The gold standards of treatment for HER2-positive metastatic breast cancer currently are taxanes and trastuzumab (Herceptin) plus pertuzumab (Perjeta; THP) in the first-line setting and trastuzumab emtansine (T-DM1; Kadcyla) as second-line treatment, with emerging novel therapies being introduced for their potential as alternative therapeutic options in the third-line setting.

Miami Breast Cancer Conference, hosted by Physicians’ Education Resource®, LLC (PER®), these therapeutic options include trastuzumab deruxtecan (Enhertu), neratinib (Nerlynx) plus capecitabine, tucatinib (Tucatinib) plus trastuzumab and capecitabine, margetuximab (Margenza) plus chemotherapy, and more.

“This continues to be an incredibly exciting time for the treatment of HER2-positive breast cancer given all of these new agents,” explained Sara A. Hurvitz, MD, FACP, in her presentation of the data. “But we are challenged to understand how to best sequence these agents which really will require us to take into account the unique safety and efficacy profiles of each of these agents.”

First, the antibody-drug conjugate trastuzumab deruxtecan received accelerated approval in December 2019 in patients receiving 2 or more prior therapies based off of positive data from the single-agent, single-arm DESTINY-Breast01 study (NCT03248492) evaluating a heavily pretreated population (median of 6 prior lines of therapy) of 184 patients with unresectable and/or metastatic breast cancer. The cohort of patients received 5.4 mg/kg of therapy with trastuzumab deruxtecan.

Updated data presented at the 2020 San Antonio Breast Cancer Symposium (SABCS) found that patients achieved an overall response rate (ORR) of 61.4% with a median progression-free survival (PFS) of over 19.4 months. More, the median duration of response was 20.8 months and median overall survival was recorded at 24.6 months.

Next, the tyrosine kinase inhibitor (TKI) neratinib in combination with capecitabine received an expanded indication for patients with advanced/metastatic HER2-positive breast cancer who received 2 or more prior anti-HER2 based regimens based off of data from the phase 3 NALA trial (NCT01808573) which compared the combination with lapatinib plus capecitabine.

 The co-primary end points of the research were PFS and OS, with secondary end points including ORR, duration of response, and safety.

The data found that the mean PFS of the neratinib combination was 8.8 months compared with 6.6 months (HR, 0.76; 95% CI, 0.63-0.93; 

 = .0003). Even with the increase of 2 months in PFS, 24% of patients receiving the neratinib combination, which used a lower dose of capecitabine than the lapatinib combination, had grade 3/4 diarrhea compared with just 13% of patients in the lapatinib group.

“There was an indication that CNS metastases were reduced in the neratinib arm, however still about a quarter of patients developed moderate to severe diarrhea with this drug in spite of the lower dose of capecitabine and the use of loperamide,” explained Hurvitz. “And this is a big limiting factor in the use of this agent.”

Another TKI discussed was tucatinib, which was approved in combination with trastuzumab and capecitabine to treat patients who received 1 or more previous HER2-targeted therapy.

 In the phase 2 HER2CLIMB trial (NCT02614794), patients who had received prior treatment with trastuzumab, pertuzumab, and T-DM1 (n = 612) were randomized 2:1 to either tucatinib or placebo plus trastuzumab and capecitabine.

At the first report in December 2019, the PFS rate at 1 year was 33.1% for patients in the tucatinib group compared with 12.3% for patients in the placebo group (HR, 0.54; 95% CI, 0.42-0.71; 

 <.001). More, the OS rate measured at 2 years was 44.9% for the tucatinib group versus 26.6% for the placebo group (HR, 0.66; 95% CI, 0.50-0.88; 

 = .005). Median OS was 21.9 months and 17.4 months for the tucatinib and placebo groups, respectively (HR, 0.66; 95% CI, 0.50-0.88; 

Finally, margetuximab in combination with chemotherapy was approved in December 2020 to treat patients with HER2-positive breast cancer who received 2 or more prior anti-HER2 regimens. This combination was analyzed in the phase 3 SOPHIA trial (NCT02492711), which compared this combination to trastuzumab plus chemotherapy.

Median PFS was recorded at 5.8 months for the margetuximab combination compared with 4.9 months for the trastuzumab combination (HR, 0.76; 95% CI, 0.59-0.98; 

“We have 4 new third-line approvals, we have a possible expanded indication for abemaciclib [Ibrance], and multiple ongoing clinical trials for novel agents,” concluded Hurvitz.

1. Hurvitz S. Novel Therapies for HER2+ Metastatic Breast Cancer. Presented at: 38th Annual Miami Breast Cancer Conference. March 4-7, 2021.

2. FDA approves new treatment option for patients with HER2-positive breast cancer who have progressed on available therapies. FDA. December 20, 2019. Accessed March 5, 2021. https://bit.ly/2tzcabv

3. Modi S, Saura C, Yamashita T, et al. Updated results from DESTINY-Breast01, a phase 2 trial of trastuzumab deruxtecan (T-DXd) in HER2-positive metastatic breast cancer. Presented at: 2020 San Antonio Breast Cancer Symposium; December 8-11; 2020; Virtual. Poster PD3-06. 

4. FDA approves neratinib for metastatic HER2-positive breast cancer. FDA. February 25, 2020. Accessed March 5, 2021. https://bit.ly/38eD3Dc

5. Saura C, Oliveira M, Feng YH, et al; NALA Investigators. Neratinib plus capecitabine versus lapatinib plus capecitabine in HER2-positive metastatic breast cancer previously treated with ≥ 2 HER2-directed regimens: phase III NALA trial. 

. 2020;38(27):3138-3149. doi: 10.1200/JCO.20.00147

6. FDA approves tucatinib for patients with HER2-positive metastatic breast cancer. FDA. April 17, 2020. Accessed March 5, 2021. 

7. Murthy RK, Loi S, Okines A, et al. Tucatinib, trastuzumab, and capecitabine for HER2-positive metastatic breast cancer. 

. 2020;382(7):597-609. doi: 10.1056/NEJMoa1914609

8. FDA approves mergetuximab for metastatic HER2-positive breast cancer. FDA. December 16, 2020. Accessed March 5, 2021. https://bit.ly/3qkZOLR

Articles

Sara A. Hurvitz, MD, FACP, of the University of California, Los Angeles, discussed a number of emerging novel therapies with the potential to treat patients with HER2-positive metastatic breast cancer in the third-line setting.

Potential Novel Therapies Emerge for Third-Line Setting in Patients with HER2+ Metastatic Breast Cancer

Following protocol amendments to the administration of oral paclitaxel plus encequidar, patients with metastatic breast cancer experienced fewer gastrointestinal (GI) adverse events (AEs), resulting in outcomes that were more in line with intravenous (IV) administration of paclitaxel, according to findings presented at the 

 Miami Breast Cancer Conference®, hosted by Physicians’ Education Resource, LLC (PER®).

“GI adverse events were initially more frequent with [oral paclitaxel plus encequidar] compared to IV [paclitaxel]. However, once the protocol amendments were initiated, with both prophylaxis and treatment of appropriate toxicities in an emergent manner, the incidence of GI adverse events was considerably lower and in line with the levels seen with IV [paclitaxel],” Hope S. Rugo, MD, FASCO, from the Helen Diller Family Comprehensive Cancer Center at the University of California, San Francisco, said during a poster presentation of the findings.

The initial protocol for the international, randomized, phase 3 KX-ORAX-001 study (NCT02594371)—designed to evaluate oral paclitaxel at 205 mg/m

 plus 15 mg of encequidar 3-times-weekly or IV paclitaxel at 175 mg/m

 every 3 weeks in 402 patients with metastatic breast cancer

—did not allow the use of antiemetics in either group. However, the IV paclitaxel group received pretreatment with antihistamines and corticosteroids, which have anti-emetogenic activity.

Therefore, a protocol amendment, which was implemented on April 7, 2017, allowed for the use of antiemetic prophylaxis. An additional amendment, implemented on October 5, 2018, allowed for the use of anti-diarrheal medication.

“During the study, it became apparent that patients with elevated liver function tests at baseline had a higher risk of early-onset [study] AEs,” investigators wrote. “The inclusion criteria were progressively amended to reduce the allowable excursions from normal range for AST/ALT, bilirubin, and [gamma-glutamyl transferase] at baseline.”

Following the amendment, the rates of grade 3 or greater nausea (7% to 3%), vomiting (7% to 4%), and diarrhea (9% to 4%) declined, compared with rates of 1%, 1%, and 2%, respectively, with IV paclitaxel. Treatment discontinuations due to GI AEs in the oral regimen group were diarrhea (1%) and nausea and vomiting (<1%). Moreover, investigators noted that tightening of baseline hepatic function criteria resulted in a decrease in study AEs, including neutropenia.

Lastly, oral administration of aprepitant, a neurokinin-1 (NK1) inhibitor, was associated with an increased incidence of paclitaxel toxicity, “potentially due to inhibition of metabolism of [oral paclitaxel plus encequidar],” the investigators explained.

“Oral chemotherapy offers patients more convenience and studies have shown that patients prefer oral therapies over IV therapies, providing efficacy is not compromised,” Rugo said. “Taxanes are among the most active chemotherapeutic agents in the management of breast cancer that are associated with treatment-limiting toxicities, but we do need more efficacious and less toxic therapies.”

Paclitaxel is known to have poor oral bioavailability due to excretion by gastrointestinal p-glycoprotein. Encequidar is a potent, specific, minimally absorbed p-glycoprotein inhibitor that allows for absorption of oral paclitaxel. The combination of the 2 drugs are a liquid-filled capsule of paclitaxel and a tablet of encequidar and does not contain Cremophor.

“GI AEs in [oral paclitaxel plus encequidar]–treated patients were managed with prophylactic use of antiemetics, primarily 5-HT3 inhibitors, and early intervention with the anti-diarrhea agents, like loperamide,” Rugo said. “The use of the oral NK1 inhibitor aprepitant in combination with [oral paclitaxel plus encequidar is not recommended.”

1. Rugo HS, Umanzor G, Barrios FJ, et al. Oral Paclitaxel and Encequidar in the Treatment of Patients With Metastatic Breast Cancer: Management of Adverse Events. Presented at: 38th Annual Miami Breast Cancer Conference®; March 4-7, 2021; virtual. Poster 24.

2. Umanzor G, Rugo HS, Barrios FJ, et al. Oral paclitaxel and encequidar (oPac+E) versus IV paclitaxel (IVPac) in the treatment of metastatic breast cancer (mBC) patients (Study KX-ORAX-001): progression-free survival (PFS) and overall survival (OS) updates. Presented at: 2020 San Antonio Breast Cancer Symposium; December 8-11, 2020; virtual. Abstract PD1-08.

Allowing for the use of antiemetic prophylaxis and anti-diarrheal medication in the phase 3 KX-ORAX-001 study reduced study drug-related gastrointestinal adverse events.

Amended Protocols Allow for Reduced GI Toxicities With Oral Paclitaxel Combo in Metastatic Breast Cancer

To kick off Colorectal Cancer Awareness month, 

 was joined by Phyllis Morgan, PhD, who is an academic coordinator for the Master of Science in Nursing degree program at Walden University, to discuss the most prevalent treatment disparities related to racial and ethnic minorities who are at risk for developing colorectal cancer (CRC).

“We know that African Americans tend to die more from colorectal cancer than other racial groups, with a mortality rate that’s about 40% higher than in other groups,” Morgan said. “Also, they are diagnosed with colorectal cancer more [frequently] than other ethnic groups.”

Morgan went on to say there are different reasons for that, including factors related to detection and screening. To mitigate these challenges, she said education about risk factors, signs and symptoms of the disease, detection methods, as well as treatment modalities are all key areas of need.

This segment comes from the CancerNetwork® portion of the MJH Life Sciences™ Medical World News®, airing daily on all MJH Life Sciences™ channels.

Phyllis Morgan, PhD, sat down with CancerNetwork® to discuss health disparities during Colorectal Cancer Awareness Month. 

Phyllis Morgan on Health Disparities in Patients At Risk for Developing Colorectal Cancer

The FDA has granted accelerated approval to the chimeric antigen receptor (CAR) T-cell therapy axicabtagene ciloleucel (Yescarta; axi-cel) for the treatment of adults with relapsed/refractory follicular lymphoma after 2 or more lines of treatment, according to Kite, a Gilead Company, who is responsible for developing the cellular therapy.

The decision follows a breakthrough therapy designation and a priority review and marks the third indication for this CAR T-cell product that was originally approved in 2017.

“Once a follicular lymphoma patient’s disease relapses, the duration of response to care shortens with each round of therapy,” Caron A. Jacobson, MD, MMSc, Medical Director of the Immune Effector Cell Therapy Program at Dana-Farber Cancer Institute and Assistant Professor of Medicine at Harvard Medical School, said in a press release. “Additionally, for follicular [lymphoma] in the third line of therapy, the 5-year survival rate is only 20%, highlighting the urgent need for treatments that offer a real chance for durable remission.”

Data supporting the approval are from the multicenter, single-arm, phase 2 ZUMA-5 trial (NCT03105336), in which investigators sought to evaluate axi-cel in 151 patients with relapsed/refractory indolent non-Hodgkin lymphoma—either follicular or marginal zone lymphoma—following 2 or more lines of therapy.

Patients with relapsed/refractory follicular lymphoma (n = 81) responded to axi-cel at a rate of 91%, with 60% of patients achieving a complete remission. Patients with continued remission at 18 months comprised an estimated 74% of the study population; median response duration was not reached at 14.5 months.

In the safety analysis (n = 146), grade 3 or greater cytokine release syndrome and neurological events, adverse events of concern with CAR T-cell therapies, occurred in 8% and 21%, respectively.

“As we look to bring the hope of survival to more patients in need, today’s FDA decision represents a real step forward in our commitment in hematologic malignancies,” Christi Shaw, Chief Executive Officer of Kite, said in a press release. “Advancing CAR T[-cell] therapies for patients across lymphomas remains a cornerstone of our cell therapy development program, and we are excited about the potential of axi-cel for patients with indolent follicular lymphoma.”

U.S. FDA Approves Yescarta for Relapsed or Refractory Follicular Lymphoma After Two or More Lines of Systemic Therapy. News release. Kite, a Gilead Company. March 5, 2021. Accessed March 5, 2021. https://www.gilead.com/news-and-press/press-room/press-releases/2021/3/us-fda-approves-yescarta-for-relapsed-or-refractory-follicular-lymphoma-after-two-or-more-lines-of-systemic-therapy

Data from the phase 2 ZUMA-5 trial supported the approval of axicabtagene ciloleucel, a chimeric antigen receptor T-cell therapy, as a treatment for patients with follicular lymphoma in the third-line setting. 

FDA Approves Axi-cel in Relapsed/Refractory Follicular Lymphoma

An adaptive therapy approach for treating HER2-positive early breast cancer in both the adjuvant and neoadjuvant settings may assist in reducing toxicity and improving outcomes for a range of patients with different baseline disease characteristics.

“For node-negative [disease], the outcomes are pretty good, so we would want to use the less toxic weekly paclitaxel and trastuzumab [Herceptin] regimen,” said Debu Tripathy, MD, at the 

 Miami Breast Cancer Conference, hosted by Physicians’ Education Resource®, LLC (PER®),

 when discussing options for adjuvant therapy. “But for node-positive disease, we are going to want to use the more intensive disease chemotherapy…and dual antibody therapy.”

Other options for patients with node-positive disease include treatment in the neoadjuvant setting, since risk can be further stratified by an in vivo real-time assay. Moreover, at the time of surgery, the achievement of pathological complete response (pCR) can be further used to determine what treatment in the adjuvant setting can be used in these patients.

In his presentation, Tripathy, who is a professor and chairman of the department Breast Medical Oncology, Division of Cancer Medicine, at The University of Texas MD Anderson Cancer Center, explored different adjuvant and neoadjuvant therapy approaches for treating patients with early-stage, HER2-positive breast cancer by chemotherapy and HER2-targeting agents.

“In the last few years, there have been the development of numerous new HER2-targeted therapies,” Tripathy said. The ones that are used for early-stage disease include trastuzumab and pertuzumab (Perjeta), which bind directly to HER2 and can interfere with its function; tyrosine kinase inhibitors, such as lapatinib (Tukysa) and neratinib (Nerlynx), which work on the intracellular portion of the HER2 receptor by inhibiting kinase activity and downregulating signaling; and immunoconjugates like T-DM1 (Kadcyla), which is similar to the structure of trastuzumab, but with highly toxic compounds allowing internalization into the cell and are specifically released into the payload to cause cell death.

Tripathy detailed the basic requirements of personalization, which involve knowing the natural history of the disease, familiarity with therapeutic effects of each therapy as well as toxicities which may affect vulnerable populations, awareness of clinical factors or biomarkers which may predict response, and awareness of the data regarding risk- or biomarker-adapted approaches.

The first way to approach risk-adaptive therapy is to identify patients who already have known low-risk disease, although Tripathy acknowledged it is difficult to perform randomized trials regarding therapy benefit in this group.

“What we know historically from patients who are treated with HER2-targeted therapies for T1a and T1b tumors…the outcomes are very good regardless of [whether or not they received treatment],” Tripathy said.

In the adjuvant setting, data from the ATEMPT trial have shown that the use of T-DM1 versus trastuzumab and paclitaxel for early HER2-positive breast cancer induced high rates of disease control with similar rates of adverse events. However, toxicity profiles varied between the 2 regimens, with T-DM1 resulting in more treatment delays.

“Overall, the toxicity rates were equal, but they were distributed differently,” Tripathy said. “There was more neurotoxicity with the weekly paclitaxel but more early treatment discontinuation due to T-DM1 due to other side effects such a thrombocytopenia, neurotoxicity, and liver function test abnormalities.”

The NeoSphere trial (NCT00545688) demonstrated that patients receiving pertuzumab in addition to trastuzumab and chemotherapy as adjuvant therapy had improved long-term outcomes, although achievement of pCR regardless of therapy was a strong indicator of long-term outcomes in all of the trial’s therapy arms.

From there, Tripathy directed attention to the KATHERINE trial (NCT01772472), which examined trastuzumab versus T-DM1 for patients with residual invasive disease after neoadjuvant therapy. Results of that trial showed a 50% reduction in disease recurrence or death with T-DM1 (

“This was an improvement in outcome, essentially a doubling, of the number of patients who recurred with trastuzumab only,” Tripathy said.

The ExteNET trial (NCT00878709) of extended adjuvant neratinib following neoadjuvant and adjuvant chemotherapy and trastuzumab showed reduced clinically relevant breast relapses without increasing long-term toxicity.

From these results, Tripathy said patients with node-negative disease can be treated with standard paclitaxel and trastuzumab. For those with node-positive disease, patients can receive trastuzumab/paclitaxel plus pertuzumab and from there, the pCR status will determine if patients receive another round of trastuzumab/pertuzumab (pCR) or T-DM1 followed by neratinib (no pCR).

1. Tripathy D. Personalizing Neoadjuvant and Adjuvant HER2-Targeted Therapy. Presented by: 38th Annual Miami Breast Cancer Conference, hosted by Physicians’ Education Resource®, LLC (PER®); March 4-7, 2021.

2. Tolaney SM, Hu J, Dang C, et al. TBCRC 033: A randomized phase II study of adjuvant trastuzumab emtansine (T-DM1) vs paclitaxel (T) in combination with trastuzumab (H) for stage I HER2-positive breast cancer (BC) (ATEMPT). Presented at: 2019 San Antonio Breast Cancer Symposium; December 10-14; San Antonio, TX. Abstract GS1-05

3. Gianni L, Pienkowski T, Im YH, et al. 5-year analysis of neoadjuvant pertuzumab and trastuzumab in patients with locally advanced, inflammatory, or early-stage HER2-positive breast cancer (NeoSphere): a multicentre, open-label, phase 2 randomised trial. 

. 2016;17(6):791-800. doi: 10.1016/S1470-2045(16)00163-7

4. von Minckwitz G, Huang CS, Mano MS; KATHERINE Investigators. Trastuzumab Emtansine for Residual Invasive HER2-Positive Breast Cancer. 

. 2019;380(7):617-628. doi: 10.1056/NEJMoa1814017

5. Martin M, Holmes FA, Ejlertsen B, et al; ExteNET Study Group. Neratinib after trastuzumab-based adjuvant therapy in HER2-positive breast cancer (ExteNET): 5-year analysis of a randomised, double-blind, placebo-controlled, phase 3 trial. 

. 2017;18(12):1688-1700. doi: 10.1016/S1470-2045(17)30717-9

At the Miami Breast Cancer Conference, Debu Tripathy, MD, reviewed adaptive therapy for the adjuvant treatment of patients with HER2-positive, early-stage breast cancer.

Adaptive Therapy Approach in HER2+ Early Breast Cancer May Improve Outcomes, Expert Says

When analyzing the breast surgery caseload of rural general surgeons, the resulting data furthered the evidence that a broad skill set in the delivery of surgical services is valuable as breast surgeries represented only a small portion of the total surgical procedures performed.

 Miami Breast Cancer Conference, hosted by Physicians’ Education Resource®, LLC®, also found that patients in a rural setting were more likely to undergo a simple mastectomy than undergo a subcutaneous mastectomy with reconstruction.

“Data regarding the caseload distribution of general surgeons working in a regional setting in Australia and who perform breast surgery remains scarce,” wrote the investigators. “In order to better examine the challenges faced by rural general surgeons, this study aims to examine the breast surgery caseload of general surgeons working in regional Australia.”

Of the 13,415 surgical procedures carried out by 9 general surgeons at Albury Base Hospital, 543 (4.05%) were breast surgery cases. Of note, there were 99 mastectomies, 214 wide local excisions, 35 re-excisions, and 62 axillary dissections conducted during the study period, with only minor breast procedures accounting for 111 breast surgery cases.

The investigators found a significantly higher number of simple mastectomies (n = 95) performed than there were subcutaneous mastectomies (n = 4) performed (

When examining the general surgeons who conduct the procedures, the research also found that all 9 surgeons performed a number of operations in different surgical specialties outside of general surgery. Some of these operations included cardiothoracic, orthopedic, otolaryngology, neurosurgical, vascular, and urological procedures.

The study initiated a retrospective review of the general surgical procedures conducted at Albury Base Hospital in Australia between January 2007 and December 2014. The research group utilized the classifications via the Royal Australasian College of Surgeons (RACS) Morbidity and Audit Logbook Tool (MALT) to group the surgical procedures and analyze them accordingly.

“The delivery of surgical services in rural and regional areas remains a challenge with the increasing trend towards urban centralisation of surgical specialties,” wrote the investigators. “In Australia, much like in the USA, there remains significant barriers to access to healthcare for patients requiring breast surgery in rural areas. While up to 33% of Australians live in rural or regional areas, only 14.8% of surgeons work in a rural or regional area.”

Overall, the investigators concluded that access to a multidisciplinary meeting is a critical variable in the delivery of breast surgery services for patients in rural areas.

Bappayya S. Caseload of Rural General Surgeons – a Focus on Breast Surgery. Presented at: 

 Miami Breast Cancer Conference® Virtual Conference; March 4-7, 2021.

Data focusing on patients seeking breast surgical procedures determined that broad skill sets are valuable for general surgeons practicing in rural areas, as breast surgeries only represented a small proportion of total surgical procedures conducted.

General Surgeons in Rural Areas Need Broad Skill Set for Delivery of Surgical Services

Patients with HER2-positive metastatic breast cancer with central nervous system (CNS) disease at baseline demonstrated improved outcomes following treatment with neratinib (Nerlynx) plus capecitabine, compared with lapatinib (Tykerb) plus capecitabine, according to study findings presented at the 38th Annual Miami Breast Cancer Conference®.

In particular, neratinib plus capecitabine improved progression-free survival (PFS) and CNS outcomes, which was consistent with findings from 3 other prospective studies – NEfERT-T, TBCRC-022, and ExteNET.

“Our findings support a role for neratinib as a systemic treatment option in the management of patients with HER2-positive brain metastases following antibody-based HER2-directed therapies,” the investigators concluded in a poster presentation of their findings.

CNS metastases from HER2-positive breast cancer have presented as a clinical challenge given the limited availability of evidence-based treatments, investigators noted, adding that there is a need for multiple lines of safe and effective CNS-directed treatments.

In the international, randomized, open-label, active-controlled phase 3 NALA trial (NCT01808573), investigators compared the addition of neratinib – an irreversible small-molecule pan-HER tyrosine kinase inhibitor – versus lapatinib to capecitabine in patients with HER2-positive metastatic breast cancer who previously received 2 or more lines of HER2-directed therapy in the metastatic setting. In their poster presentation, investigators aimed to report efficacy and safety outcomes in the subgroup of patients from the trial who had CNS metastases at baseline, with a particular focus on CNS-specific end points.

Patients were eligible for the trial if they had asymptomatic metastatic brain disease managed with stable doses of corticosteroids for 14 or more days prior to randomization; patients were excluded if they had symptomatic or unstable brain metastases.

Investigators randomized patients 1:1 to receive either 240 mg neratinib once daily plus 750 mg/m2 capecitabine twice daily or 1250 mg lapatinib once daily plus 1000 mg/m2 capecitabine twice daily.

Centrally-assessed PFS and overall survival (OS) served as the co-primary end points. Intervention for symptomatic metastatic CNS disease was a secondary end point.

In the NALA trial, treatment with neratinib plus capecitabine showed a significant improvement in PFS, compared with lapatinib plus capecitabine (HR, 0.76; 95% CI, 0.63-0.93; 

 = .0059). In addition, fewer interventions for CNS disease were required with the neratinib combination, compared with lapatinib (

 = .043). Lastly, intracranial overall response rate (ORR) among patients with 1 or more target CNS lesion (n = 32) was 26.3% with neratinib, compared with 15.4% with lapatinib.

Of the 621 patients enrolled in the NALA trial, 101 (16%) had documented baseline CNS disease and 520 (84%) had no CNS disease at baseline. Of the 101 patients with documented baseline CNS disease, 51 received the neratinib combination and 50 received the lapatinib combination.

Mean age in the CNS subgroup was 54 years (range, 25-75 years). Overall, patients had an ECOG performance status of 1, and 51 (50.5%) patients had hormone receptor-positive disease. Among patients with CNS disease, 81 (80.2%) previously received CNS radiation and/or surgery (whole brain, n = 59 [58%]; stereotactic, n = 17 [17%]; unknown, n = 2 [2%]) and 5 (5%) underwent CNS surgery.

Median duration of study treatment was 5.7 months (range, 0.4–28.6 months) for neratinib and 3.5 months (range, 0.5-20.8 months) for lapatinib. The study cut-off date was September 28, 2018.

The neratinib combination demonstrated superior PFS (7.8 vs 5.5 months; HR, 0.66; 95% CI, 0.41-1.05; 

= .0741) and OS (16.4 vs 15.4 months; HR, 0.90; 95% CI, 0.59-1.38; 

Time to intervention was 25.5 months and 36.0 months with neratinib and lapatinib, respectively (

 = .430), with neratinib demonstrating superior CNS PFS (12.4 vs 8.3 months; HR, 0.62; 95% CI, 0.32-1.18; 

Three patients reported leptomeningeal disease (LMD), of which 2 treated with neratinib had disease progression after 5.6 and 9.8 months, respectively, and OS times of 17.4 and 19.8 months. The 1 patient who received lapatinib had disease progression after 4.3 months and an OS of 6.5 months.

The safety profile appeared consistent with adverse events (AEs) previously observed. The most common AEs included diarrhea, nausea, vomiting, and palmar-plantar erythrodysesthesia syndrome. The most common CNS AEs associated with neratinib and lapatinib included headache (18% vs 29%, respectively), dizziness (18% vs 16%), hemiparesis (4% vs 4%), seizure (4% vs 4%), and gait disturbance (0% vs 8%). Of note, CNS AEs were slightly more common in the CNS subgroup of patients, compared with the overall patient population in the NALA trial.

“The data suggest an association between (neratinib plus capecitabine) and improved PFS and CNS outcomes in patients with CNS metastases from HER2-positive metastatic breast cancer compared with (lapatinib plus capecitabine) in the phase 3 NALA trial,” investigators concluded. “A unique feature of NALA was the inclusion of patients with LMD, 2 of whom were treated with (neratinib plus capecitabine) with good outcomes.”

Saura C, Ryvo L, Hurvitz S, et al. Impact of Neratinib on Outcomes in HER2-Positive Metastatic Breast Cancer Patients with Central Nervous System Disease at Baseline: Findings from the Phase 3 NALA Trial. Presented at: 38th Annual Miami Breast Cancer Conference®; March 4-7, 2021; virtual. Poster 10.

The addition of neratinib to capecitabine improved progression-free survival and central nervous system outcomes in patients with HER2-positive metastatic breast cancer with central nervous system disease.

Neratinib Combo Improves Outcomes in Patients With HER2+ Metastatic Breast Cancer With CNS Disease

During a single-institution study, investigators determined that there was no correlation between recurrence rates and recurrence score (RS) in patients with early-stage estrogen receptor (ER)–positive breast cancer when RS was used for selection of adjuvant treatment following intraoperative radiation therapy (IORT).

Scoring by 21 Gene Recurrence Score guided therapy selection in patients receiving single-fraction (20 Gy) IORT, with those who scored high being more likely to receive adjuvant chemotherapy than those who scored low.

“High RS results (RS > 25), which guided chemotherapy recommendations in appropriate [patients receiving IORT], did not correlate with recurrence,” the investigators wrote in their poster, which was presented during the 

 Miami Breast Cancer Conference, hosted by Physicians’ Education Resource®, LLC (PER®). “The success of IORT observed in this trial as local therapy for early-stage breast cancer…was independent of genomic or patient risk factors.”

In total, 115 patients with a median age of 63 years (range, 43-84) completed both monotherapy IORT per protocol using disposable balloon technology and RS assessment were assessed for outcomes. The median follow-up was 6.8 years, with patients being treated between November 2011 and January 2016. Median tumor size was 1.1 cm (range, 0.2-2.4 cm).

Patients were distributed evenly by RS, with 25 (22%) having an RS below 11, 20 (17%) in the 11 to 15 range, 53 (46%) between 16 and 25, 9 (8%) with an RS from 26 to 30, and 8 (7%) with an RS over 30.

At the median follow-up, recurrences occurred in 4 patients for a recurrence rate of 3.5%. Of those, 3 had local recurrence and 1 had axillary recurrence. Of the local recurrences, the 3 patients had RS of 0, 17, and 18; the axillary recurrence occurred in a patient with an RS of 19.

One patient with a local recurrence and RS of 0 declined endocrine therapy. In one patient with local recurrence (RS 17) and the patient with axillary recurrence, neither received chemotherapy but both complied with endocrine therapy. The final patient with local recurrence and an RS of 18 was treated with cyclophosphamide and docetaxel, but later tested positive for a 

Two patients who had local recurrence chose to be treated with lumpectomy and excision of the area treated with IORT followed by whole breast radiotherapy, and the remaining 2 patients (1 local recurrence and 1 axillary recurrence) both had mastectomies.

Receipt of systemic therapy by recurrence score showed that no patients with scores of 15 or below received chemotherapy. In those with scores in the range of 16 to 25, the rate of chemotherapy treatment was 19%. The highest rates of chemotherapy treatment were in those with a RS at or above 26, with 78% in the 26-to-30 range and 63% with scores over 30 receiving this therapy.

“Recurrence rates were comparable to those reported in IORT peer-reviewed published data and treatment using breast conserving surgery plus whole breast radiation therapy,” the study authors wrote in their conclusion.

Schwartzberg B, Howell K, Moore J, Devchand P, et al. Evaluation of the 21 Gene Recurrence Score (RS) Assay Results Following Successful Intraoperative Radiation Therapy (IORT) Treatment of Patients (pts) with Early-Stage Breast Cancer. Presented at: 

 Miami Breast Cancer Conference, hosted by Physicians’ Education Resource®, LLC (PER®).

More patients with early-stage estrogen receptor–positive breast cancer with high recurrence scores received chemotherapy following radiation in a single-institution study, and this resulted in a low recurrence rate across all patients examined.

Adjuvant Therapy Selection by Recurrence Score After IORT May Lower Recurrence Rates for ER+ Early Breast Cancer 

Data from the KEYNOTE-119 study (NCT02555657) produced estimated trends that suggest tumor cell expression is a significant component for PD-L1, acting as a predictive biomarker for pembrolizumab (Keytruda) efficacy in patients with metastatic triple-negative breast cancer (mTNBC), according to a poster presented at the 

 Miami Breast Cancer Conference, Physicians’ Education Resource®, LLC®.

More, the research suggests a significant number of responders were missed and overall survival (OS) benefits saw higher hazard ratio estimates when only immune cells were used to measure PD-L1 expression.

“Pembrolizumab monotherapy did not significantly improve overall survival (OS) compared with chemotherapy as second- or third-line treatment for patients with metastatic triple-negative breast cancer in the randomized, open-label, phase 3 KEYNOTE-119 study,” wrote the investigators. “However, the benefit of pembrolizumab compared with chemotherapy appeared to be greater with increasing PD-L1 expression, as quantified by combined positive score (CPS).”

Of the 622 patients enrolled in study, 601 had tumor samples that were available for the exploratory analysis. The patient population was randomized 1:1 to either the pembrolizumab arm (n = 309) or to the chemotherapy arm (n = 292).

In the pembrolizumab arm, the overall response rate was recorded at 9.7% (30 of 309 patients) versus 11.3% (33 of 292 patients) in the chemotherapy arm.

When comparing quantitative immune cell density (QID), tumor proportion score (TPS), and CPS, the featured scoring methods, the receiver operating characteristics (ROC) analysis found that CPS (0.69; 95% CI, 0.58-0.80) is better at enriching for responders better than both QID (0.66; 95% CI, 0.55-0.77) and TPS (0.55; 95% CI, 0.46-0.64) across all practical cutoffs.

Specifically, at each cutoff point, the research team observed that QID had both a lower estimated sensitivity and Youden Index than CPS, suggesting that immune cells measured with QID missed responders, not immune cells measured with CPS.

“Using a lower cutoff with QID to capture missed responders is not a viable solution because there will always be a CPS cutoff that detects at least as many responders as a QID cutoff but that misclassifies fewer nonresponders,” wrote the investigators.

In terms of the ORR advantage with CPS, there appears to be a translation with an OS benefit. Specifically, the hazard ratio for OS was slightly lower for CPS than it was for QID.

The data suggest that in tumor cells and immune cells, CPS should be utilized to quantify PD-L1 status for patients with mTNBC.

In regard to the scoring methods, TPS was defined by the research team as “the percentage of PD-L1‒expressing tumor cells (partial or complete membrane staining) relative to the total number of tumor cells.” More, CPS was “the number of PD-L1‒staining cells (tumor cells, lymphocytes, macrophages) divided by the total number of viable tumor cells, multiplied by 100” and QID was “CPS minus TPS.”

Patient eligibility required centrally confirmed mTNBC and those who underwent 1 or 2 systemic treatments for metastatic disease. Once deemed eligible, patients were then randomized 1:1 to receive either 200 mg of pembrolizumab every 3 weeks for up to 35 cycles or a single-agent chemotherapy including capecitabine, eribulin, gemcitabine, or vinorelbine.

“Emerging evidence has demonstrated that PD-L1 expression on tumor cells and immune cells is associated with better antitumor activity in response to immune checkpoint inhibitors in mTNBC,” wrote the investigators.

These results were previously reported at the Virtual 2020 San Antonio Breast Cancer Symposium, held December 8 through 12, 2020.

Emancipator K, Winer EP, Lipatov O, et al. Analysis From KEYNOTE-119 in Triple-Negative Breast Cancer (TNBC) Exploring the Contribution of Tumor and Immune Cells to PD-L1 as a Predictive Biomarker. Presented at: 

 Miami Breast Cancer Conference® Virtual Conference; March 4-7, 2021. Poster 29.

The analysis of the KEYNOTE-119 study presented at the Miami Breast Cancer Conference, hosted by Physicians’ Education Resource®, LLC®, found trends estimating a significant role for tumor cell expression in PD-L1 as a predictive biomarker for pembrolizumab efficacy.

Tumor Cell Expression of PD-L1 is Key in Predicting Efficacy of Pembrolizumab for Patients With mTNBC

A phase 3 trial (NCT04586231) evaluating the efficacy and safety of belzutifan (MK-6482) plus lenvatinib (Lenvima) compared with cabozantinib (Cabometyx) in patients with advanced clear cell renal cell carcinoma (ccRCC) who have progressed on prior anti–PD-1/L1 therapy was announced at the American Society of Clinical Oncology (ASCO) 2021 Genitourinary Cancers Symposium.

The randomized, open-label, active-controlled, multicenter trial will include adults with histologically confirmed, unresectable, locally advanced or metastatic ccRCC with progressive disease on or after first- or second-line systemic treatment with an anti–PD-1/L1 therapy. Approximately 708 patients will be randomly assigned 1:1 to receive either MK-6482 plus lenvatinib or cabozantinib. Treatment will continue until disease progression, unacceptable toxicity, or withdrawal of consent.

The co-primary end points are progression-free survival per RECIST v1.1 as assessed by blinded independent central review (BICR) and overall survival. Key secondary end points include objective response rate, duration of response per RECIST v1.1 as assessed by BICR, and safety.

, Robert J. Motzer, MD, a medical oncologist at Memorial Sloan Kettering Cancer Center, discussed what he believes clinicians should understand about this trial in progress.

This is a trial that looks at patients who have progressed on an [immuno-oncology; IO] therapy and compares cabozantinib, a standard therapy, to a standard [tyrosine kinase inhibitor; TKI], lenvatinib. [Lenvatinib] is also a standard TKI in the second-line [when its] combined with everolimus, but substituting for everolimus [in this combination] is MK-6482, which is a new HIF inhibitor that there’s been a lot of excitement around. It looks like it’s particularly effective in heavily pretreated patients or in patients that have resistant tumors. And so, with the advent of these new IO therapies in first-line, we’re grappling for what’s the best treatment in second or third line and I think this particular trial is really a priority. It looks to identify what’s the best treatment now that the paradigm has changed in first line. It brings in this new novel drug MK-6482, a HIF inhibitor, and it looks at the question as to whether that HIF plus TKI gives additional efficacy. I’m really excited about that trial. I think it’s going to be a priority global trial and a very good option for patients.

Motzer RJ, Liu Y, Perini RF, Zhang Y, Heng DYC. Phase III study evaluating efficacy and safety of MK-6482 + lenvatinib versus cabozantinib for second- or third-line therapy in patients with advanced renal cell carcinoma (RCC) who progressed after prior anti-PD-1/L1 therapy. 

. 2021;39(suppl 6):TPS372. doi: 10.1200/JCO.2021.39.6_suppl.TPS372

Videos

The medical oncologist at Memorial Sloan Kettering Cancer Center highlighted what clinicians treating patients with advanced ccRCC should understand about this trial in progress.