The coronavirus disease 2019 (COVID-19) pandemic had a tremendous impact on the surgical care of patients with breast cancer, according to Cindy Matsen, MD, who added that practice patterns needed to be rapidly adjusted to continue to safely provide care during a time when resources were very limited.

“When the COVID-19 pandemic hit our country, especially during March [2020], when we went into lockdown, we saw huge impacts on surgical care,” Matsen said. “We were anticipating a big surge of patients who would affect our system's capacity to be able to [manage] these patients. As such, we very quickly had to start triaging patients into different groups to understand who needed [surgery immediately] versus who could [have their procedures] delayed safely.”

® during an Institutional Perspective in Cancer webinar on Breast Cancer, Matsen, a breast surgeon and an assistant professor in the Department of Surgery at the Huntsman Cancer Institute, of the University of Utah, shared the protocols her institution put into place to ensure safe surgical practice for patients with breast cancer during the COVID-19 pandemic and how protective measures have evolved over the past year.

: What were some of the main challenges that arose during lockdown with regard to surgery in patients with breast cancer?

: The main challenge was that we were asked to cancel all surgeries very quickly; it all happened basically over a weekend. We got an email on Friday, saying, ‘Hey, we think that we're going to need to cancel all surgeries.’ As such, over that weekend, we had to come up with lists of who we could cancel versus who we could not. There still was some operating room availability [at that time], but it was much more limited than it had been.

A lot of phone calls [were being made], with both our patients and our clinic staff. We were trying to get everything worked out and deal with the psychological consequences of having to cancel [these procedures]. Everyone was reeling from the idea of a lockdown. We were all hoping that by shutting everything down, we were going to be able to truly flatten the curve and return to normal in about 4 to 6 weeks; that obviously didn't happen. However, it did allow us time to plan a little better for when the surge did actually happen.

At that time, we were also dealing with a scarcity of personal protective equipment [PPE], which was very concerning. This was something that really impacts surgery specifically, because we need to wear masks, gowns, and gloves [for those procedures]. If that equipment is not available, then we can't do surgery. [Our concerns went beyond] seeing a big surge and not having enough beds. [We were worried about] whether we would have the basic equipment available to us to be able to perform any sort of surgery.

[We also had to figure out] who to have in the operating room. All of a sudden, all our residents, all our students, everyone is gone. Even if you went to the operating room, it was a very limited team, which is very different from how this normally works for us.

You mentioned that a lot of important decision making happened via phone over that weekend. What did you discuss and what are some of the solutions you came up with?

We used those phone calls among our group to come up with some protocols for canceling all non–time sensitive surgery. Who is time sensitive and who is not? Receptor status, the type of surgery that was scheduled, and the phase of treatment were all factors we took into account to come up with a triage system for who would be most at risk for having bad outcomes if we delayed their surgery, and who we felt could safely be delayed with strategies like neoadjuvant endocrine therapy.

That was probably the biggest shift: patients with estrogen receptor–positive, HER2-negative, early-stage disease, who would normally go to surgery first [turned to] other options. We're lucky in breast cancer that we have other options for these patients. Many received neoadjuvant endocrine therapy during that time period.

It's interesting because we don't have data for short-term neoadjuvant endocrine therapy, but it felt like that was the right thing to do, knowing that there was some uncertainty about when we would actually get these patients to the operating room. We knew that this would at least allow some window for us to be able to delay [surgery] safely, [while] still treating their cancer.

What are some of the steps that were taken as the lockdown started to lift?

During the lockdown, we saw fewer new patients. Fewer people were getting screened and fewer people were getting diagnosed with breast cancer during that time; that gave us a little bit of wiggle room. When we did reopen, our operating rooms were not already packed with patients who have been diagnosed during that time; that provided us with a little more flexibility to get the patients who had been delayed into [the clinic for their surgery].

During the months of June and July, things were very busy because we were trying to treat patients who were just diagnosed and also move all our patients who were on those lists that we made during lockdown into their surgical phase of treatment. It went fairly smoothly. We would talk to patients every week to determine when we might be able to get them in. Some of [these conversations were on] when reconstruction would be available; that was something we didn't start again until July 2020. Some patients were delayed longer depending on what kind of surgery they needed.

It took a lot of interpersonal communication with each individual patient to figure out what the plan was going to be for them. Our operating rooms didn't open up to full capacity right away; they kind of did a limited ramp up. This [decision was made] to protect staff and to figure out how much PPE we had; we still had concerns about those things. It took some time over the course of June 2020 and July 2020 to get everything ramped up to normal volumes. After that, things have been operating fairly normally.

What changes have been made with regard to managing patients around the time of surgery?

When we first opened up, there were no visitors of any kind; that was really hard for people. Patients had to get dropped off to have their surgery and then picked up; they were not to be able to have anyone with them during that time. That was a huge change for all of us.

Also, we now wear full PPE the whole time [that we are working]. I never take off my mask now. I always have on my goggles and I always have on my head covering. Not seeing people's faces or being able to shake their hand when you meet them [were] all things we had to get used to. That was a hard part of re-entry; it was a completely different way of practicing.

What changes were made in the operating room?

Our protocols around intubation and extubation evolved over time. When we first started up, we were very cautious, allowing only the anesthesiologist and 1 person to be at the head of the bed with full protective gear on. We would wait 15 minutes outside the room to let the circulation of the ventilation system happen before we would re-enter. Part of that had to do with the lack of availability of testing. It took some time to be able to get enough tests available that we could actually start testing all patients. Once we had more tests available, then we started testing all patients [who needed surgery]. Then we were able to feel more comfortable with adjusting some of those protocols around intubation and extubation.

In the very beginning, we were very cautious. We did a slow ramp up [until] we got back to full volume, which happened over time. We also had an increase in test capacity, which allowed us to start testing all patients. Then, things [started to feel] a little bit more normal. We also then felt safe having 1 visitor per person, which made a difference. However, a whole bunch of things changed. Nothing is truly normal about what we're doing. We get the surgeries done, but the way we do it, who's in the room, and who's not in the room—all of that is still evolving on a regular basis.

This article was originally published on OncLive as, "

Matsen Spotlights Best Practices for Breast Cancer Surgery Amidst the COVID-19 Crisis

Articles

A breast surgeon discusses the best practices for breast cancer surgery during the COVID-19 pandemic.

Breast Cancer Surgery in a Pandemic: What's the Best Approach?

The FDA granted a regular approval to sacituzumab govitecan (Trodelvy) for the treatment of patients with unresectable locally advanced or metastatic triple-negative breast cancer (TNBC) who had 2 or more previous systemic therapies, with at least 1 being for metastatic disease.

Recommended dosing for the drug is 10 mg/kg once a week on days 1 and 8 of 28-day treatment cycles or until progression or unacceptable toxicity.

The approval was based on findings from the multicenter, open-label, randomized ASCENT trial (NCT02574455), which included 529 patients with unresectable or locally advanced metastatic TNBC who experienced progression on 2 or more chemotherapies, one of which could have been in the neoadjuvant setting if progression occurred within 12 months.

Participants in ASCENT were randomized 1:1 to receive either intravenous sacituzumab govitecan or physician’s choice of single-agent chemotherapy.

The primary endpoint of the study was progression-free survival (PFS) in patients without brain metastases, per RECIST 1.1 criteria. Average PFS was 4.8 months in the sacituzumab govitecan arm, compared with 1.7 months in the chemotherapy arm.

Sacituzumab govitecan also bested chemotherapy when it came overall survival (OS), with median OS being 11.8 months in the treatment arm compared to 6.9 months in the control arm.

Common adverse events from sacituzumab govitecan, which occurred in more than 25% of patients, were nausea, neutropenia, diarrhea, fatigue, alopecia, anemia, vomiting, constipation, rash, decreased appetite, and abdominal pain.

The FDA granted a regular approval to sacituzumab govitecan (Trodelvy) for previously treated patients with unresectable locally advanced or metastatic triple-negative breast cancer.

FDA Approves Sacituzumab Govitecan for Pretreated, Metastatic TNBC

Data from the pivotal phase 3 KATHERINE (NCT01772472) has led to the addition of ado-trastuzumab emtansine (T-DM1; Kadcyla) to the HER2-positive breast cancer treatment arsenal, but the toxicities associated with the approach must be appropriately managed so that patients can continue to receive it, according to Jane L. Meisel, MD.

The phase 3 KATHERINE trial examined ado-trastuzumab emtansine (T-DM1; Kadcyla) vs trastuzumab (Herceptin) and showed that the former resulted in a 50% reduction in the risk of invasive disease recurrence or death (HR, 0.50; 95% CI, 0.39-0.64; 

 <.0001). These data led to the May 2019 FDA approval of T-DM1 for use as an adjuvant treatment in select patients with HER2-positive early breast cancer.

Notably, 25.7% of the patients in the T-DM1 arm experienced a grade 3 or higher adverse effect (AE) vs 15.4% in the trastuzumab arm. Additionally, 18% of patients in the T-DM1 arm experienced AEs that lead to discontinuation of treatment.1

“It's tricky because these patients have been through a lot,” Meisel said. “It's a diagnosis of breast cancer, first of all, and it is a relatively toxic, intense, up-front therapy. It’s not the easiest thing, but for many patients, particularly those with high-risk disease, it really does make a difference. We try to do all we can to support patients through that.”

® during an Institutional Perspectives in Cancer webinar on breast cancer, Meisel, an associate professor for the Departments of Hematology and Medical Oncology, and Gynecology & Obstetrics at Winship Cancer Institute, Emory University School of Medicine, discussed the use adjuvant T-DM1 and the management of associated toxicities and the benefit of the combination pertuzumab (Perjeta)/trastuzumab in HER2-positive breast cancer.

®: What were the implications of the phase 3 KATHERINE and FeDeriCa trials (NCT03493854) now that more mature data have read out?

: KATHERINE was a fascinating study because it not only allowed us to take a very high-risk group and randomize them to a potential intervention, but it also showed that they really did much better when, instead of being given just 1 year of trastuzumab after not achieving a pathologic complete response [pCR], they were switched over to adjuvant T-DM1. That 3-year progression free survival [PFS] difference of 11% is really statistically significant, as well as clinically significant, and this has changed the way we treat our patients. Routinely, we are switching [patients] over to T-DM1 as was done in KATHERINE, and I believe this will start to change outcomes, as we see more and more of these patients do better.

FeDeriCa was a study that looked at pertuzumab and trastuzumab given subcutaneously as opposed to intravenously, with the primary end point being pertuzumab concentration, so more of a pharmacologic/pharmacokinetic end point as opposed to a clinical end point. The authors also looked at PCR rates with the subcutaneous administration and found that both the trough concentrations as well as the PCR rates were the same with subcutaneous versus IV administration.

[This is an] intervention that changes convenience for the patient, and in terms of safety, particularly during the pandemic, [it can prevent] time spent in the infusion center. This is a preparation which, technically, could be given in one's home as opposed to even in the clinic. Certainly, for patients who want to have the port removed or don't want to receive IV treatment for longer than they have to, this offers an opportunity to do just a little injection as opposed to an infusion. In terms of quality of life for patients, which really is a huge [factor] after they've been through so much, this represents a major step forward.

Were there any prohibitive toxicities observed in KATHERINE?

In the study, approximately 18% of patients discontinued T-DM1 because of toxicity. Generally, the populations that we see in studies are inherently a motivated, relatively well population of patients, while those we see in clinic may have more comorbidities or may not be as motivated as those who choose to join trials. As such, more [efforts are needed] to monitor these patients and to encourage them to stay on the T-DM1 because it is a little more challenging than the pertuzumab/trastuzumab. However, the benefit is there, so when patients seem as though they're going to benefit and they fit the criteria for the trial, we do try to get them to stay on [the drug].

I find it works best if I tell patients about the possibility [of toxicity] in the beginning. When I describe the neoadjuvant, anti-HER2–directed regimen, I talk about the fact that we'll use their surgery as both a part of their treatment, but also as an information-gathering piece. The result of the surgery, whether they get to PCR or not, will inform the next step. If they get to PCR, [they] would [then receive] trastuzumab, likely plus pertuzumab, or switch to T-DM1 if they don't. Once I get closer to that time point after the surgery, and if the patient is going to receive T-DM1, then we talk about what that will look like.

Often, I do see the patients each visit with T-DM1, at least in the beginning, just to see whether they're experiencing [effects] like nosebleeds, gastrointestinal distress, or worsening neuropathy. These are some of the most common [effects] that we see with the T-DM1 regimens, so we prefer to get on top of these effects and manage them right away. [Then] patients can either make the decision to discontinue and go back to pertuzumab/trastuzumab if they need to or can feel empowered that we have ways to manage the AEs and get through as much of that year of T-DM1 as possible.

Could you elaborate on some of the strategies used to manage those toxicities?

With neuropathy, one of the main strategies that we have is gabapentin, which can be helpful. Additionally, there's solid clinical trial data that support that icing the fingers and toes during chemotherapy treatment helps prevent neuropathy from getting worse; that can also be empowering: to know that there's something they can do, or can try, to help with that. In terms of the nosebleeds, which can happen with T-DM1, it's important to keep the nostrils moist. Vaseline or nasal sprays [can be used] sparingly if the nosebleeds are particularly bothersome. If a patient is having recurrent nosebleeds, we will refer them to an ear, nose, and throat [specialist].

In terms of liver function abnormalities, we do encourage patients to not drink heavily while they're on treatment and to abstain from Tylenol or other medications that might interfere with liver function tests.

Also, [we see] fatigue, [which] is multifactorial. We certainly see that [when patients are] on breast cancer therapies of all kinds.

Turning to FeDeriCa, now that the subcutaneous administration is approved, do you believe that patients will be more likely to pursue that option if they experience a milder toxicity?

They might, because options are everything. Some patients may be sticklers for the data, who may say they want to wait a little longer and see more before they make the switch. For other patients, the pharmacokinetics, and the fact that it's FDA approved, may be enough for them. They may want to make the switch if they feel like it's palatable.

Insurance coverage may be another issue. I'm not sure that every insurance company is going to cover it to the same degree as they cover intravenous administration. Finances may play a role, but I do believe this is going to be something that has legs, for sure.

von Minckwitz G, Huang CS, Mano MS, et al. Trastuzumab emtansine for residual invasive HER2-positive breast cancer. 

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

Miesel on Managing Toxicities With T-DM1 in HER2+ Breast Cancer

Data from the pivotal phase 3 KATHERINE has led to the addition of ado-trastuzumab emtansine to the HER2-positive breast cancer treatment arsenal, but the toxicities associated with the approach must be appropriately managed so that patients can continue to receive it.

T-DM1 Toxicity Management in Breast Cancer

A biologics license application has been submitted to the FDA for the approval of F-627 (Ryzneuta; formerly efbemalenograstim alpha) as a treatment option for patients with breast cancer who have chemotherapy-induced neutropenia, according to an announcement from Evive Biotech.1

The submission follows the completion of two phase 3 clinical trials examining the agent (NCT03252431 and NCT02872103) which both met their primary and secondary end points and showed strong and durable activity in this population.

“This is a significant milestone for Evive and demonstrates our full in-house capability to develop a novel biological drug from laboratory bench to global market launch,” Dr. Jubo Liu, chief executive officer of Evive Biotech, stated in a press release. “With this submission, we are looking forward to working with our partners to make [F-627] accessible to patients suffering from chemotherapy-induced neutropenia.”

F-627 is a recombinant fusion protein that contains granulocyte colony–stimulating factor at the amino terminal and human IgG2-Fc fragment at the carboxyl terminal. The protein is expressed in Chinese Hamster Ovary cells and it exists as a dimer with 2 molecules of rhG-CSF that are covalently linked with disulfide bonds made between the Fc fragment of the molecule.

F-627 triggers white blood cell production, which assists the immune system in fighting infection. Many patients who receive chemotherapy experience a drop in their white blood cell count; the protein was developed to boost those counts and enhance immune system response.

In the first multicenter, single-dose, open-label, phase 3 trial, investigators examined the safety and efficacy of the agent in patients with breast cancer who were receiving treatment with chemotherapy.2,3 To be eligible for enrollment, patients needed to have stage I-III invasive breast cancer who were to receive either neoadjuvant or adjuvant myelotoxic TC chemotherapy comprised of 75 mg/m2 of docetaxel and 600 mg/m2 of cyclophosphamide.

Twenty-four hours after chemotherapy completion in each cycle, patients in arm A were given F-627 at a fixed dose of 20 mg on day 2 of each 4 chemotherapy cycles, while those in arm B received pegfilgrastim (Neulasta) at a fixed dose of 6 mg on day 2 of each 4 chemotherapy cycles. Participants were randomized in a 1:1 fashion.

In the other phase 3 trial, investigators set out to evaluate the safety and efficacy of once-per-cycle F-627 in patients with stage II-IV breast cancer who were receiving myelotoxic TA chemotherapy comprised of docetaxel at 75 mg/m2 and doxorubicin at 60 mg/m2.4

To be eligible for enrollment, patients had to aged 18 years or older but under the age of 75 years, have stage II-IV disease, be scheduled to receive 4 cycles of TA chemotherapy, have an ECOG performance status of 0 to 2 and a white blood cell count of at least 4.0 x 109/L, hemoglobin of at least 11.5 g/dL, and a platelet count of at least 150 x 109/L.

Here, F-627 or placebo were administered subcutaneously 24 hours following chemotherapy in each 21-day cycle of chemotherapy treatment. The primary outcome measure for this trial was duration in days of grade 4 neutropenia observed in chemotherapy cycle 1 with F-627 vs placebo, while secondary measures included duration of grade 4 neutropenia for chemotherapy cycles 2, 3, and 4, and over all cycles; duration in days of grade 2, grade 3, and 4 neutropenia over all cycles; and others.

Previously, the agent was found to significantly reduce the duration of grade 4 neutropenia in chemotherapy cycle 1 (

 <.0001) among 122 patients with stage II-IV breast cancer who were receiving myelotoxic chemotherapy, according to data presented at the 2018 San Antonio Breast Cancer Symposium.5 The mean treatment difference was 2.8 days, with 1.1 days in the investigative arm and 3.9 days in the control arm. F-627 also resulted in a lower incidence and shorter duration of grade 2, 3, and 4 neutropenia.

F-627 also significantly reduced incidence of febrile neutropenia compared with the control in cycle 1, at 4.8% and 28.2%, respectively (

 <.0016). Additionally, F-627 resulted in lower rates of antibiotic and pain medication use.

The agent was found to be safe and well tolerated. No deaths or injection site reactions were reported with F-627. Moreover, less gastrointestinal adverse effects were reported in the investigative arm vs the placebo arm. During cycle 1, the most frequently reported treatment-emergent toxicities were leukopenia, anemia, thrombocytopenia, nausea, and alopecia.

Evive Biotech submits biologics license application to US FDA for Ryzneuta. News release. Evive Biotech. March 31, 2021. Accessed March 31, 2021. 

Evive Biotech meets primary and secondary endpoints in global phase III clinical trial for their novel chemotherapy-induced neutropenia treatment. News release. Evive Biotech. July 7, 2020. Accessed July 9, 2020. 

Neulasta-controlled trial of F-627 in women with breast cancer receiving myelotoxic chemotherapy. ClinicalTrials.gov. Updated February 5, 2020. Accessed March 31, 2021. 

https://clinicaltrials.gov/ct2/show/NCT03252431

Placebo-controlled trial of F-627 in women with breast cancer receiving myelotoxic chemotherapy. Updated March 26, 2019. Accessed March 31, 2021. 

https://clinicaltrials.gov/ct2/show/NCT02872103

Generon presented positive phase III results from a double-blind, placebo controlled-clinical trial of F-627 in women with breast cancer receiving myelotoxic chemotherapy. News release. Generon BioMed Holding Ltd. December 8, 2018. Accessed March 31, 2021. 

FDA Approval Sought for F-627 for Chemotherapy-Induced Neutropenia in Breast Cancer.

A biologics license application has been submitted to the FDA for the approval of F-627 as a treatment option for patients with breast cancer who have chemotherapy-induced neutropenia.

BLA Submitted for F-627 to Treat Chemo-Induced Neutropenia in Breast Cancer

The FDA has issued a complete response letter (CRL) to Merck stating that regulatory decision for the supplemental biologics license application (BLA) seeking approval for pembrolizumab (Keytruda) for use in patients with high-risk, early-stage triple-negative breast cancer (TNBC) plus chemotherapy as neoadjuvant treatment, then continuing as a single agent as adjuvant treatment following surgery, should be deferred.

The BLA is based on data from the phase 3 KEYNOTE-522 trial (NCT03036488), which showed that the pathologic complete response (pCR) rate was 64.8% (95% CI, 59.9%-69.5%) with pembrolizumab/chemotherapy vs 51.2% (95% CI, 44.1%-58.3%) with placebo/chemotherapy; this translated to an estimated treatment difference of 13.6 percentage points (95% CI, 5.4-21.8; 

Ahead of the Prescription Drug User Fee Act action date for the application, the regulatory agency’s Oncologic Drugs Advisory Committee voted 10 to 0 that a decision be deferred until further findings from KEYNOTE-522 trial become available. The next interim analysis from the trial is expected to occur in the third quarter of 2021.

Notably, the CRL does not impact any currently approved indications for the PD-1 inhibitor, such as its indication for use with chemotherapy in patients with locally recurrent unresectable or metastatic TNBC whose tumors have PD-L1 positivity.

In KEYNOTE-522, investigators set out to examine the safety and efficacy of neoadjuvant pembrolizumab plus chemotherapy vs neoadjuvant placebo plus chemotherapy followed by adjuvant pembrolizumab or placebo in patients with TNBC.

To be eligible for enrollment, patients needed to be at least 18 years of age and have centrally confirmed TNBC; have newly diagnosed, previously untreated, nonmetastatic disease; an ECOG performance status of 0 or 1; and acceptable organ function. Notably, patients who had bilateral multifocal primary tumors and inflammatory breast cancers were permitted for inclusion.

If patients had autoimmune disease for which they received systemic treatment within the prior 2 years, a diagnosis of immunodeficiency or use of immunosuppressive therapy within the prior week, or a history of human immunodeficiency virus infection, they were excluded. Additional exclusion criteria included having a history of noninfectious pneumonitis for which the patient received glucocorticoids, current pneumonitis, active tuberculosis, active hepatitis B or C virus, or any active infection for which they are receiving systemic treatment, or clinically significant cardiovascular disease.

In the trial, a total of 1174 participants were randomized 2:1 to receive either pembrolizumab (n = 784) or placebo (n = 390). In the neoadjuvant phase of the trial, patients were given 4 cycles of an intravenous infusion of pembrolizumab at 200 mg or placebo once every 3 weeks plus paclitaxel at 80 mg/m2 and carboplatin at area under the curve of 5 mg/mL/min once every 3 weeks or 1.5 mg/mL/min once weekly within the first 12 weeks. This was followed by 4 cycles of pembrolizumab or placebo plus doxorubicin at 60 mg/m2 or epirubicin at 90 mg/m2 plus cyclophosphamide at 600 mg/m2 once every 3 weeks in the subsequent 12 weeks.

The co-primary end points of the trial were pCR and event-free survival (EFS) in the intent-to-treat population, while key secondary end points comprised pCR in all patients, pCR per all definitions in all patients with PD-L1–positive tumors, and EFS among those with PD-L1 positivity.

The median age of patients was 48.5 years, 56.3% of patients were postmenopausal, 82.5% had PD-L1–positive tumors, and 87.0% had an ECOG performance status of 0. About 80% of patients across the arms had a lactase dehydrogenase level less than the upper limit of normal, 57.3% received carboplatin on a weekly basis, and the majority of patients had a primary tumor classification of T1 to T2. Moreover, 51.5% had nodal involvement, 75.0% had stage II disease, and 74.6% had a HER2 status score of 0 to 1.

Additional results from the interim analysis of the trial indicated that the pCR benefit observed with pembrolizumab plus chemotherapy were generally consistent across subgroups analyzed, including those with PD-L1 expression. The percentage of PD-L1–positive patients with a pCR was 68.9% (n = 230/334) among those on the investigative arm vs 54.9% (n = 90/164) of those on the control arm; among those with PD-L1–negative tumors, these rates were 45.3% and 30.3%, respectively.

Moreover, Kaplan–Meier estimates of the percentage of patients at 18 months who were alive without disease progression that precluded definitive surgery, without local or distant recurrence, and without a second primary tumor was 91.3% (95% CI, 88.8%-93.3%) in the investigative arm vs 85.3% (95% CI, 80.3%-89.1%) in the control arm; the median had not yet been reached in either treatment arm. The hazard ratio for disease progression, local or distant recurrence or a second primary tumor, or death from any cause favored the pembrolizumab/chemotherapy arm (HR, 0.63; 95% CI, 0.43-0.93).

Regarding safety, in the neoadjuvant phase of the trial, any-grade adverse effects (AEs) determined to be associated with trial treatment by investigators were reported in 99.0% and 99.7% of those in the investigative and control arms, respectively. Treatment-related AEs (TRAEs) that were grade 3 or higher in severity were experienced by 76.8% of those who received pembrolizumab/chemotherapy vs 72.2% of those given placebo/chemotherapy.

Serious TRAEs were experienced by 32.5% and 19.5% of patients in the investigative and control arms, respectively. The most frequently reported serious TRAEs comprised febrile neutropenia (14.6% vs 12.1%, respectively), anemia (2.6% vs 2.1%), and pyrexia (2.6% vs 0.3%).

Toxicities of interest were reported in 38.9% and 18.3% in the pembrolizumab/chemotherapy and placebo/chemotherapy arms, respectively; these effects were grade 3 or higher in 12.9% and 1.8%, respectively. Specifically, 3.8% of patients in the investigative arm experienced severe skin reactions, 2.6% had infusion reactions, and 1.3% had adrenal insufficiency.

Moreover, 23.3% of those in the investigative arm experienced TRAEs that led to discontinuation vs 12.3% of those in the control arm. The majority of TRAEs were and AEs of interest were experienced in the neoadjuvant phase of the trial.

In the adjuvant phase, TRAEs were experienced in 48.1% and 43.0% of those in the investigative and control arms, respectively.



Merck receives complete response letter from US FDA for supplemental biologics license application (sBLA) for KEYTRUDA (pembrolizumab) in high-risk early-stage triple-negative breast cancer (TNBC). News release. Merck. March 29, 2021. Accessed March 29, 2021. 

Schmid P, Cortes J, Pusztai L, et al. Pembrolizumab for early triple-negative breast cancer. 

. 2020;382(9):810-821. doi:10.1056/NEJMoa1910549

FDA Issues Complete Response Letter for Neoadjuvant Pembrolizumab for High-Risk TNBC

Ahead of the Prescription Drug User Fee Act action date for the application, the regulatory agency’s Oncologic Drugs Advisory Committee voted 10 to 0 that a decision be deferred until further findings from KEYNOTE-522 trial become available.

FDA Defers Decision on Pembrolizumab for TNBC: Here's Why

Palbociclib (Ibrance) in combination with endocrine therapy resulted in improved survival outcomes in a real-world population of patients with hormone receptor (HR)–positive, HER2-negative, metastatic breast cancer vs letrozole alone in the first-line setting, according to data from a retrospective observational analysis published in 

At a median follow-up of 24.2 months, and after balancing for baseline demographic and clinical characteristics, the median real-world progression-free survival (rwPFS) was significantly longer with the palbociclib combination compared with letrozole alone, at 20.0 months vs 11.9 months, respectively (HR, 0.58; 95% CI, 0.49-0.69; 

Additionally, the median overall survival (OS) had not been reached in the palbociclib arm vs 43.1 months in the letrozole-alone arm (HR, 0.66; 95% CI, 0.53-0.82; 

 =.0002). The 2-year OS rates were 78.3% and 68.0% in the investigative and control arms, respectively.

“Real-world evidence is woven into the fabric of how we innovate and advance care for patients with breast cancer, supporting our randomized clinical trials,” Chris Boshoff, MD, PhD, chief development officer of Oncology at Pfizer Global Product Development, stated in a press release.2 “With more than 6 years of patient experience, a positive benefit-risk profile, strong clinical data and robust real-world data, the totality of evidence solidifies the role of [palbociclib] plus endocrine therapy as a treatment for patients with HR-positive, HER2-negative metastatic breast cancer.”

The goal of the retrospective observational analysis was to provide real-world evidence on the efficacy of the combination of palbociclib and letrozole compared with letrozole alone in a large cohort of patients from across the United States in routine clinical practice.

The analysis was conducted through the use of electronic health records within the Flatiron Health Analytic Database. Investigators identified a total of 1430 women with HR-positive, HER2-negative metastatic breast cancer who started either palbociclib/letrozole (n = 772) or letrozole alone (n = 658) as their frontline treatment between February 3, 2015, and February 28, 2019. The majority, or 94.0%, of patients were from the community setting, while 6.0% were from the academic setting.

Notably, the demographic and clinical characteristics between the 2 arms evaluated differed. Patients on the palbociclib arm were younger, had a better performance status, a higher incidence of visceral disease, and more metastatic sites, than those on the letrozole-only arm. After stabilized inverse probability treatment weighting (sIPTW) adjustment, patient characteristics were well balanced.

After sIPTW adjustment, the mean age of patients was 66.8 years vs 67.1 years in the investigative and control arms, respectively. Additionally, about 68.0% of patients in both arms were White. The median duration of follow-up in the palbociclib and letrozole-alone arms was 24.2 months and 23.3 months, respectively.

Results from a sensitivity analysis using the propensity score matching (PSM) method (n = 928) showed that the median rwPFS was also significantly extended with the palbociclib regimen over letrozole alone, at 20.2 months (95% CI, 18.2-23.7) vs 11.9 months (95% CI, 10.4-14.5), respectively (HR, 0.54; 95% CI, 0.46-0.65; 

 <.0001). Palbociclib/letrozole showcased a consistent PFS benefit compared with letrozole alone, across all subgroups analyzed.

Additional OS data showed that more patients on the letrozole-alone arm died (n = 266; 40.4%) than those in the palbociclib arm (n = 210; 27.2%). Using PSM as a sensitivity analysis, the median OS in the letrozole-alone arm was 43.1 months (95% CI, 34.2–not estimable) and had not been reached in the palbociclib/letrozole arm (HR, 0.58; 95% CI, 0.46-0.73; 

 <.0001). Again, additional analyses of OS revealed that the benefit achieved with the palbociclib combination over letrozole alone was generally observed across all subgroups examined.

Approximately 56% of patients in the investigative arm and about 67% of those in the control arm had available data pertaining to second-line treatment. Of those with available information, 42.2% in the palbociclib arm and 62.9% in the letrozole-alone arm went on to receive a CDK4/6 inhibitor as second-line treatment; 25.6% and 9.4%, respectively, went on to receive chemotherapy in the second line.

Data from the analysis proved to be consistent with data from the phase 3 PALOMA-2 trial (NCT01740427), which evaluated palbociclib in combination with letrozole vs placebo/letrozole as initial endocrine-based therapy in post-menopausal women with estrogen receptor–positive, HER2-negatgive metastatic breast cancer.

“Although findings from the PALOMA trials demonstrate the efficacy of palbociclib among patients who met study inclusion and exclusion criteria, real-world evidence of effectiveness provides further support for clinical decision-making in patients encountered in routine clinical practice,” the study authors concluded. “In this comparative effectiveness analysis, first-line palbociclib plus letrozole was associated with longer rwPFS and OS than letrozole alone in a heterogeneous population and among various patient subgroups.”

DeMichele A, Cristofanilli M, Brufsky A, et al. Comparative effectiveness of first-line palbociclib plus letrozole versus letrozole alone for HR+/HER2– metastatic breast cancer in US real-world clinical practice. 

. 2021;23(1):37. doi:10.1186/s13058-021-01409-8

Real-world evidence supports effectiveness of first-line IBRANCE (palbociclib) combination therapy in HR+, HER2- metastatic breast cancer. News release. Pfizer Inc. March 25, 2021. Accessed March 25, 2021. 

First-Line Palbociclib/Letrozole Shows Real-World Survival Benefit in HR+ Metastatic Breast Cancer

Palbociclib in combination with endocrine therapy resulted in improved survival outcomes in a real-world population of patients with hormone receptor–positive, HER2-negative, metastatic breast cancer vs letrozole alone in the first-line setting.

Palbociclib/Letrozole Improves Survival in HR+ Metastatic Breast Cancer

Intravenous (IV) cetirizine (Quzyttir) showed comparable efficacy to IV diphenhydramine for the prevention of infusion reactions (IRs) in patients with cancer who are undergoing treatment with an anti-CD20 antibody or paclitaxel, according to results from a prospective, phase 2 trial (NCT04189588) that were presented during the 

Findings showed that the IR rate in patients who received IV cetirizine was 11.8% (n = 2/17) compared with 17.6% (n = 3/17) in those who received IV diphenhydramine. One of 3 patients with breast cancer experienced an IR.

“This was the first prospective, randomized, controlled trial evaluating IV antihistamine pretreatment for the prevention of IRs,” Jarrod P. Holmes, MD, FACP, medical oncology at St. Joseph Health Medical Group, and coinvestigators noted in the poster presented at the meeting. “IV cetirizine was associated with less sedation, less time in the treatment center, and fewer treatment-related [adverse effects (AEs)] than IV diphenhydramine.”

Pretreatment with antihistamine for drug-induced hypersensitivity is recommended to be used with other chemotherapies, including paclitaxel, for patients with breast cancer. IV cetirizine is a second-generation IV antihistamine and has been shown to treat patients with acute urticaria with outcomes comparable to that of IV diphenhydramine but with fewer toxicities. The study authors suggested that IV cetirizine may also show promise as a pretreatment of IRs.

In the prospective, double-blind, randomized, controlled, phase 2 trial, investigators sought to compare the incidence of IRs to treatment with an anti-CD20 antibody, such as rituximab (Rituxan), or paclitaxel, following pretreatment with IV cetirizine (n = 17) or IV diphenhydramine (n = 17) during infusion.

IRs were defined as flushing, itching, alterations in heart rate and blood pressure, dyspnea, chest discomfort, acute back or abdominal pain, fever, shaking, chills, nausea, vomiting, diarrhea, skin rashes, throat tightening, hypoxia, seizures, syncope, or dizziness.

Pretreatment was given with a single IV dose of 10-mg cetirizine or IV diphenhydramine at 50 mg in 34 patients who were being treated with paclitaxel, rituximab or a rituximab biosimilar, or obinutuzumab (Gazyva) at the first cycle or retreatment after 6 months or in patients with persistent IRs while on maintenance or retreatment.

To be eligible for enrollment, patients had to be 18 years or older, could be male or female, and required treatment premedication with an antihistamine for hypersensitivity IRs linked with rituximab or paclitaxel. Those who had a high risk of developing tumor lysis syndrome, may have contraindications with an antihistamine, had received any antihistamine within 24 hours prior to receiving the study drug regardless of the administration route, and who had received an H2 antagonist in the prior 4 hours before receiving study drug, were excluded.

The primary end point of the trial was the incidence of IRs following pretreatment; the key secondary end point was sedation score due to IV antihistamines. Sedation was assessed by health care providers as well as patients on a scale of 0 to 4 (0 = none; 4 = extremely severe/asleep). Time to readiness for discharge served as another efficacy end point, the investigators noted in the poster.

The patient population comprised those with both hematologic and solid tumors, including breast cancer, and were enrolled between March 25, 2020 and November 23, 2020. An addition of patients receiving paclitaxel was added to the protocol in amendment 2 on August 10, 2020. Twenty-five patients had received an anti-CD20 agent and 9 had been given paclitaxel; those who had received the anti-CD20 drug had hematologic malignancies or immune disorders, while those who had paclitaxel had solid tumors, 3 of whom had breast cancer.

The median age of the participants was 66.0 years (range, 36-87), 35.3% were female, and most were White (76.5%) and not Hispanic or Latino (82.4%).

Additional data showed that the mean sedation scores in the IV cetirizine arm was 0.5 (0.72), 0.6 (0.61), and 0.1 (0.33) vs 1.3 (1.26), 0.9 (1.14), and 0.4 (0.71) in the IV diphenhydramine arm at 1 hour, 2 hours, and at discharge, respectively, as rated by the patients enrolled on the trial. Moreover, these data were similar with the health care provider­–rated sedation scores.

The median time for readiness for discharge was 24 minutes less with IV cetirizine compared with IV diphenhydramine, at 4 hours and 18 minutes and 4 hours and 42 minutes, respectively.

Regarding safety, fewer patients experienced treatment-related AEs with IV cetirizine (n = 2) vs IV diphenhydramine (n = 4). Treatment-emergent AEs (TEAEs) occurred in 8 and 9 patients, respectively. In the IV cetirizine arm, these TEAEs were mild in 2 patients, moderate in 4, severe in 1, and life-threatening in 1; none were fatal. In the IV diphenhydramine arm, 3 cases were mild, 5 were moderate, and 1 was fatal; no severe or life-threatening TEAEs were reported.

Overall, 2 and 4 TEAEs were possibly related to study treatment; there were 0 AEs that led to discontinuation of study treatment in either arm.

The TRAEs in the IV cetirizine arm included insomnia, dyspepsia, and malaise; in the IV diphenhydramine arm, these effects were diarrhea, injection site pain, headache, somnolence, dizziness, and lightheadedness.

In the poster, investigators noted that study limitations include the small sample size without formal statistics.

“However, the results of key secondary end points of sedation score, time to discharge, and safety profile are consistent with the results from the studies with IV cetirizine in acute urticaria,” the authors stated.

Holmes JP, Dasanu CA, Peguero J, et al. Aphase 2 exploratory study of intravenous cetirizine versus intravenous diphenhydramine in the prevention of hypersensitivity infusion reactions in patients with breast cancer and other malignancies. Presented at: 

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

Intravenous Cetirizine Prevents Infusion Reactions From Paclitaxel in Breast Cancer, Other Tumors.

Intravenous cetirizine showed comparable efficacy to IV diphenhydramine for the prevention of infusion reactions in patients with cancer who are undergoing treatment with an anti-CD20 antibody or paclitaxel.

Preventing Paclitaxel-Related Infusion Reactions

Anthracyclines and taxanes remain a backbone in the early-stage setting of triple-negative breast cancer (TNBC) as further evaluations of immunotherapy in the neoadjuvant and adjuvant settings needs to be conducted—efforts that will continue to shape the treatment paradigm, explained William J. Gradishar, MD, in a presentation during the NCCN 2021 Virtual Annual Conference.

“In early-stage disease, anthracycline/taxane therapy—the sequence not so critical—remains foundational,” Gradishar said. “The addition of […] checkpoint inhibitors can increase the [pathologic complete response] rate, but the data in the adjuvant setting are still awaited. We need event-free survival to determine the overall impact.”

Moreover, for patients with residual disease following neoadjuvant therapy, capecitabine is an appropriate treatment, said Gradishar, professor of medicine of the Robert H. Lurie Comprehensive Cancer Center of Northwestern University.

However, in the metastatic setting, immunotherapy has improved progression-free and overall survival (OS) in a subset of patients with TNBC, and the antibody-drug conjugates (ADCs) have provided another option for those who have progressed on prior treatment.

All these advances with evidence-backed data led to updates in the latest version of the National Comprehensive Cancer Network® Guidelines Version 2.2021 in Invasive Breast Cancer.

The updated guidelines list the following as preferred preoperative/adjuvant therapy regimens—as category 2A recommendations —in HER2-negative breast cancer:

Dose-dense doxorubicin/cyclophosphamide followed by paclitaxel every 2 weeks

Dose-dense doxorubicin/cyclophosphamide followed by weekly paclitaxel

Capecitabine for patients with TNBC and residual disease after preoperative treatment with taxane-, alkylator-, and anthracycline-based chemotherapy

In the metastatic setting, the following regimens are noted as category 1 recommendations in HER2-negative metastatic breast cancer:

Atezolizumab (Tecentriq) plus nab-paclitaxel (Abraxane) as a preferred frontline therapy for patients with PD-L1 expression with 1% or greater tumor-infiltration immune cells (ICs)

Pembrolizumab (Keytruda) plus chemotherapy (either nab-paclitaxel, paclitaxel, or gemcitabine and carboplatin) as a preferred frontline therapy for PD-L1–positive patients with a combined positive score (CPS) of 10 or higher

Carboplatin and cisplatin for TNBC and germline 

Sacituzumab govitecan (Trodelvy) is also considered a recommended regimen in recurrent or stage IV HER2-negative breast cancer. A number of chemotherapy regimens also remain as preferred options in the NCCN guidelines for use in the metastatic setting.

In his presentation on the evidence behind the guideline updates, Gradishar touched upon selecting optimal localized therapy for patients with locally advanced TNBC, recognizing key patient factors to influence systemic treatment selection for metastatic disease, and optimally managing common adverse effects (AEs) linked with new agents used to manage this malignancy.

Gradishar homed in on the summary of neoadjuvant platinum-based therapy in TNBC, adding that carboplatin augments pathologic complete response (pCR) in TNBC. For example, when carboplatin was added to chemotherapy regimens for patients with TNBC in the GeparSixto, CALGB 40603, and BrighTNess studies, the pCR rates increased to 53.2%, 54%, 58% and 53% (both BrighTNess), respectively.

However, there has been controversy with using platinum agents concomitantly with chemotherapy, which was seen in GeparSixto. Also, in CALGB 40603, the addition of carboplatin resulted in markedly higher toxicity, which led to significantly fewer patients (less than 65%) receiving 11 to 12 doses of paclitaxel vs the control group (more than 85%).

A meta-analysis of 9 randomized trials evaluated the role of platinum-based therapy as neoadjuvant therapy for TNBC (n = 2109). Data showed that platinum therapy significantly improved pCR from 37.0% to 52.1% (odds ratio [OR], 1.96; 95% CI, 1.46-2.62; 

 <.001), even when restricting the analysis to 3 studies with standard chemotherapy regimens (n = 611; OR, 2.53; 95% CI, 1.37-4.66; 

However, no improvement was observed in a subset of patients with germline 

 mutations (OR, 1.17; 95% CI, 0.51-2.67; 

 = .711). There was also a significantly higher risk of grade 3/4 hematologic adverse events (AEs).

The guidelines state that, “Several studies have shown improved pCR rates with the incorporation of platinum. However, long-term outcomes remain unknown. The routine use of platinum agents as part of neoadjuvant therapy for TNBC is not recommended for most patients (including 

 mutation carriers), but it may be considered in select patients, such as those for whom achieving better local control is necessary.”

Citing the updated guidelines, Gradishar noted that the inclusion of platinum agents in the neoadjuvant setting remains controversial.

“For most patients, this would not be viewed as standard, but it could be used in individual patients,” he added.

Capecitabine has also been noted in the guidelines as an option for patients with residual disease following neoadjuvant therapy. In the CREATE-X trial, which had 887 evaluable patients with stage I to IIIB, HER2-negative breast cancer, who did not have a pCR and/or were node positive after surgery and neoadjuvant chemotherapy, patients received capecitabine at 2500 mg/m2 daily on days 1 to 14, repeated every 3 weeks for 8 cycles, plus standard therapy or standard therapy alone.

Thirty-two percent of patients had TNBC, 95% were treated with anthracyclines and taxanes, and 41% were node positive.6 Results showed that the real impact of capecitabine was seen in the TNBC subset, in regard to disease-free survival (DFS; HR, 0.58; 95% CI, 0.39-0.87) and overall survival (OS; HR, 0.52; 95% CI, 0.30-0.90).

“The use of capecitabine can be justified in such patients with residual triple-negative disease following preoperative therapy,” said Gradishar, citing the ongoing ECOG-ACRIN EA1131 (NCT02445391) and SWOG 1418 (NCT02954874) trials as efforts to evaluate adjuvant capecitabine in basal-like residual TNBC and adjuvant pembrolizumab (Keytruda) in TNBC, respectively.

Immunotherapy for PD-L1–Positive Disease

Checkpoint blockade has been evaluated in both the neoadjuvant and metastatic settings. In his presentation, Gradishar focused on the IMpassion031 trial of neoadjuvant atezolizumab with nab-paclitaxel, which showed a pCR rate of 58% compared with 41% with chemotherapy alone (

KEYNOTE-522, a phase 3 trial of pembrolizumab and carboplatin/paclitaxel vs carboplatin/paclitaxel and placebo in previously untreated patients with stage II or III TNBC, garnered attention in 2020 and 2021 this year. At an interim analysis with a median follow-up of 15.5 months, data showed that pembrolizumab improved event-free survival (EFS) over chemotherapy alone (HR, 0.63; 95% CI, 0.43-0.93).

“pCR rates that go up are great, but does it translate into an improvement in EFS, and hopefully, downstream even further [with] overall survival?” asked Gradishar. “If you ask the question: Who are the patients who are gaining the greatest benefit? For the most part, [it is] in the patients with PD-L1–positive disease.”

Data from KEYNOTE-522 were further extrapolated at an FDA Oncology Drugs Advisory Board Meeting (ODAC) on February 8, 2021. Although the pembrolizumab arm did have an improved pCR rate versus placebo with neoadjuvant chemotherapy, the ODAC committee voted 10 to 0 against an approval of pembrolizumab in this setting, adding that a regulatory decision should be deferred until further data from KEYNOTE-522 become available.

“The biggest reason is not because the pCR rate was questioned, but rather, the pCR rate over time, was actually starting to decrease,” Gradishar shared. “Most importantly, there were insufficient data at that point to say [whether this] affected EFS. This does not stick a dagger in the idea of checkpoint inhibitors preoperatively, but rather, it requires further follow-up to see whether the impact is going to have an outcome measure on the overall outcome of patients.”

The current role for immunotherapy in the metastatic setting of TNBC is based upon the IMpassion130, IMpassion131, and KEYNOTE-355 studies, Gradishar emphasized.

In the phase 3 IMpassion130 trial, atezolizumab plus nab-paclitaxel compared with nab-paclitaxel and placebo was evaluated in the first-line treatment of patients with metastatic or unresectable locally advanced TNBC (n = 902). Patients had to be treatment naïve in the metastatic setting and have an ECOG performance status of 0 or 1. The co-primary end points were progression-free survival (PFS) and OS in both the intent-to-treat (ITT) and PD-L1–positive population.

PD-L1 IC status was assessed via the SP142 assay. In the PD-L1–positive population, the median PFS was 7.5 months compared with 5.3 months for the atezolizumab and placebo arms, respectively (HR, 0.63; 95% CI, 0.50-0.80; 

 <.0001).10 A similar trend was seen in this subset for OS at 25.0 and 18.0 months, respectively (HR, 0.71; 95% CI, 0.54-0.93). No benefit was observed with atezolizumab in the PD-L1–negative groups for PFS (HR, 0.93) nor OS (HR, 0.97).

Most recently, at the ESMO 2020 Virtual Congress, findings of the final OS analysis showed that the median OS with atezolizumab was 25.4 months vs 17.9 months for placebo/nab-paclitaxel (HR, 0.67; 95% CI, 0.53-0.86) in the PD-L1–positive population.11 The 3-year OS rates were 36% and 22% in this subgroup, respectively.

Similarly, in the phase 3 KEYNOTE-355 study, patients with previously untreated locally recurrent inoperable or metastatic TNBC, with no active central nervous system metastases or active autoimmune disease, were randomized 2:1 to receive pembrolizumab/chemotherapy or placebo/chemotherapy until disease progression or cessation of study treatment. Chemotherapy regimens consisted of nab-paclitaxel, paclitaxel, and gemcitabine and carboplatin.

Data showed that, in the ITT population, PFS was favored in the pembrolizumab/chemotherapy arm vs placebo/chemotherapy at 7.5 months and 5.6 months, respectively (HR, 0.82; 95% CI, 0.69-0.97), but was higher in those with PD-L1 combined positive score (CPS) of 1 or greater (HR, 0.74; 

 value boundary of .00111 was not met.12 This benefit was even higher in patients with a PD-L1 CPS of 10 or greater (HR, 0.65; 

 = .0012). In the ITT population, statistical significance was not tested due to the prespecified hierarchical testing strategy.

“In this dataset, we don’t yet have a survival advantage that has been demonstrated or reported,” explained Gradishar. “We simply don’t have enough events yet to report OS.”

However, it was the double-blind, placebo-controlled, randomized, phase 3 IMpassion131 study that Gradishar coined as a “fly in the ointment.”

Anthracyclines and taxanes remain a backbone in the early-stage setting of triple-negative breast cancer as further evaluations of immunotherapy in the neoadjuvant and adjuvant settings needs to be conducted—efforts that will continue to shape the treatment paradigm.

Breast Cancer