3 study, which enrolled 509 patients, was similar across subgroups, said Ayoub. The median OS was 32.4 months with veliparib, carboplatin, and paclitaxel and 27.1 months with chemotherapy in the HR-positive subgroup (HR, 0.96; 95% CI, 0.68-1.36; 2-sided 

 = .829). Among patients with TNBC, the median OS was 35.0 months with the 3 drug regimen versus 30.0 months with carboplatin and paclitaxel (HR, 0.92; 95% CI, 0.62-1.36; 2-sided 

 value was significant, according to Ayoub, who also noted that the addition of veliparib did not improve the objective response rate or clinical benefit rate in either patient subgroup. However, responses “appeared to be more durable in the veliparib arms,” said Ayoub. “This may account for the difference that you see in median PFS to a likely carryover effect of the veliparib-treated patients where we see improvement in PFS to 20.3 months in hormone receptor-positive versus 16.6 months in the placebo arm.”

The overall toxicity profile “was not substantially different between the treatment arms and was generally comparable in the subgroups of patients with HR-positive disease and triple-negative breast cancer,” Ayoub said. Additionally, safety in the HR-positive and TNBC subgroups was similar in the intent-to-treat population.

In both subgroups, the incidence of any-grade anemia, neutropenia, nausea, and diarrhea was increased by more than 5% in the veliparib arms versus the chemotherapy arms. Although there were some differences between the subgroups, they were not directionally consistent. Neutropenia (78.2%), anemia (40.8%), thrombocytopenia (35.6%), leukopenia (32.2%), and fatigue (6.3%) were the 5 most common grade 3 or higher adverse events observed in veliparib-receiving HR-positive patients. This finding was consistent in the veliparib-treated TNBC group, where these toxicities affected 84.0%, 44.4%, 43.8%, 25.9%, and 8.0% of patients, respectively.

Ayoub J-P, Friedlander ML, Dieras VC, et al. Veliparib plus carboplatin-paclitaxel in patients with HER2-negative advanced/metastatic gBRCA-associated breast cancer: results in hormone receptor-positive and triple-negative breast cancer subgroups from the phase III BROCADE3 trial. Presented at: 2020 ESMO Breast Cancer Virtual Meeting; May 22-23, 2020. Abstract 140O.

The PARP inhibitor veliparib increased progression-free survival in women with hormone receptor-positive breast cancer and triple-negative breast cancer who harbored a germline BRCA1/2 mutation when co-administered with carboplatin and paclitaxel, according to findings from the phase 3 BROCADE3 trial (NCT02163694). 

Addition of Veliparib to Carboplatin-Paclitaxel Increases PFS in HR+ Breast Cancer, TNBC

Developing diagnostics to identify the molecular drivers of breast cancer and model the mechanisms of disease progression will be a key priority of the investigative efforts aimed at improving patient outcomes in the field over the next decade, according to Fabrice Andre, MD, PhD.

"We need to develop methods to model the biological mechanisms of tumor evolution at the individual level and we need new biotechnology to create new therapies. If we can model the mechanisms of progression, then we can [develop new therapies] to target these mechanisms," Andre said during a keynote lecture of the 2020 ESMO Breast Cancer Virtual Meeting.

Advancing this biological approach hinges on identifying the molecular mechanisms that drive cancer progression. Several genomic alterations have already been identified as drivers of disease progression in metastatic breast cancer, such as 

, which activate intracellular signaling. Drivers in the estrogen receptor pathway include 

, which is mutated in approximately 15% of patients, and 

, explained Andre, director of Research at the Institut Gustave Roussy in Villejuif, France.

, which presents in mutant form in about 15% of patients with metastatic disease and promotes resistance to endocrine therapy,1 represent an "emerging field in breast cancer for which [clinicians] are going to generate new drugs," said Andre, who added that understanding whether epigenetic modulation is involved in cancer progression for each patient will be critical to personalizing targeted approaches.

Modeling mechanisms of clonal evolution will be equally important as selecting drivers of disease progression: "We know that metastatic breast cancer can be stable for a long time, and [then], suddenly, the cancer can escape, so we need to understand the mutational processes that [allow] escape," Andre explained.

APOBEC, a cytidine deaminase, and homologous recombination deficiency are 2 genomic scars that could aid not only the genomic evasion of targeted therapy, but also the evolution and aggressiveness of disease. Biological models of metastatic disease will need to determine whether or not these mutational processes are active in patients.

The next step in producing biological models involves tracking subclones that can create resistance to therapeutic intervention, and assessing circulating tumor DNA samples at baseline or during patient follow-up may offer an avenue to trace these subclones, Andre said, adding that a biologically based modeling methodology will also need to address the molecular mechanisms that promote resistance to immunotherapy.

Laying a Foundation for New Biotechnologies

Once clinicians are able to identify drivers of disease progression, model mechanisms of clonal evolution and immune escape, and track subclones in each patient with metastatic breast cancer, this knowledge can be used to develop a diagnostic device for target identification that would guide individual treatment decisions. "One of the main priorities in the field of metastatic breast cancer is being able to model the biology [of disease] in each patient in order to propose personalized therapy that specifically targets mechanisms of cancer progression," Andre said.

Improving patient outcomes entails a more comprehensive understanding of the biological mechanisms of tumor evolution and the use of new biotechnologies to develop targeted therapies, particularly as the field gravitates away from a single-gene approach and moves instead towards a complex mode of management, wherein the biology of disease must be assessed in each patient and treated accordingly.

Biotechnologies could be useful in the development of complex drugs that hit multiple molecular targets, and are already present in breast cancer, where they are used to engineer complex drugs like antibody-drug conjugates and construct the conjugates' specific or bispecific antibodies. The application of biotechnology in breast cancer drug development has also yielded new linkers that are tailored to the therapeutic need, and cytotoxic agents. As the field advances, Andre hypothesized that biotechnologies could even be used to develop therapies for individual patients: "My intuition is that, in the future, we could construct a complex drug for each patient based on [their] biology."

Predicting patient outcomes as early as possible in the disease course will also be a priority in the field over the next decade and goes hand in hand with new drug development, Andre explained. For example, identifying patients with very poor outcomes who are in urgent need of experimental therapies would allow the field to more expeditiously fast track investigational agents. Establishing methods to predict patient outcomes could also guide the evaluation and initiation of new therapies in patients at a high risk of relapse.

To move the needle in metastatic breast cancer, the field must prioritize reducing toxicities to subsequently improve quality of life (QOL).

 "For a very long time, [we have known] that we are using drugs that impact [patients'] quality of life," Andre said. "[However], until recently, we did not have evidence based on epidemiology data that the [effects] of systemic treatment are important and relevant for patients."

Andre cited results from a recent epidemiological study of systemic therapy in pre- and postmenopausal women with early-stage breast cancer. The prospective evaluation of patient reported outcomes collected from 4262 eligible patients who participated in the CANTO study (NCT01993498) of cancer treatment toxicities in individuals with nonmetastatic breast cancer

 "clearly showed that the drugs we are using have a deleterious impact on quality of life," Andre said.

Premenopausal women comprised 37.2% of the patient population; 62.8% of women were postmenopausal. Among premenopausal participants, chemotherapy was found to reduce cognitive functioning.

 "This is a major need that we need to address," Andre said.

In postmenopausal women, endocrine therapy negatively affected overall health status and quality of life (QOL) score.

 Interpreting data from the prospective study as a microcosm of the need to reduce the occurrence of adverse events that debilitate QOL, Andre concluded that "decreasing toxicity to improve [patient] quality of life after cancer is one of the top 4 priorities" in the next decade of breast cancer research.

Andre F. Priorities in breast cancer in the next 10 years. Presented at: 2020 ESMO Breast Cancer Virtual Meeting; May 22-23, 2020.

Ferreira AR, Di Meglio A, Pistilli B, et al. Differential impact of endocrine therapy and chemotherapy on quality of life of breast cancer survivors: a prospective patient-reported outcomes analysis. 

. 2019;30(11):1784-1795. doi:10.1093/annonc/mdz298

Developing diagnostics to identify the molecular drivers of breast cancer and model the mechanisms of disease progression will be a key priority of the investigative efforts aimed at improving patient outcomes in the field over the next decade.

Top Priorities Outlined in Next Decade of Breast Cancer Research

The oral selective estrogen receptor degrader (SERD) LSZ102 was found to be well tolerated and demonstrate clinical activity in combination with either ribociclib (Kisqali) or alpelisib (Piqray) in patients with estrogen receptor (ER)—positive breast cancer who have progressed on endocrine therapy, according to findings of a phase 1/1b trial that were presented during the 2020 ESMO Breast Cancer Virtual Meeting.

In the 3-arm study, investigators evaluated LSZ102 alone (arm A), in combination with ribociclib (arm B), and in combination with alpelisib (arm C). In arm A, single-agent LSZ102 led to an objective response rate (ORR) of 1.3%, a clinical benefit rate (CBR) of 9.1%, and a median progression-free survival (PFS) of 1.8 months (95% CI, 1.7-2).

In arm B, the combination of LSZ102 plus ribociclib elicited a 15.8% ORR and a CBR of 35.5%; the median PFS was 6.2 months (95% CI, 4.4-6.4). When LSZ102 was combined with alpelisib, the ORR was 5.4%, the CBR was 18.9%, and the median PFS was 3.5 months (95% CI, 1.8-5.5).

"This is the first clinical report of an oral SERD in combination with either a CDK4/6 inhibitor or an alpha-specific PI3K inhibitor. LSZ102 is a safe and relatively well-tolerated agent both alone and in combination with ribociclib or alpelisib, with gastrointestinal-related toxicities being the most common toxicity across all 3 arms," said lead study author Komal Jhaveri, MD, FACP, a medical oncologist at Memorial Sloan Kettering Cancer Center, in a presentation during the meeting.

"Downregulation of the ER protein was observed across all arms. Additionally, exploratory analyses reveal the clinical activity for both ribociclib and alpelisib combinations with LSZ103 that was observed in heavily pretreated patients with ER-positive breast cancer, regardless of mutational status in [circulating tumor] DNA at baseline."

The combination of the ER pathway can be targeted by endocrine therapies, Jhaveri explained. Moreover, endocrine-resistance pathways identified in ER-positive breast cancer include the cyclin D-CDK4/6-retinoblastoma protein pathway or PI3K/AKT/mTOR pathway. Additional resistance mechanisms involve 

 mutations, which drive ER-dependent transcription and proliferation in the absence of estrogen.

Currently, fulvestrant (Faslodex) is the sole FDA-approved SERD, which has demonstrated a PFS and overall survival benefit when used in combination with ribociclib, and a PFS benefit when added to alpelisib.

Fulvestrant is administered via intramuscular injection; however, LSZ102 is an oral SERD, which could potentially achieve higher systemic exposures and lead to enhanced efficacy and potential clinical activity against 

 mutations, Jhaveri added. Preclinical models have shown that LSZ102 has synergistic activity with ribociclib and also with alpelisib in ER-positive breast cancer.

 Earlier findings of this trial also showcased activity in arm A and B, Jhaveri noted.

In the 3-arm, open-label, phase 1/1b CLSZ102X2101 (NCT02734615) trial, patients with pre- or postmenopausal, histologically confirmed, ER-positive breast cancer were enrolled. In all arms, patients were 18 years or older with an ECOG performance status of 0 or 1. Patients were required to have demonstrated disease progression on endocrine therapy for locally advanced disease that was not amendable to curative therapy or metastatic disease; or recurrence either during adjuvant therapy or within 1 year of completion. Prior treatment with fulvestrant or CDK4/6 inhibitors was permitted.

Specifically, to be treated with the combination of LSZ102 and alpelisib, patients could not have received prior therapy with PI3K, mTOR, or AKT inhibitors. Patients with and without 

As mentioned, the study comprised 3 arms. In arm A (n = 78) investigators administered LSZ102 at 200 mg to 900 mg; in arm B (n = 76), 200 mg to 600 mg of LSZ102 plus 200 mg to 600 mg of ribociclib; and in arm C (n = 39), 300 mg to 450 mg of LSZ102 and 200 to 300 mg of alpelisib. LSZ102 was tested daily alone or in combination with ribociclib daily on a 3-week-one/1-week-off schedule or continuously, while alpelisib was given daily.

The primary end points were safety and tolerability, as well as identification of the recommended dose for expansion. Secondary end points were preliminary antitumor activity, pharmacokinetics, and pharmacodynamics (PD) with ER via immunohistochemistry (IHC). Exploratory outcome measures were PD via serial circulating tumor DNA (ctDNA) and response/resistance by baseline 

Baseline characteristics were similar between the arms. The median age was 59.0 years in arms A (range, 30-70) and B (range, 33-79), and 55 (range, 36-74) in arm C. The ECOG performance status was 0 in 53, 57, and 29 patients in arms A, B, and C, respectively. Twenty-five, 19, and 10 patients had an ECOG performance status of 1 in arms A, B, and C, respectively. The median number of prior lines of antineoplastic therapy in the locally advanced/metastatic setting was 4 in arms A and B, and 3 in arm C. The median number of prior lines of chemotherapy in all arms was 1.

Across all 3 arms, 57.2% of patients received prior fulvestrant, 55.3% of patients received prior treatment with a CDK4/6 inhibitor, and 67.96% of patients received chemotherapy.

Zero patients in arm A had treatment ongoing at the time of data cutoff, which was July 2019, 13 patients (17.1%) in arm B, and 8 patients (20.5%) in arm C had ongoing treatment. All patients in arm A discontinued treatment, compared with 63 patients (82.9%) in arm B and 31 patients (79.5%) in arm C. In arm A, most patients discontinued treatment (n = 71; 91%) due to disease progression, compared with 58 patients (76.3%) in arm B and 25 patients in arm C (64.1%). There were 3 deaths overall, all of which occurred in arm C, and were unrelated to study treatment.

Regarding safety, results showed that the most frequent adverse events (AEs) across all 3 arms were gastrointestinal related, consisting of nausea, vomiting, and diarrhea. In arm B, grade 3 AEs included neutropenia (13.2%) and increased aspartate aminotransferase (AST; 3.9%) and were likely driven by ribociclib. In arm C, grade 3 hyperglycemia (10%), skin rashes (15.4%) and were likely driven by alpelisib.

The number of dose-limiting toxicities in arms A, B, and C, were 5, 3, and 7, respectively. In arm A, this was comprised of diarrhea (n = 2), vomiting (n = 1), increased alanine aminotransferase (n = 1), increased AST (n = 1). In arm B, dose-limiting toxicities were febrile neutropenia, sepsis, and decreased appetite (n = 1 each). In arm C, this comprised diarrhea (n = 1), stomatitis (n = 1), hyperglycemia (n = 2), and maculo-papular rash (n = 3).

To determine the recommended dose for expansion for arm C, 4 dose levels were explored: LSZ102 at 300 mg plus alpelisib at 200 mg (n = 12), LSZ102 at 450 mg plus alpelisib at 200 mg (n = 13), LSZ102 at 300 mg plus alpelisib at 300 mg (n = 12), and LSZ102 at 300 mg plus alpelisib at 250 mg (n = 2). Five DLTs were identified at the 300-mg LSZ102 dose plus 300 mg of alpelisib and was determined to not be tolerable.

Based on these data, the recommended dose was determined to be LSZ102 at 300 mg daily plus 250 mg of alpelisib daily. After the data cutoff, an additional 4 patients received this dosage of the combination.

Additional findings showed that the ER protein is downregulated by LSZ102 across all arms. Paired biopsies were collected at screening as well as day 15 of cycle 1, and were analyzed for ER through IHC. These analyses showed a trend of dose dependent ER protein loss in patients who were treated with LSZ102 alone. Moreover, adding either ribociclib or alpelisib to LSZ102 did not impact downregulation of ER protein.

In the ctDNA analysis, investigators noted that the genomic landscape of heavily pretreated patients is dominated by 

 mutations. These abnormalities were reported in all 3 arms. However, these mutations did not correlate with response, and are not enriched upon progression in patients with matched baseline and end-of-treatment samples, Jhaveri noted.

Through exploratory analyses, it was also observed that pairing LSZ102 with either ribociclib or alpelisib led to similar outcomes, regardless of the mutational status in baseline ctDNA. In arm B, patients with baseline 

 wild-type status had an ORR of 9.38%, a CBR of 31.25%, and a median PFS of 6.2 months. For 

-mutant patients, the ORR was 13.79%, the CBR was 31.03%, and the median PFS was 5.6 months (HR, 0.99; 0.54-1.79). For patients with 

 undetectable ctDNA, the ORR was 33.33%, the CBR was 53.33%, and the median PFS was 6.5 months (HR, 0.43; 95% CI, 0.19-1.02).

The exploratory analysis also stratified patients by baseline 

 wild-type patients, the ORR, CBR, and median PFS were 7.14%, 14.29%, and 3.4 months, respectively. For patients who had 

-mutant tumors, the ORR was 6.67%, the CBR was 20%, and the median PFS was 3.5 months (HR, 0.64; 95% CI, 0.26-1.6). In patients with 

 undetectable ctDNA, the ORR was 0%, the CBR was 25%, and the median PFS was 15.3 months (HR, 0.15; 95% CI, 0.02-1.16).

Incoming data suggest relative enhanced activity of the combination in 

Saverio Cinieri, MD, clinical director, director of the Breast Unit at Ospedale Perrino in Brindisi BR, Italy, who also served as a discussant on the study during the virtual meeting, stated that during the COVID-19 era, the use of oral therapies, such as SERDs, will be even more necessary to limit access to hospitals for patients.

"The overcoming of a molecule like the intramuscularly administered fulvestrant goes in this direction," he concluded. "The clinical efficacy and the biomolecular profile of LSZ102 seems to be able to meet these real needs."

Jhaveri K, Juric D, Yap Y-S, et al. Interim results of a phase 1/1b study of LSZ102, an oral selective estrogen receptor degrader, in combination with ribociclib or alpelisib in patients with ER+ breast cancer who had progressed after endocrine therapy. Presented at: 2020 ESMO Breast Cancer Virtual Meeting; May 22-23, 2020. Abstract LBA1.

Jhaveri K, Juric D, Cresta S, et al. A phase 1/1b study of LSZ102, an oral selective estrogen receptor degrader (SERD), in combination with ribociclib in patients with estrogen receptor-positive (ER+) advanced breast cancer (ABC) who had progressed after endocrine therapy (ET). 

. 2020;80(4). doi:10.1158/1538-7445.SABCS19-PD7-09

Novartis R&D Day. Novartis AG Investor Relations. Published December 5, 2019. https://bit.ly/2XpqT4a. Accessed May 25, 2020.

Jhaveri K, Curigliano G, Yap Y-S, et al. Phase 1/1b study of novel oral selective estrogen receptor degrader (SERD) LSZ102 for estrogen receptor-positive (ER+) advanced breast cancer (ABC) with progression on endocrine therapy (ET). 

. 2019;79(4). doi: 10.1158/1538-7445.SABCS18-PD1-08.

LSZ102 was found to be well tolerated and demonstrate clinical activity in combination with either ribociclib or alpelisib in patients with estrogen receptor–positive breast cancer who have progressed on endocrine therapy.

LSZ102 Shows Encouraging Activity in Combination With Ribociclib, Alpelisib in ER+ Breast Cancer

Fam-trastuzumab deruxtecan-nxki (Enhertu) demonstrated continued benefit in patients with HER2-positive breast cancer who had stable, treated brain metastases at baseline, according to results from a subgroup analysis of the DESTINY-Breast01 (NCT03248492). The analysis of the central nervous system (CNS) subgroup also demonstrated a consistent safety profile when compared with the overall population.

Of the 24 patients with CNS metastases at baseline, 58.3% had a confirmed objective response rate (ORR; 95% CI, 36.6%-77.9%) with 4.2% achieving a complete response (CR), 54.2% experiencing a partial response (PR), and 33.3% having stable disease. These data are comparable with the analysis of all patients (n = 184), of which 60.9% had a confirmed ORR (95% CI, 53.4%-68.0%) with 6.0%, 54.9%, and 36.4% achieving a CR, PR, SD, respectively.

 Of the 4 patients who experienced progressive disease, 1 was in the CNS subgroup.

These subgroup analysis data were presented by Guy Jerusalem, MD, a professor of Oncology at the Liege University, Belgium, and head of Medical Oncology at the University Hospital of Lieg, as part of the 2020 ESMO Breast Cancer Virtual Meeting.

Jerusalem noted that although similar results were observed in the CNS subgroup as in the overall population, it is important to note the wide confidence intervals in the CNS group.

Investigators enrolled 184 patients with unresectable or metastatic HER2-positive breast cancer who were heavily pretreated, including with ado-trastuzumab emtansine (T-DM1; Kadcyla) and other HER2-targeted treatments. All patients included in the intent-to-treat analysis received the recommended dose of trastuzumab deruxtecan, at 5.4 mg/kg every 3 weeks. The primary end point of the trial was confirmed ORR by independent central review per RECIST v1.1.

The baseline characteristics of the overall population and the CNS subgroup were well matched with each population having received a median of 6 prior treatments, with 100% of patients having received prior T-DM1 and trastuzumab (Herceptin), and 62.5% and 65.8% having received prior pertuzumab (Perjeta), respectively.

The disease control rate in the CNS subgroup was 91.7% compared with 97.3% in the overall population. Furthermore, those patients with CNS metastases experienced a longer median duration of response, at 16.9 months (95% CI, 5.7-16.9) versus 14.8 months (95% CI, 13.8-16.9) in the overall population. The median time to response was 2.8 months (95% CI, 1.3-4.1) for the CNS subgroup versus 1.6 months (95% CI, 1.4-2.6) for all patients.

At median follow-up of 11.0 months, the median progression-free survival in the CNS subgroup was 18.1 months (95% CI, 6.7-18.1) versus 16.4 months (95% CI, 12.7-not evaluable) at 11.1 months follow-up in the overall population.

The sites of progression were similar among all patients and the CNS subgroup. Of the 48 patients who experienced progression while on the study, only 4 (2.2%) were in the CNS. The CNS site progression occurred at days 78 and 85 in the CNS subgroup and at days 323 and 498 in those patients without a history of CNS metastases (n = 160). Other sites of metastases in the CNS subgroup and the non-CNS patients were lung (12.5% vs 10.6%, respectively), liver (8.3% vs 7.5%), and the bone (4.2% vs 1.3%).

At the time of data cutoff, 45.8% of patients with CNS metastases were ongoing and 54.2% of patients discontinued primarily for progressive disease (6/24; 25.0%).

The safety analysis demonstrated consistent treatment-emergent adverse events (TEAEs) between the CNS subgroup and the overall patient population. The predominant TEAEs were gastrointestinal or hematologic in nature. Two patients in the CNS subgroup discontinued due to TEAEs other than pneumonitis or interstitial lung disease (ILD). In the overall population, adverse events that led to discontinuation in at least 2 patients included pneumonitis (n = 11) and ILD (n = 5).

Prior reported analyses, simultaneously published in the 

, demonstrated the safety and efficacy of trastuzumab deruxtecan in the overall population. These results led to the approval of the novel antibody-drug conjugate for the treatment of unresectable or metastatic HER2-positive breast cancer after treatment with at least 2 prior anti—HER2-based regimens in the United States, or after prior chemotherapy in Japan.

In a case report presented by Jerusalem, a 48-year-old woman with HER2-positive (IHC 3+)/hormone receptor—negative metastatic breast cancer demonstrated a 55% regression of a metastatic brain lesion while receiving trastuzumab deruxtecan.

The patient had received 17 prior lines of treatment, including prior T-DM1, pertuzumab, trastuzumab, and lapatinib (Tykerb). Prior treatment for CNS metastases included whole brain radiotherapy and stereotactic radiosurgery 3 years prior to enrollment. Target lesions at baseline included brain, lymph nodes, and retroperitoneum. Nontarget lesions were present in the lung, pancreas, bone, and axillary lymph node.

At 6-week evaluation, scans showed that the brain lesion reduced by 36% from baseline with partial response (PR) in all target lesions. At 12 weeks, the lesion was reduced by 55% with continued PR in all target lesions. Despite this progress, “New lesions were observed in the chest wall and unfortunately, the response was progressive disease and we had to stop treatment,” explained Jerusalem.

Jerusalem concluded by describing 3 important international large phase 3 studies that are ongoing in patients with HER2-expressing breast cancer. First, the DESTINY-Breast02 trial (NCT03523585) is evaluating trastuzumab deruxtecan versus standard of care after T-DM1 in HER2-positive disease. A head-to-head examination of T-DM1 versus trastuzumab deruxtecan in patients previously treated with trastuzumab and taxane in the advanced/metastatic setting is being explored in the DESTINY-Breast03 trial (NCT03529110). Finally, the DESTINY-Breast04 trial (NCT03734029) is investigating trastuzumab deruxtecan versus chemotherapy in patients with HER2-low expressing breast cancer that has spread or cannot be surgically removed.

Jerusalem G, Park YH, Yamashita T, et al. CNS metastases in HER2-positive metastatic breast cancer treated with trastuzumab deruxtecan: DESTINY-Breast01 subgroup analyses. Presented during 2020 ESMO breast cancer virtual meeting; May 23-24, 2020. Abstract 138O.

Modi S, Saura C, Yamashita T, et al. Trastuzumab deruxtecan in previously treated HER2-positive breast cancer. N Engl J Med. 2020;382(7):610-621. doi:10.1056/NEJMoa1914510

Enhertu. Package insert. Daiichi Sankyo, Inc; 2019. Accessed May 23, 2020. https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/761139s000lbl.pdf

Enhertu approved in Japan for treatment of patients with HER2 positive unresectable or metastatic breast cancer. New release. March 25, 2020. Accessed May 23, 2020. bit.ly/2Zxr2VJ

Fam-trastuzumab deruxtecan-nxki (Enhertu) demonstrated continued benefit in patients with HER2-positive breast cancer who had stable, treated brain metastases at baseline.

Trastuzumab Deruxtecan Shows Efficacy in HER2+ Breast Cancer Brain Mets

Although little evidence exists with regard to how to best treat patients with breast cancer during the COVID-19 pandemic, guidelines have been issued by organizations like ESMO to assist providers with making those decisions. The most important thing to remember is to treat as closely as possible to standard evidence-based recommendations, and to mindfully adapt procedures to ensure patient safety, according to Sibylle Loibl, MD, PhD.

“We should treat our patients with cancer as closely as possible to the standard of evidence-based medicine recommendations,” said Loibl, chair of the German Breast Group, University of Frankfurt/M, Centre of Haematology and Oncology, in Frankfurt, Germany, in the first keynote lecture during the 2020 ESMO Breast Cancer Virtual Meeting. “I would like to remind you that we need to mindfully adapt our procedures and we should not overreact; this is very important. Otherwise, we risk the patients’ safety and we risk the integrity of our clinical trials; this will have consequences later on.”

As of May 23, 2020, a total of 5,175,476 cases of COVID-19 have been reported since December 31, 2019, according to the European Centre for Disease Prevention and Control; this includes 338,039 deaths.

 In Europe, COVID-19 case counts continued to rise from late January until the end of February, according to Loibl, who added that the number of deaths associated with the virus appears to have recently plateaued.

In any new or unusual situation such as this one, providers must approach the challenge as follows: create a plan, do something, check what has been done, and then act. “[The plan portion of the theory consists of creating] guidelines and prioritization of our patients. We then need to triage the patients and treat them accordingly,” explained Loibl. “After that, we need to look at outcomes and check the workflow. Eventually, we need to discuss with our patients or amongst ourselves the outcome, or what we have seen, and adapt accordingly.”

In light of the COVID-19 crisis, the treatment of patients with cancer must be prioritized, according to Loibl. To this end, a conceptual framework for prioritizing the use of radiotherapy and systemic treatments during the pandemic across all tumor types was recently published, with patients with breast cancer falling within the middle category.

“We have the high-risk patients with breast cancer with neoadjuvant or adjuvant indications who might derive a substantial benefit from their treatment,” said Loibl. “Then, we have some patients with palliative indications; they range from low priority to higher priority and it really depends on the stage of the metastatic breast cancer, the seriousness of their symptoms, and the type of underlying problems and conditions they have in addition to their risk of acquiring a COVID-19 infection.” For example, patients categorized to be very low risk may have bone metastases that are manageable with medications, are stable, and are appropriate for active surveillance.

In an attempt to develop guidance to mitigate the negative effects of the COVID-19 crisis, ESMO released recommendations specifically for the management and treatment of patients with breast cancer. Similar to the conceptual framework, the approach is organized by priority: high, medium, and low.

If a patient is categorized as “high” priority, their condition is considered to be immediately life threatening, clinically unstable, or an intervention could result in significant survival benefit or substantial improvement in quality of life. For a situation to be classified as “medium” priority, it is considered to be noncritical, with the understanding that a delay in treatment for longer than 6 months could impact outcome, or the benefit of intervention qualifies for intermediate priority. If a patient’s condition is stable enough that treatment can be delayed for the duration of the pandemic or an intervention would not result in survival gain, their situation is classified as “low” priority.

Patients with a post-operative, unstable clinical scenario should be seen as an outpatient in the clinic, irrespective of the risk to acquire infections, according to Loibl. For these “high” priority patients who do need to visit the clinic, many hospitals have put precautionary measures in place to protect them from exposure to COVID-19. Patients with breast cancer who are pregnant are also considered to be “high” priority.

“Medium” category scenarios include those who receive a new diagnosis of invasive breast cancer, those on treatment who experience new adverse events, those who receive a new diagnosis of non-invasive breast cancer, and certain patients without any complications who require post-operative visits.

Established patients without any new issues, survivorship follow-up, follow-up for those at high risk of breast cancer or at high risk of relapse, and psychological support visits, are all considered to be “low” priority scenarios.

“High risk, again, are those patients who have breast cancer surgery complications and complications of reconstructing surgery. Also, surgery in patients who have completed the neoadjuvant chemotherapy-based treatment [fall in this category], because we know those patients are not operated on within 3 to 4 weeks, and especially those with residual disease who have a higher risk of relapse when they are not operated on very soon,” explained Loibl.

“Medium” or “high and medium” priority scenarios include the excision of malignant recurrence, depending on the phenotype and extent; clinically low-risk primary breast cancer, and discordant biopsies expected to be malignant.

On the other side of the spectrum, excision of benign lesions and duct excision; surgery of non-invasive breast cancer, except for extended high-grade ductal carcinoma in situ; discordant biopsies likely to be benign; breast reconstruction; and prophylactic surgery for asymptomatic but high-risk patients are all considered to be “low” priority.

With regard to radiation oncology, palliative treatment of bleeding or painful breast mass considered to be inoperable, when control of symptoms cannot be achieved pharmacologically, is determined to be “high” priority, along with patients who are already receiving radiation treatment. “The adjuvant post-operative radiotherapy for our high-risk patients is, of course, important and should not be postponed, [and] should not be adapted,” said Loibl.

Adjuvant post-operative radiotherapy for low- or intermediate-risk patients with breast cancer is considered to be “medium” priority, and the use of hypofractionated regimens should be taken into consideration as a means to decrease visits to the hospital.

“On the other side, we have the in situ carcinomas and we have the elderly patients, where it might be more helpful to start the adjuvant therapy, endocrine treatment, and maybe postpone radiotherapy, because they are at high risk of acquiring COVID-19 infection,” added Loibl.

Patients with triple-negative breast cancer (TNBC), especially those with higher risk of relapse, should receive treatment with neoadjuvant and adjuvant chemotherapy; their treatment should not be delayed, said Loibl. Likewise, patients with HER2-positive breast cancer should continue treatment with neoadjuvant and adjuvant chemotherapy in combination with targeted therapy.

Additionally, adjuvant capecitabine treatment in patients with high-risk TNBC, and ado-trastuzumab emtansine (T-DM1; Kadcyla) in patients with high-risk HER2-positive breast cancer should be considered, according to Loibl.

“We might have more options for delaying or adapting treatment in our medium-risk patients,” said Loibl. “We can use endocrine treatment, or can use adjuvant trastuzumab [Herceptin] alone, which can be postponed for some weeks.”

Additionally, if a patient is clinically asymptomatic or exhibit clinical signs of response in the neoadjuvant setting, follow-up imaging, restaging studies, echocardiograms, and bone density scans can be delayed.

For patients with early breast cancer, standard adjuvant therapy in the pre- and post-menopausal setting should be continued, and telemedicine should be utilized to address potential associated toxicities that are reported by the patient. Additionally, neoadjuvant endocrine therapy can be used in patients with estrogen receptor (ER)—positive, HER2-negative stage I or II disease to allow for surgery to be deferred by 6 to 12 months.

“We should think about providing more supportive treatment to avoid unnecessary toxicity, especially toxicity associated with higher infection like neutropenia. We can give G-CSF support as primary prophylaxis, or we can add on antibiotics. We might consider reducing the immune suppression, especially in the elderly population,” said Loibl. “LHRH agonists and analogs can be given every 3 months instead of monthly, but monthly at-home administration is actually the preferred recommendation for our patients, and the blood tests should be done near home to avoid unnecessary travel.”

When chemotherapy is recommended for patients with metastatic breast cancer, oral options are preferred as a way to reduce visits to the hospital. It is recommended that the chemotherapy schedules be modified to an every-3-week dosing schedule rather than weekly dosing, when appropriate.

“LHRH [analogues can be given] every 3 months and bone agents can be given every 3 months. The incorporation of CDK4/6 inhibitors into endocrine treatments should align with recommendations and resource availability,” said Loibl. “We know there’s risk associated with neutropenia, but we don't know how often the neutropenia is actually associated with an infection. We need to discuss this risk with our patients.”

Elderly patients are at higher risk, and thus, providers might consider postponing the start of CDK4/6 inhibitors in this population. For patients with low-risk metastatic breast cancer, endocrine therapy should be started first and then the CDK4/6 inhibitor can be added later on.

“We have the checkpoint inhibitor as additional treatment for our patients with PD-L1—positive metastatic TNBC; that option can be considered,” added Loibl. “So far, we haven't seen a higher complication rate. However, we need to closely monitor symptoms—especially as they can be associated with pneumonitis or infection&mdash;and promptly withdraw the patient in case we have additional COVID-19 infection diagnosis.”

The COVID-19 pandemic has also significantly impacted clinical trials, resulting in temporary holds or deactivation. When the trial is examining a drug that is providing significant benefit for high-risk patients, investigators are working hard to ensure the research continues. In comparison, if a trial is being conducted purely from an academic standpoint, and patients need to make extra trips to the hospital, the research might be temporarily halted, according to Loibl.

It’s important that investigators mindfully adapt their procedures and avoid overreacting in this situation.

“A 5% to 10% decrease in survival in high income countries has been predicted [as a result of not mindfully adapting our cancer treatment], and this will account for hundreds of thousands of excess deaths—this [number] will dwarf those caused by COVID-19,” concluded Loibl.

Loibl, S. Breast cancer treatment and research in the Covid 19 era. Presented at: 2020 ESMO Breast Cancer Virtual Meeting; May 23-24, 2020; Virtual. Keynote lecture.

COVID-19 situation update worldwide, as of 23 May 2020. European Centre for Disease Prevention and Control. Accessed May 23, 2020. bit.ly/3ec6o1G

Hanna TP, Evans GA, Booth CM. Cancer, COVID-19 and the precautionary principle: prioritizing treatment during a global pandemic. Nat Rev Clin Oncol. 2020;17(5):268-270. doi:10.1038/s41571-020-0362-6

ESMO management and treatment adapted recommendations in the COVID-19 era: breast cancer. European Society for Medical Oncology. Accessed May 23, 2020. bit.ly/2A0tmKu

Although little evidence exists with regard to how to best treat patients with breast cancer during the COVID-19 pandemic, guidelines have been issued by organizations like ESMO to assist providers with making those decisions.

Mindful Adaptation of Breast Cancer Treatment Necessary Amid COVID-19 Crisis

Adding the oral AKT inhibitor ipatasertib to paclitaxel continued to demonstrate a clinically meaningful extension in overall survival (OS) in patients with locally advanced or metastatic triple-negative breast cancer (TNBC), according to the final analysis of the phase 2 LOTUS trial presented during the 2020 ESMO breast cancer virtual meeting.

“This is a clinically meaningful improvement of 9 months in overall survival. Which, indeed, is not too dissimilar to what we see in patients with PD-L1—positive TNBC who are receiving immune checkpoint inhibition in combination with chemotherapy,” said lead LOTUS author Rebecca Dent, MD, head of the Department of Medical Oncology at National Cancer Center Singapore. “The median overall survival [with ipatasertib] of greater than 2 years clearly represents a meaningful outcome in metastatic TNBC.”

Dent did note, however, that, “the [hazard ratio] confidence interval does cross 1, and, therefore, we do need confirmatory phase 3 results.”

The median OS favored the ipatasertib combination across all biomarker-defined subgroups. Among patients with normal tumor IHC PTEN status, the median OS was 28.5 versus 17.1 months with ipatasertib versus placebo, respectively (HR, 0.70; 95% CI, 0.36-1.36), and the 1-year OS rates were 85% versus 68%, respectively. Among patients with low PTEN status, the median OS and 1-year OS rates also favored the ipatasertib arm at 23.1 versus 15.8 months (HR, 0.83; 95% CI, 0.42-1.64) and 79% versus 64%, respectively.

In patients with non-altered PIK3CA/ACT1/PTEN status by NGS, the median OS was 23.1 months with ipatasertib compared with 16.2 months with placebo (HR, 0.72; 95% CI, 0.39-1.33), with 1-year OS rates of 81% versus 67%, respectively. Among patients with altered PIK3CA/ACT1/PTEN status by NGS, the median OS was 25.8 months with ipatasertib compared with 22.1 months with placebo (HR, 1.13; 95% CI, 0.52-2.47), with 1-year OS rates of 88% versus 63%, respectively.

Dent said that the IHC PTEN and NGS PIK3CA/ACT1/PTEN cohorts were all too small to make any definitive conclusions; therefore, as with the ITT data, a confirmatory phase 3 trial is needed.

The phase 2 LOTUS trial included 124 patients with previously untreated measurable locally advanced or metastatic TNBC not amenable to curative resection. Patients had to be at least 6 months removed from chemotherapy.

Patient characteristics were well balanced between the 2 arms. Specifically in the ipatasertib arm, the median age was 54 (range, 44-63), 71% had an ECOG performance status of 0, 29% had an ECOG performance status of 1, and 66% had prior neo(adjuvant) therapy (50% had prior taxane). The Targos PTEN H-score was 0 in 16% of patients; 1 to 150 in 44% of patients; and more than 150 in 40% of patients. Sites of metastases included lung (44%), liver (31%), lymph nodes (58%), and bone (26%). The chemotherapy-free interval was 6 to 12 months for 29% of patients and more than 12 months for 37% of patients, with the remaining 34% of patients having no prior chemotherapy.

“What was different about this study compared to other studies in the first-line metastatic setting is that the chemotherapy-free interval was greater than or equal to 6 months. And as you know, in many studies, it’s actually 12 months. So this study included a group of patients with quite aggressive disease,” said Dent.

Patients were randomized 1:1 to paclitaxel at 80 mg/m

 on days 1, 8, and 15, with either ipatasertib (n = 62) at 400 mg/day or placebo (n = 62) on days 1 to 21 of a 28-day cycle until progression or unacceptable toxicity. The coprimary end points were progression-free survival (PFS) in the ITT and IHC PTEN-low populations. Key secondary end points included OS, overall response rate, and safety.

Dent highlighted the OS activity with ipatasertib in subgroups defined by age. Among patients aged <50 years, the median OS was 35.2 months with ipatasertib compared with 15.1 months with placebo (HR, 0.41; 95% CI, 0.20-0.85). In patients aged ≥50 years, the median OS was 21.8 months with ipatasertib compared with 20.9 months with placebo (HR, 1.21; 95% CI, 0.71-2.07).

“What you can see [in patients aged <50 years] is that we have a hazard ratio of 0.41 that does not cross 1 in the confidence interval and we see…a 20-month improvement in overall survival. Now, this is hypothesis generating and needs to be confirmed in a phase 3 study, but I think it is biologically plausible, as many of us would agree, that patients who are under 50 who are triple-negative likely represent a different subgroup of [TNBC patients] who might be particularly susceptible to AKT inhibition,” said Dent.

Previously reported data from the LOTUS trial showed that the study had met the comprimary PFS end points.

 In the ITT population the median PFS was 6.2 months in the ipatasertib arm versus 4.9 months in the placebo arm (HR, 0.60; 95% CI, 0.37-0.98; 

 = .037). In the IHC PTEN-low population, the median PFS was 6.2 versus 3.7 months, respectively (HR, 0.59; 95% CI, 0.26-1.32, 

Overall, 77% of patients in the ipatasertib arm had subsequent systemic anticancer therapy compared with 90% of patients in the placebo arm. These included immunotherapy (11% in ipatasertib arm vs 18% in control arm) and chemotherapy (77% vs 89%, respectively). Regarding specific chemotherapy treatment, platinum-containing regimens were administered to 53% of the ipatasertib arm versus 52% of the placebo arm, with non-platinum regimens being administered to 77% versus 89%, respectively.

Grade ≥3 adverse events (AEs) occurred in 56% of the ipatasertib arm compared with 45% of the placebo arm. Ipatasertib specifically led to AE-related treatment discontinuation in 7% (n = 4) of patients, AE-related dose interruption in 36% (n = 22), and AE-related dose reduction in 21% (n = 13).

“This combination is extremely well tolerated, especially when we compare it to other agents targeting this pathway. [We did] see noticeable diarrhea—in this particular study there were no prophylactic antidiarrheals given. What we also saw was an increase in sensory neuropathy, which is not entirely unexpected given that patients [in the ipatasertib arm] were on therapy longer and thus were exposed to a longer duration of paclitaxel, and hence, neuropathy would increase,” said Dent.

Key ongoing phase 3 trials of ipatasertib include IPATunity130 (NCT03337724) and IPATunity170 (NCT04177108). IPATunity130 is studying ipatasertib in combination with paclitaxel in patients with PIK3CA/AKT1/PTEN-altered, locally advanced or metastatic TNBC or hormone receptor—positive, HER2-negative breast cancer. IPATunity170 is evaluating ipatasertib plus atezolizumab (Tecentriq) and paclitaxel in patients with locally advanced or metastatic TNBC.

Dent R, Antunes de Melo E Oliveira AM, Isakoff  SJ, et al. Final results of the double-blind placebo (PBO)-controlled randomised phase II LOTUS trial of first-line ipatasertib (IPAT) + paclitaxel (PAC) for inoperable locally advanced/metastatic triple-negative breast cancer (mTNBC). Presented during 2020 ESMO breast cancer virtual meeting; May 23-24, 2020. Abstract 139O.

Kim S-B, Dent R, Im S-A, et al. Ipatasertib plus paclitaxel versus placebo plus paclitaxel as first-line therapy for metastatic triple-negative breast cancer (LOTUS): a multicentre, randomised, double-blind, placebo-controlled, phase 2 trial. 

. 2017;18(10):1360-1372. doi: 10.1016/S1470-2045(17)30450-3

In the intention-to-treat (ITT) population, the median OS was 25.8 months with ipatasertib plus paclitaxel versus 16.9 months in the control arm of placebo plus paclitaxel (HR, 0.80; 95% CI, 0.50-1.28). The 1-year OS rates were 83% versus 68%, respectively. The analysis occurred at a median follow-up of 19 months in the ipatasertib arm and 16 months in the placebo arm.

Adding ipatasertib to paclitaxel continued to demonstrate a clinically meaningful extension in overall survival in patients with triple-negative breast cancer. 

Ipatasertib Survival Results Continue to Impress in TNBC

Yeon Hee Park, MD, professor, Breast Cancer Center, Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, discusses the utility and benefit of fam-trastuzumab deruxtecan-nxki (Enhertu) in HER2-positive metastatic breast cancer, specifically in patients with central nervous system (CNS) metastases.

The space of HER2 metastatic breast cancer already has many active, HER2-directed drugs; however, patients die from disease progression, says Park. The phase 2 DESTINY-Breast01 trial showed that trastuzumab deruxtecan may prolong and improve overall survival (OS) in this patient population.

HER2-positive breast cancer also has a high aphinity for CNS metastases. Trastuzumab deruxtecan has shown potential to control the CNS metastases that develop in these patients. In a subgroup analysis of the DESTINY-Breast01 trial, clinical responses were reported in patients with CNS metastases. Overall, with extended follow-up, physicians may find that the drug may improve the CNS metastases in patients with HER2-positive breast cancer, concludes Park.

Yeon Hee Park, MD, discusses the utility and benefit of fam-trastuzumab deruxtecan-nxki in HER2-positive metastatic breast cancer, specifically in patients with central nervous system metastases.

Dr. Park on the Benefit of Trastuzumab Deruxtecan in HER2+ Breast Cancer

Rebecca Dent, MD, senior consultant and head of Medical Oncology Department, National Cancer Center, Singapore, discusses the findings from the phase 2 LOTUS trial that treated patients with inoperable locally advanced/metastatic triple-negative breast cancer (TNBC) with first-line ipatasertib plus paclitaxel.

At the 2020 ESMO Breast Cancer Virtual Meeting, the data for the final overall survival (OS) outcomes in the phase 2 LOTUS trial were presented, says Dent; there are about 60 patients in each arm. The overall primary endpoint was PFS and researchers saw a prolonged benefit in the biomarker-positive population, as well as the intent-to-treat population. In the intent-to-treat population, ipatasertib/paclitaxel improved the median OS by 9 months, leading to a median OS of 25.8 months.

A phase 3 trial will be needed to confirm results; however, investigators saw a hazard ratio (HR) of .8 and an improvement of about 15% in 1-year OS.

Rebecca Dent, MD, discusses the findings from the phase 2 LOTUS trial that treated patients with inoperable locally advanced/metastatic triple-negative breast cancer with first-line ipatasertib plus paclitaxel.

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