Updates to the National Comprehensive Cancer Network (NCCN) guidelines now include 2 recommendations involving neratinib (Nerlynx) for the treatment of patients with HER2-positive breast cancer, according to a news release from Puma Biotechnology.

The first update recommends neratinib for the adjuvant treatment of patients with HER2-positive breast cancer under the designation of Useful in Certain Circumstances. The guideline indicates that extended adjuvant neratinib is recommended for patients with hormone receptor (HR)–positive, HER2-positive disease who have a perceived high risk of disease recurrence.

The second guideline recommends a dose-escalation strategy with neratinib to improve tolerability when the agent is utilized in the adjuvant setting for patients with HER2-positive disease.

Notably, this update is in agreement with the FDA approval of a labeling supplement in June 2021 to the United States Prescribing Information for neratinib. The labeling update includes the dose-escalated use of the agent in patients with HER2-positive breast cancer, as examined in the phase 2 CONTROL trial (NCT02400476), and the new 133-count commercial Nerlynx SKU.

“Oncologists should be aware of an important recent update to the NCCN guidelines that now include adjuvant neratinib to be used in certain circumstances, [including] high-risk HR-positive, HER2-positive, early-stage breast cancer patients,” Joyce A. O’Shaughnessy, MD, co-chair of Breast Cancer Research and chair of Breast Cancer Prevention Research at Baylor-Sammons Cancer Center and The US Oncology Network said in the news release.

“These high-risk patients need access to every available treatment option proven to decrease their risk of recurrence, and the new NCCN guidelines update supports neratinib in this context,” O’Shaughnessy added.

Single-agent neratinib is associated with the following adverse events (AEs): diarrhea, nausea, abdominal pain, fatigue, vomiting, rash, stomatitis, decreased appetite, muscle spasms, dyspepsia, increased AST/ALT, nail disorder, dry skin, abdominal distention, epistaxis, decreased weight, and urinary tract infection.

Furthermore, patients who receive neratinib in combination with capecitabine have reported diarrhea, nausea, vomiting, decreased appetite, constipation, fatigue/asthenia, weight decreased, dizziness, back pain, arthralgia, urinary tract infection, upper respiratory tract infection, abdominal distention, renal impairment, and muscle spasms.

Patients should not receive neratinib with proton pump inhibitors. Similarly, neratinib should be separated from antacids by at least 3 hours and should be separated from H2-receptor antagonists by at least 2 hours before or 10 hours after. Patients should not breastfeed while receiving this medication.

Neratinib has 2 FDA indications in breast cancer. The first is as a single agent for extended adjuvant treatment of adult patients with early-stage HER2-positive breast cancer following adjuvant trastuzumab (Herceptin)-based therapy. The second indication is in combination with capecitabine (Xeloda) for the treatment of adult patients with advanced or metastatic HER2-positive breast cancer who have received 2 or more prior anti–HER2-based regimens in the metastatic setting.

The NCCN guideline updates are supported by findings from the pivotal phase 3 ExteNET trial (NCT00878709), which randomized 2840 women with early-stage HER2-positive breast cancer who had prior trastuzumab-based therapy to 1 year of neratinib given once daily at 240 mg (n = 1420) vs 1 year of placebo (n = 1420).

In patients who completed prior trastuzumab-based therapy within 1 year prior to randomization, the results of the study demonstrated a 5.1% absolute benefit in invasive disease-free survival (iDFS) at 5 years with neratinib vs placebo, as well as a 42% reduction in the risk of disease recurrence. The 5-year iDFS rate was 90.8% (95% CI, 88.1%-93.0%) with neratinib vs 85.7% (95% CI, 82.6%-88.3%) with placebo (HR, 0.58; 95% CI, 0.41-0.82).

In the intention-to-treat population, the 2-year iDFS rate was 94.2% with neratinib vs 91.9% with placebo (HR, 0.66; 0.49-0.90; 

Notably, neratinib demonstrated iDFS improvement vs placebo across several prespecified subgroups, including nodal status, hormone receptor status, and age at randomization.

Regarding safety, neratinib was not found to induce cardiac or serious pulmonary toxicity or increase a patient’s risk for secondary malignancy.

“The NCCN guidelines are utilized by many institutions, practices, and clinicians who treat [patients with] breast cancer. These updates help to increase the awareness of neratinib within the guidelines and should further support neratinib as an appropriate option to reduce the risk of recurrence for patients battling HER2-positive breast cancer,” Alan H. Auerbach, chief executive officer and president of Puma Biotechnology, concluded in the news release.

Puma Biotechnology’s NERLYNX included in two important NCCN clinical practice guideline updates for the treatment of breast cancer. News release. Puma Biotechnology, Inc. January 12, 2022. Accessed January 14, 2022. https://bit.ly/3K9CzzA

FDA approves dose escalation label update for Puma Biotechnology’s NERLYNX (neratinib) in HER2-positive early stage and metastatic breast cancer. News release. Puma Biotechnology, Inc. July 1, 2021. Accessed January 14, 2022. 

Chan A, Moy B, Mansi J, et al. Final efficacy results of neratinib in HER2-positive hormone receptor-positive early-stage breast cancer from the phase III ExteNET trial. 

2021;21(1):80-91.e7. doi:10.1016/j.clbc.2020.09.014

Puma Biotechnology. US Food and Drug Administration Oncologic Drugs Advisory Committee. Accessed January 17, 2021. https://www.fda.gov/media/105941/download

This article was originally published on OncLive as “NCCN Guidelines Include Neratinib-Based Recommendations for HER2+ Breast Cancer”

Articles

The update is in agreement with the FDA approval of a labeling supplement in June 2021 to the United States Prescribing Information for neratinib in HER2-positive breast cancer. 

Updated NCCN Guidelines Now Include Neratinib for HER2+ Breast Cancer

The PD-L1 inhibitor durvalumab (Imfinzi) in conjunction with gemcitabine and cisplatin demonstrated superior overall survival (OS) in patients with advanced biliary tract cancer (BCT) compared with placebo, according to the results of the phase 3 TOPAZ-1 trial (NCT03875235) that will be presented during the 2022 Gastrointestinal Cancers Symposium.

The findings demonstrated a 20% reduction in the risk of death with durvalumab plus chemotherapy vs placebo plus chemotherapy in this patient population (HR, 0.80; 95% CI, 0.66-0.97; 

At a median follow-up of 13.7 months in the durvalumab/chemotherapy arm and 12.6 months in the placebo/chemotherapy arm, the median OS was 12.8 months (95% CI, 11.1-14) vs 11.5 months (95% CI, 10.1-12.5), respectively. The 18-month OS rates were 35.1% (95% CI, 29.1%-41.2%) vs 25.6% (95% CI, 19.9%-31.7%), respectively. The 24-month OS rates were 24.9% (95% CI, 17.9%-32.5%) vs 10.4% (95% CI, 4.7%-18.8%), respectively.

“TOPAZ-1 is the first phase 3 trial to show that adding immunotherapy to standard chemotherapy can increase survival in [BTC], and importantly, does so without inducing any new serious [adverse] effects [AEs],” lead study author Do-Youn Oh, MD, PhD, a professor in the Division of Medical Oncology of the Department of Internal Medicine at Seoul National University Hospital and Seoul National University College of Medicine in Seoul, South Korea, said in a news release.

BTC is a rare and heterogenous type of cancer that is associated with poor patient outcomes. Checkpoint inhibitors may have clinical utility in BTC based on immunogenic features of the disease; however, limited clinical activity has been observed with single-agent therapy in the advanced setting.

Gemcitabine plus cisplatin has been the standard chemotherapy option for patients with advanced BTC in the United States.

“The current standard of care for inoperable biliary tract cancer is combined chemotherapy. That standard has not changed in over a decade. TOPAZ-1 is the first phase 3 trial to demonstrate the benefit of immunotherapy for improved [OS], in combination with chemotherapy, creating a new standard of care. Patients have a greater reason for hope given the positive results seen with the use of immunotherapy in [BTC],” said Cathy Eng, MD, FACP, FASCO, the David H. Johnson Chair in Surgical and Medical Oncology at Vanderbilt-Ingram Cancer Center.

Moreover, the results of a phase 2 study demonstrated encouraging antitumor activity with durvalumab in combination with gemcitabine and cisplatin for patients with advanced BTC. As such, the TOPAZ-1 trial was developed to further evaluate the immunotherapy-containing regimen compared with chemotherapy alone.

The double-blind study randomized 685 patients with previously untreated, unresectable locally advanced, recurrent, or metastatic BTC 1:1 to receive 1500 mg of durvalumab every 3 weeks vs placebo plus 1000 mg/m2 of gemcitabine and 25 mg/m2 of cisplatin on days 1 and 8 every 3 weeks. Patients were treated for up 8 cycles, which was followed by 1500 mg of durvalumab every 4 weeks or placebo until disease progression or unacceptable toxicity.

Patients were stratified by disease status (initially unresectable vs recurrent) and primary tumor location (intrahepatic cholangiocarcinoma vs extrahepatic cholangiocarcinoma vs gallbladder cancer).

The primary end point of the study was OS; secondary end points included progression-free survival (PFS), objective response rate (ORR), and safety.

Overall, 341 patients were randomized to durvalumab/chemotherapy and 344 were randomized to placebo/chemotherapy. The median age was 64 years in both arms and approximately half of patients were female (50.4% vs 48.8%, respectively) with an ECOG performance status of 0 (50.7% vs 47.4%, respectively).

Notably, 55% of patients had intrahepatic cancers, 19% had extrahepatic cancers, and 25% had gallbladder cancer.

Patients were enrolled from centers in the United States, as well as 17 other countries; over half of patients (55%) were enrolled from centers in Asian countries, including South Korea, Thailand, Japan, and China.

Further results showed that the median PFS was 7.2 months (95% CI, 6.7-7.4) with durvalumab plus gemcitabine and cisplatin vs 5.7 months (95% CI, 5.6-6.7) with placebo plus gemcitabine and cisplatin (HR, 0.75; 95% CI, 0.64-0.89; 

The ORR was 26.7% with durvalumab compared with 18.7% with placebo.

Regarding safety, the most common AEs included anemia (48.2%), neutropenia (31.7%), and nausea (40.2%). Potentially serious AEs were observed in 62.7% of patients receiving the durvalumab-containing regimen compared with 64.9% of patients receiving the placebo-containing regimen. Notably, this suggests that most AEs resulted from the chemotherapeutic agents.

Additionally, grade 3 or 4 AEs were observed in 75.7% of patients who received durvalumab/gemcitabine/cisplatin (n = 338) compared with 77.8% of patients who received placebo/gemcitabine/cisplatin (n = 342). Treatment-related AEs (TRAEs) leading to discontinuation of any drug were observed in 8.9% vs 11.4% of patients, respectively. TRAEs leading to death occurred in 0.6% vs 0.3% of patients, respectively.

“We are hopeful that durvalumab plus gemcitabine and cisplatin will become a new standard of care for advanced [BTC]. Our first task at this time is boosting communication with patients and family members about the potential for this immunotherapy combination and what it may mean for their ongoing care,” concluded Oh.

Oh DY, He AR, Qin S, et al. A phase 3 randomized, double-blind, placebo-controlled study of durvalumab in combination with gemcitabine plus cisplatin (GemCis) in patients (pts) with advanced biliary tract cancer (BTC): TOPAZ-1. 

Durvalumab significantly improves survival for patients with biliary tract cancer compared to chemotherapy alone. News release. ASCO. January 18, 2022. Accessed January 18, 2022. https://bit.ly/33OeU6X

Checkpoint inhibitors may have clinical utility in BTC based on immunogenic features of the disease; however, limited clinical activity has been observed with single-agent therapy in the advanced setting.

Patients With Biliary Tract Cancers Benefit From Durvalumab Plus Chemotherapy

Despite years of negative clinical trials and minimal advancement, frontline immunotherapy regimens are beginning to show significant promise in revamping the treatment landscape of gastrointestinal (GI) malignancies, including upper GI cancer and hepatocellular carcinoma (HCC), explained Syma Iqbal, MD.

According to Iqbal, the next research steps involve determining optimal sequencing with these drugs.

“The biggest [advance] in GI oncology has been the addition of immunotherapy,” said Iqbal in an interview during an 

® Institutional Perspectives in Cancer (IPC) webinar on GI malignancies. “We have had VEGF inhibitor therapy in some format across tumors in GI oncology, including gastric and colon cancers, as well as HCC with the TKIs. Now, by incorporating immunotherapy we have made advances across these disease types in GI oncology.”

In the interview, Iqbal, co-chair of the IPC event, shared the main highlights from the meeting, which centered on the evolving landscapes and importance of implementing best practices for patients with hepatobiliary cancers, locally advanced and advanced pancreatic cancer, advanced gastric/gastroesophageal junction (GEJ) cancer, and metastatic colorectal cancer (mCRC). Iqbal is an assistant professor of medicine, assistant program director of the Oncology Fellowship Program, educational officer, co-director of the Liver Cancer Program in the Division of Oncology at the Keck School of Medicine at the University of Southern California.

®: During the IPC meeting, your presentation discussed the emergence of checkpoint inhibitors and targeted therapy in gastric/GEJ cancer. What have been some of the most significant changes to this paradigm?

: This has been a big year for upper GI tumors. We’ve had several positive studies after a very long time of multiple negative trials. We’ve been able to incorporate checkpoint inhibitors into the frontline setting in HER2-negative and HER2-positive disease. That has been the biggest change we have had this year.

Also, in the adjuvant setting, checkpoint inhibitors have been approved for patients with GEJ and esophageal adenocarcinoma, having shown a doubling in disease-free survival. That was a huge step forward for upper GI tumors.

Although it has been a good year, [the advances] have thrown a wrench into ongoing studies and studies that were designed. Oncologists who are working on those studies need to take a step back to figure out how we are going to deal with this new standard to still investigate new [strategies] for the future.

Do you foresee any of the protocols of the ongoing trials being amended to incorporate the new standards?

Many of the protocols are being amended to incorporate immunotherapy, at least into the standard-of-care arms. The trials that don’t include immunotherapy as standard of care are going to suffer. We are already seeing that because patients are coming in and asking for immunotherapy. Patients are aware of it; they see commercials on television. Now that there are data to support it, it is a hard discussion with patients to offer them something that doesn’t include [immunotherapy].

As it stands, the immunotherapy approvals are for all-comers, whereas the guidelines recommend the therapies for more specific indications. Do you anticipate modifications will be made to the guidelines to broaden the recommendations?

More is likely to come on that as these approvals get reviewed, but that is correct. The National Comprehensive Cancer Network guidelines came out prior to the FDA approvals. When the guidelines for [nivolumab (Opdivo)] in HER2-negative patients were proposed, they were based on CheckMate649 [NCT02872116], where the primary end point was a combined positive score [CPS] of 5 or greater. The guidelines reflected that and are recommended for patients who have a CPS of 5 or greater. The FDA gave a broad approval [to nivolumab plus chemotherapy] for all-comers as it appeared that all-comers benefitted. However, if we look at the subgroups, the benefit in the CPS less than 5 population is quite small, if at all.

This will continue to evolve because there may be some modifications around the approval. For now, [immunotherapy] is something that can be offered to all patients. At most academic centers in the upper GI oncology world, it seems that patients with a CPS less than 5 are receiving other therapeutics or non-immunotherapy combinations.

We also saw the FDA approval of fam-trastuzumab deruxtecan-nxki (Enhertu) in the second-line setting for patients with HER2-positive gastric/GEJ cancer paradigm. What is next for that agent?

We would like to hear more about trastuzumab deruxtecan in the second-line setting. Although [the approval was based on] phase 2 data, we also have data in refractory disease. We haven’t seen a positive trial for HER2 suppression after frontline HER2-directed therapy plus chemotherapy. That was also a promising step forward for second-line therapy for patients with HER2-positive disease that offers continued benefit.

During the IPC meeting, Heinz-Josef Lenz, MD, FACP, of the USC Norris Comprehensive Cancer Center, discussed the evolving treatment landscape of mCRC. How is the field navigating salvage-line treatment selection and sequencing?

The first thing that he emphasized was profiling these tumors to know exactly how best to treat specific populations. We’ve learned a lot more about the BRAF-mutant population with the use of encorafenib [Braftovi]. The combination [of encorafenib/binimetinib (Mektovi)/cetuximab (Erbitux)] showed more toxicity but not necessarily an improvement in outcome.

The other relevant information from his talk was regarding sequencing of the many therapeutics that we have. There has been hesitancy to use drugs like regorafenib [Stivarga] and TAS-102 [trifluridine/tipiracil; Lonsurf] based on the randomized data that we have because oncologists feel there isn’t much benefit to using these drugs. However, the regorafenib data that were presented [were encouraging], particularly with the ReDOS trial [NCT02368886] that showed that starting patients on a low dose of regorafenib [allows them to] tolerate the therapeutic better. This is likely because patients were able to stay on therapy.

We don’t pay enough attention to sequencing in CRC, and that is particularly so when going to the refractory setting to choose regorafenib or TAS-102. Dr Lenz’s presentation gave strong support for the use of appropriately dosed regorafenib up front in patients with good performance status and adequate albumin. Those patients tend to do better when started with regorafenib in the refractory setting vs starting with TAS-102.

Steven Grossman, MD, PhD, of USC Norris Comprehensive Cancer Center, discussed ensuring best approaches are utilized for patients with locally advanced pancreatic cancer in his presentation. What has been learned as a community about treatment selection between FOLFIRINOX or gemcitabine/nab-paclitaxel (Abraxane) in that setting?

For locally advanced and borderline resectable disease, we as a community have used modified FOLFIRINOX [mFOLFIRINOX], assuming it was better than gemcitabine/nab-paclitaxel. We learned from the SWOG-S1505 trial [NCT02562716] that in the perioperative setting, there was no difference in outcome whether patients got mFOLFIRINOX or gemcitabine/nab-paclitaxel up front.

Something about locally advanced disease is that we still must incorporate assessment of the whole patient when choosing a regimen. Otherwise, it seems that radiation remains controversial, and these patients are treated similarly to patients in the advanced-stage setting. We don’t have an optimal pathway for all-comers. These are unique, tailored approaches to individual patients in the locally advanced setting.

Are you more inclined to select mFOLFIRINOX or gemcitabine/nab-paclitaxel for fit patients with locally advanced disease?

To be honest, most people are still more inclined to use mFOLFIRINOX. We are swayed by the metastatic data, even though the local randomized data look similar. As we are evaluating patients, we are still looking at other factors like performance status, comorbidities, and [patient preference] knowing that it is not necessarily going to impact outcome if we use gemcitabine/nab-paclitaxel in that patient population. We always feared that it was inferior based on the metastatic data, but they’re 2 separate trials.

With that in mind, Diana Hanna, MD, of the Hoag Family Cancer Institute, gave a presentation on novel combination strategies for patients with advanced pancreatic cancer. What is the significance of profiling pancreatic cancer tumors to inform treatment selection with PARP inhibition?

For a long time now, we have become comfortable with the use of FOLFIRINOX or mFOLFIRINOX and gemcitabine/nab-paclitaxel as standard regimens in this disease. The steps forward are related to profiling these tumors, specifically [to identify] 

 mutations. This is the first time now in pancreas cancer where profiling has impacted outcome. The use of PARP inhibition with olaparib [Lynparza] as maintenance therapy in the 

-[mutated] population is relevant to care, so profiling should occur prior to starting patients on therapy. The protein profiling is also assessing for the very small number of patients who have microsatellite instability–high disease so we can try to incorporate immunotherapy.

It’s very disappointing that the study with the CPI compound that targeted the Krebs cycle was negative. People thought that was going to be positive, as we always do in the early phase when the data look so promising. That was disappointing, but it will be interesting to see the formal presentations to see if there was any subgroup that benefitted from that agent.

Finally, your co-chair Anthony El-Khoueiry, MD, of USC Norris Comprehensive Cancer Center, discussed shifting treatment strategies for patients with hepatobiliary cancers. How has this field evolved from an area of significant need to one with a crowded armamentarium? What challenges with regard to sequencing have arisen amid recent FDA approvals?

We’ve seen huge changes in hepatobiliary cancer. We have several positive trials now in the frontline setting combining immunotherapy with VEGF inhibitors, both using agents such as bevacizumab [Avastin] and TKIs. That has been a big change in how we approach clinical care in HCC. We now have options in the frontline setting for these patients, including the combination of atezolizumab [Tecentriq] plus bevacizumab and immunotherapy plus CTLA-4 inhibitors.

What this has done in HCC is confuse us because it has created an issue where we don’t know how to sequence these patients or pick the best first-line regimen. Why do we need another frontline regimen when we have atezolizumab/bevacizumab, which looks good? [It’s because] many of these patients may not be candidates for bevacizumab because of varices, history of recent bleeds, or platelet counts. Having an alternative frontline option opens the door for therapeutics to a population that wouldn’t have been candidates for [atezolizumab/bevacizumab].

The challenge now in HCC is [determining] how to sequence the TKIs and what to use in the second-, third-, and fourth-line settings. Many of these patients with Child-Pugh A cirrhosis can go through multiple lines of therapy. Anytime we have options, it confuses us more, but it is a great place for us to be. HCC has had huge changes and there is more to come here.

Given the heterogeneity of the patients who present with comorbidities related to varices, bleeding, or portal hypertension, having an alternative to a risky drug like bevacizumab [is important]. Now we just have to determine what do we do with everything else.

In cholangiocarcinoma, we have also seen significant changes. What is most relevant here is the importance of profiling these tumors. We know that 

 mutations are relevant to the treatment of this disease. This wasn’t a disease that most folks were profiling before, but now that we have interesting data looking at moving immunotherapy in the frontline setting for these patients, [profiling is important]. We are also awaiting results from a phase 2 trial [NCT02392637] evaluating the triplet of nab-paclitaxel plus standard gemcitabine/cisplatin. We will see whether there is a further change to our standard of care up front in cholangiocarcinoma.

This article was originally published on OncLive as “Immunotherapy Approvals Overcome Years of Stagnation in GI Cancers”

Event co-chair, Syma Iqbal, MD, discusses key points from a recent OncLive® Institutional Perspectives in Cancer webinar, which focused on the evolving landscapes in gastrointestinal cancer. 

Immunotherapy Approvals Propel the Future of GI Cancer Treatment 

The ESMO Clinical Practice Guidelines for metastatic breast cancer, published in the 

 state that disease management should be nuanced and multidisciplinary across all subtypes in order to improve personalize locoregional, systemic, and supportive care.

“The rapid pace at which scientific knowledge is currently advancing means that new evidence may emerge between the time at which documents like the ESMO Clinical Practice Guidelines are developed and their eventual publication and use by clinicians,” Giuseppe Curigliano, MD, PhD, an associate professor of medical oncology at the University of Milano, head of the Division of Early Drug Development at the European Institute of Oncology, IRCCS, in Italy, and chair of the ESMO Guidelines Committee, said in a news release.

“The up-to-date guideline on metastatic breast cancer was therefore designed to integrate even the most recent, potentially practice-changing data by providing graded recommendations for different treatment choices according to the levels of evidence available to support them, based on their rating within the ESMO Magnitude of Clinical Benefit Scale and the ESMO Scale for the Clinical Actionability of Molecular Targets,” Curigliano added.

Although survival outcomes have improved for patients with metastatic breast cancer, 5-year survival rates remain around 38%.

 Therefore, optimization of available therapies is needed to maintain and further improve outcomes for patients. As such, establishing international guidelines could help to standardize treatment options and outcomes across the world.

The guidelines include a proposed diagnostic work-up and staging flow chart. It states that all patients with newly diagnosed or current metastatic breast cancer should have a biopsy of their metastatic lesion to confirm histology and reassess biomarker status, such as estrogen receptor (ER), progesterone receptor (PR), and HER2 status. Additionally, tumor heterogeneity should be considered for each new line of treatment.

Other therapeutically relevant biomarkers should be routinely tested for, including germline 

 mutations in HER2-negative metastatic breast cancer, PD-L1 status in triple-negative breast cancer (TNBC), and 

 mutations in ER/PR-positive, HER2-negative metastatic disease. Genomic profiling by tumor tissue or circulating tumor DNA should be performed when results could change treatment selection.

Imaging for staging and risk assessment should incorporate at least a CT scan of the chest and abdomen and a bone scintigraphy. Treatment should be initiated no more than 4 weeks after imaging and response evaluation should occur every 2 to 4 months.

Additionally, brain imaging should not be routinely performed for all asymptomatic patients at diagnosis or during disease monitoring; however, subtype-oriented brain imaging can be considered if the presence of central nervous system metastases will alter treatment decisions for patients with HER2-positive breast cancer or TNBC that have a higher rate of brain metastases. Symptomatic patients should always undergo brain imaging.

Patients with ER-positive, HER2-negative metastatic breast cancer should receive estrogen therapy with an aromatase inhibitor or fulvestrant (Faslodex) plus a CDK4/6 inhibitor in the frontline setting. In patients for whom organ failure is imminent, chemotherapy followed by maintenance or next-line endocrine therapy plus a CDK4/6 inhibitor should be considered.

Upon progression, patients without a risk of organ failure are eligible for fulvestrant plus a CDK4/6 inhibitor if not previously used, everolimus/exemestane or everolimus/fulvestrant, fulvestrant/alpelisib (Piqray) if 

 mutated. Chemotherapy should be given upon progression after several lines of endocrine therapy with or without targeted therapies.

In the first-line setting, patients with hormone receptor (HR)–positive, HER2-positive disease with chemotherapy contraindications should receive trastuzumab (Herceptin) with or without pertuzumab (Perjeta) and endocrine therapy. Patients with HR-negative, HER2-positive disease with chemotherapy contraindications should receive trastuzumab/pertuzumab. Regardless of HR status, patients without chemotherapy contraindications should receive docetaxel or paclitaxel, trastuzumab, and pertuzumab followed by trastuzumab, pertuzumab, and endocrine therapy.

Second-line treatment for patients with active brain metastases for whom local intervention is indicated are eligible for resection with or without stereotactic radiotherapy or whole-beam radiation therapy based on the number of active brain metastases. In patients for whom local intervention is not indicated or for those without active brain metastases, tucatinib (Tukysa)/capecitabine/trastuzumab or fam-trastuzumab deruxtecan-nxki (Enhertu) is indicated. Third-line and beyond treatment recommendations are the same for patients with active brain metastases; however, in patients without active brain metastases, ado-trastuzumab emtansine (T-DM1; Kadcyla) can be considered in the third-line setting, followed by lapatinib (Tykerb)/trastuzumab, trastuzumab/chemotherapy, margetuximab (Margenza)/chemotherapy, or neratinib (Nerlynx)/chemotherapy in subsequent lines of therapy.

Patients with PD-L1–positive TNBC should receive atezolizumab (Tecentriq) plus nab-paclitaxel (Abraxane) or pembrolizumab (Keytruda) plus chemotherapy. Patients with 

-mutated TNBC should receive chemotherapy- or PARP inhibitor–based treatment. Patients with PD-L1–negative, 

 wild-type TNBC should receive anthracycline/taxane–based therapy, taxane/bevacizumab (Avastin), or capecitabine/bevacizumab if organ failure is imminent, or taxane or anthracycline monotherapy if organ failure is not imminent.

Upon progression, sacituzumab govitecan-hziy (Trodelvy) or chemotherapy is indicated for all patients followed by chemotherapy with eribulin (Halaven), capecitabine, or vinorelbine.

Hereditary Breast Cancer and Oligometastatic Disease

Patients with HER2-negative metastatic breast cancer who harbor germline pathogenic or likely pathogenic variants in 

 should be considered for PARP inhibitor therapy with olaparib (Lynparza) or talazoparib (Talzenna) irrespective of HR status.

In patients for whom oligometastatic disease is confirmed, a multidisciplinary team should consider the site of metastases, management of primary tumor and axilla, systemic treatment options, and localized approaches when making treatment decisions for patients.

Supportive and Palliative Care Recommendations

In all cases of metastatic breast cancer, multidisciplinary care should be utilized. Moreover, specialized oncology or breast care nurses should proactively screen patients for treatment-emergent toxicities, which should be managed accordingly. Quality-of-life assessments should be incorporated into the evaluation of treatment efficacy, and dose reductions or delays should be utilized in cases of toxicity.

It is important to incorporate palliative care early in inpatient and outpatient settings. With the rising median overall survival in metastatic breast cancer, patients are more likely to develop metastases in several areas of the body. As such, optimal symptom control, as well as psychological, social, and spiritual support should be implemented after patients receive best available therapy.

Shared-decision making between the provider and patient/family should be utilized to educate, establish goals and expectations, and optimize care.

Finally, health care professionals should have mental health support available to them to ensure they are able to provide sensitive and effective care to patients.

Gennari A, André F, Barrios CH, et al. ESMO clinical practice guidelines for the diagnosis, staging and treatment of patients with metastatic breast cancer. 

. Published October 13, 2021. Accessed November 2, 2021. doi:10.1016/j.annonc.2021.09.019

Metastatic breast cancer: new ESMO guideline with evidence-based recommendations [ESMO press release]. News release. ESMO. October 19, 2021. Accessed November 2, 2021. 

This article was originally published on OncLiver as “ESMO Guidelines Recommend Personalized Treatment and Multidisciplinary Decision Making in Breast Cancer

Nuanced and multidisciplinary decision making are needed to optimize and personalize locoregional, systemic, and supportive care in metastatic breast cancer. 

New ESMO Breast Cancer Guidelines Emphasize Personalized Treatment, Multidisciplinary Decision Making

To ensure that patients with cancer receive optimal care, the definition of personalized medicine needs to be broadened to include social determinants of health, according to Karen Winkfield, MD, PhD.

“Unfortunately, the COVID-19 pandemic has shown that in the United States, we don’t quite have the public health infrastructure that we need, not yet,” said Winkfield, executive director of the Meharry-Vanderbilt Alliance, the Ingram Professor of Cancer Research, and professor of radiation oncology at Vanderbilt University Medical Center, during the Greenspan Lecture at the 

 CFS®, a program hosted by the Physicians’ Education Resource® (PER®), LLC.

“However, we have an opportunity to think about it in a way that impacts communities at large, and, more specifically, the individual patients that are walking through our doors. What ways can we impact what is happening to the people that we serve?” Winkfield asked during her presentation entitled: “Precision Medicine: Ensuring every patient gets the right treatment at the right time.”

The field of precision oncology has grown significantly in recent years with the integration of broad molecular testing, identification of new prognostic markers, and understanding of mechanisms of resistance. With the development of targeted therapy, many patient populations can receive care that directly reflects unique characteristics of their tumor genomics and personal genetics.

However, Winkfield advises the field to further broaden the role of precision medicine to include not only genomic factors, but microbiome features, patient exposures and behaviors, clinical tests, and patient-contributed data to create a knowledge network that will allow for precision medicine to become more personalized.

“There are components of both [precision and personalized medicine] that we really need to think about today as we are talking about all the innovations that are being made in terms of how we manage chemotherapeutics. It is important to think about what we mean when we talk about precision oncology. Are we doing our best to personalize medicine?” Winkfield questioned.

Factors of Health Disparities in Cancer Care

Despite the downward trends in cancer-related deaths observed across all racial and ethnic patient populations, health disparities still exist, Winkfield explained.

 For example, one of the most widely known disparities in cancer care exists between White and African American patients.

There has been a decline in disparity for overall cancer death between African Americans and Whites from 33% in 1990 to 14% in 2016.

 However, achieving health equity remains a key goal in cancer care, Winkfield said.

Although biologic determinants like genetics, biology, and comorbidities inevitably have a role in creating these disparities, Winkfield hypothesized that social determinants, such as socioeconomic status, access to care, and sociocultural barriers, are the main contributors to these gaps.

Social determinants of health include economic stability, neighborhood and physical environment, education, food, community and social context, and health care system factors. Negative social determinants, such as low income, lack of access to transportation, food, and social support, literacy challenges, and limited health care provider availability, are associated with poor health outcomes, including increased mortality and morbidity, lowered life expectancy, increased health care expenditures, decreased health status, and functional limitations.

“The social determinants go beyond just food; it is transportation, employment, literacy, and health literacy. These are all issues we have to think about when we ask ourselves how we design personalized medicine programs and holistic care to the person who is right in front of us,” Winkfield said.

Although social determinants of health are becoming more understood, significant efforts from a socioeconomic and political context are needed to address them and provide precision medicine to all patients.

Notably, the COVID-19 pandemic required rapid integration of many technologies that may start to bridge some of these gaps that are influenced by social determinants of health, such as accessibility. The utility of telemedicine during the height of the pandemic is one lesson that can be taken away. Winkfield underscored that the pandemic showed feasibility with localized or virtual care for certain procedures and patient conversations. Additionally, even without the context of COVID-19, clinical trial consent forms are likely able to be signed virtually rather than having patients come into the clinic.

Importantly, adding virtual elements to cancer care can significantly lower the burden of treatment for patients, particularly for those who live in rural communities or who must rely on public transportation.

“Our ability to innovate the way that we have done with COVID-19 where telehealth is being compensated, these are the sorts of things we need to advocate for because, frankly, it makes it much easier for patients. This is what patient-centric care is about,” Winkfield said.

International Journal of Radiation Oncology, Biology, Physics

 stated that achieving health equity is of critical importance for patients receiving radiation therapy and that the renewed passion to protect vulnerable patients observed during the COVID-19 pandemic should continue to address the disparities in care.

Winkfield advised oncologists to be advocates of bringing more equitable cancer care in clinical trials and policy implications to their institutions and communities. Additionally developing a diverse workforce and working in direct collaboration with community-engaged researchers is a great start at addressing these gaps.

Specifically, Winkfield called attention to the need for redesigned and inclusive clinical trials. She highlighted the example of multiple myeloma where although African Americans comprise 20% of the multiple myeloma population in the United States, they comprise only 5% of FDA registration trials in multiple myeloma.

In addition to African American patients, adolescent/young adults, older adults, other racial/ethnic minorities, LGBTQ+ individuals, individuals in rural areas, and patients of lower socioeconomic status are some of the patients at the greatest risk for exclusion from clinical trials.

“If we are only getting the clinical trials in the spaces at the places that are very homogenous or have not done a good job at being inclusive, are we really moving the needle?” Winkfield asked.


Developing an actionable framework for stakeholders to address cancer care disparities within medically underserved populations is of paramount importance to ensure population-health care is implemented.

Ultimately, developing an understanding of the cross-cutting issues that span the entire cancer care continuum from prevention to detection, diagnosis, and treatment to survivorship and end of life is critical. In addition to health equity, some of these issues include quality of care, communications, and decision making.

“We need to figure out how we can create an environment where we provide precision oncology, but we provide it for every patient so that every patient gets the right treatment at the right time,” Winkfield concluded.

Winkfield K. Precision medicine: ensuring every patient gets the right treatment at the right time. Presented at: 39th Annual CFS®: November 3-5, 2021; New York, NY.

AACR cancer disparities progress report 2020. AACR. Accessed November 4, 2021. 

https://cancerprogressreport.aacr.org/disparities/

Siker ML, Deville C Jr, Suneja G, et al. Lessons from COVID-19: addressing health equity in cancer care. 

. 2020;108(2):475-478. doi:10.1016/j.ijrobp.2020.06.042

Loree JM, Anand, Dasari A, et al. Disparity of race reporting and representation in clinical trials leading to cancer drug approvals from 2008 to 2018. 

. 2019;5(10):e191870. doi:10.1001/jamaoncol.2019.1870

Winkfield KM, Regnante JM, Miller-Sonet E, et al. Development of an actionable framework to address cancer care disparities in medically underserved populations in the United States: expert roundtable recommendations. 

. 2021;17(3):e278-e293. doi:10.1200/OP.20.00630

This article was originally published on OncLive as “Personalized Medicine Could Be the Key to Bridging Health Disparities in Cancer Care”

The COVID-19 pandemic has demonstrated that personalized medicine should consider social determinants of health disparities as well as genomic factors. 

Personalized Medicine May Help Alleviate Certain Health Disparities in Cancer Care

The initial findings from the IMPACT study (NCT00261456) revealed that men who carry the 

 pathogenic variants are at an increased risk for prostate cancer compared with age-matched non-carrier individuals.

 The risk identified in these pathogenic variants, which are associated with Lynch Syndrome, highlight the potential value of regular prostate-specific antigen (PSA) screening starting at age 40.

“Prostate cancer screening isn’t recommended for the general population, but we believe it could benefit some groups of men at high inherited risk. Our new findings show that PSA testing in men with Lynch syndrome is much more likely to pick up life-threatening prostate cancer than in the general population,” Rosalind (Ros) Eeles, FMedSci, PhD, FRCP, FRCR, IMPACT study lead, professor of oncogenetics at The Institute of Cancer Research and a consultant in clinical oncology and oncogenetics at The Royal Marsden NHS Foundation Trust, said in a news release.

Lynch syndrome is characterized by pathogenic variants in 

which are mismatch repair genes. The familial cancer syndrome is associated with a predisposition to several cancers, including colorectal and endometrial. Data suggest that these genetic alterations confer an increased risk of early-onset, aggressive prostate cancer as well.

As such, the goals of the IMPACT study were to assess the utility of PSA screening in men with and without germline pathogenic variants in the genes in question, understand the incidence of prostate cancer among these men, and characterize tumors after the first round of screening.

The primary end point of the study was to determine the incidence, stage, and pathology of screening-detected prostate cancer in carriers of these pathogenic variants compared with non-carriers.

Overall, the international prospective study enrolled 828 men with mismatch repair gene pathogenic variants without a previous diagnosis of prostate cancer. Of these, 4 did not undergo PSA screening. Of the men who did undergo PSA screening, 203 were 

 non-carrier controls. An additional 134 

 non-carriers were randomly selected to increase the sample size for the non-carrier control groups.

Additionally, of the 828 men with confirmed pathogenic variants, 186 (19%) had a family history of prostate cancer.

Patients had to be between 40 and 69 years of age. They were required to have undergone genetic testing and tested positive or negative for known familial pathogenic variants. Men who had a 50% risk of inheriting a pathogenic variant but had not undergone genetic testing yet were eligible for enrollment.

Overall, patients were a median age of 53 years (range, 46-59). Most were of European ancestry (94%) and 41% were university graduates. Most patients did not have previous urinary symptoms (78%) or a previous PSA test (62%).

Men whose PSA level was higher than 3.0 ng/mL were offered a transrectal, ultrasound-guided prostate biopsy and histopathological analysis. Additionally, all participants are receiving at least 5 years of annual screening.

Within the first round of screening, 6% (n = 56) of men had a PSA concentration above 3.0 ng/mL and 4% (n = 35) underwent a prostate biopsy.

The results showed a prostate cancer incidence of 1.9% (n = 18; 95% CI, 1.1%-2.9%). The incidence of prostate cancer was 4.3% in 

 carriers (n = 13; 95% CI, 2.3%-7.2%), 0.5% in 

non-carriers (n = 1; 0.0%-2.6%), and 3% in 

 carriers (n = 4; 95% CI 0.8%-7.4%). No cases of prostate cancer were identified in 

Using a PSA threshold of more than 3.0 ng/mL, prostate cancer was detected more frequently among 

 carriers vs non-carriers (4.3% vs 0.5%; 

Ultimately, the positive predictive value of a prostate biopsy with a PSA threshold of 3.0 ng/mL was 51.4% (95% CI, 34%-68.6%). The positive predictive value of a PSA threshold of 3.0 ng/mL was 32.1% (95% CI, 20.3%-46%).

“Targeted screening has the potential to pick out aggressive prostate cancers at an early stage in men at high inherited risk, increasing their chances of survival. Because cancers in these men are more likely to be aggressive and potentially life-threatening, they would need to have radical treatment,” Eeles concluded. “I anticipate that these results, and evidence from our ongoing follow-up work, will influence future national and international screening guidelines for this group of men, with the aim of picking out prostate cancer earlier and potentially saving lives.”

Bancroft EK, Page EC, Brook MN, et al. A prospective prostate cancer screening programme for men with pathogenic variants in mismatch repair genes (IMPACT): initial results from an international prospective study. 

. Published online October 19, 2021. Accessed October 29, 2021. doi:10.1016/S1470-2045(21)00522-2

Targeted prostate cancer screening could benefit men with inherited cancer syndrome. News release. The Institute of Cancer Research. October 19, 2021. Accessed October 29, 2021. 

This article was originally published on OncLive as “PSA Screening for Aggressive Prostate Cancer Supported in Men With Lynch Syndrome–Associated Pathogenic Variants”

The increased risk of prostate cancer associated with MSH2 and MSH6 pathogenic variants point to a need for annual PSA screening in men over the age of 40. 

Relationship Between MSH2, MSH6 and Prostate Cancer Incidence Highlights Value of PSA Screenings

Because there is a significant infection risk associated with CAR-T cell therapies, special considerations are needed when designing COVID-19 vaccination and booster strategies for patients with heavily pretreated relapsed/refractory hematologic malignancies receiving this therapy. Furthermore, more data are needed to inform COVID-19 vaccine practices among this patient population, according to findings from a review published in 

“Although CAR T[-cell] therapy prolongs the survival of patients with relapsed/refractory diseases, the associated on-target, off-tumor toxicities, particularly infections, limit the effective utilization of this curative therapy,” wrote lead study author Juliet Meir, MD, a PL2 categorical resident at Westchester Medical Center of the Westchester Medical Center Health Network, and coauthors in the study publication.

To date, several CD19- and BCMA-directed CAR T-cell therapies have been FDA approved across multiple relapsed/refractory hematologic malignancies, including acute lymphoblastic leukemia, diffuse large B-cell lymphoma and other lymphomas with similar histopathological features, mantle cell lymphoma, and multiple myeloma.

With all products, CAR T-cell therapy is associated with unique short- and long-term toxicities and infection risks in patients with hematologic malignancies who were heavily pretreated with anti-cancer agents and, often, allogeneic hematopoietic stem cell transplant (allo-HSCT).

Acute toxicities, such as cytokine release syndrome (CRS) and immune effector cell–associated neurotoxicity syndrome, confer an early risk of infection following CAR T-cell therapy infusion. CAR T-cell therapy recipients are further predisposed to severe infections from long-term toxicities, including prolonged B-cell aplasia, hypogammaglobulinemia, and cytopenias. Moreover, these long-term adverse effects hinder the chance for remission associated with CAR T-cell therapy.

Ultimately, the risk of infections with CAR T-cell therapy is largely variable and depends on several patient-, disease-, and CAR T-cell therapy–related factors. Some of these factors include age at the time of CAR T-cell therapy, race/ethnicity, body mass index, Karnofsky performance status, disease status, cytogenetics, prior lymphodepletion chemotherapy regimens, the interval between cell collection and infusion, bridging therapy, minimal residual disease status at CAR T-cell therapy infusion, disease burden, CAR T-cell dose, signaling and costimulatory domains, target antigen, and duration of lymphopenia and hypogammaglobulinemia.

Notably, data suggest that CD19-directed CAR T-cell therapies induce more bacterial infections, whereas BCMA-directed therapies induce more viral infections because of differential expression patterns on the B-cell surface.

CAR T-cell therapies represent a potent treatment option for patients with heavily pretreated relapsed/refractory hematologic malignancies, however, the infection risk associated with treatment may hinder the efficacy of COVID-19 vaccines in this population.

Jessica Hergert

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