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Baseline clinical characteristics coupled with measurable cardiac parameters can be used to predict the risk of heart failure (HF) among adults with acute leukemia who receive anthracycline-based therapy, according to recent study findings.

Investigators developed a 21-point scoring system to evaluate the potential for HF among patients with newly diagnosed acute myeloid leukemia (AML) or acute lymphoblastic leukemia (ALL). The formula stratifies patients into high-, moderate-, or low-risk groups.

Although prior research has shown that patients with hematologic malignancies experience the highest rates of symptomatic HF and cardiac death compared with other patients with cancer treated with anthracyclines, investigators said data are limited when it comes to evaluating comorbidities in those with acute leukemia.

“While we are more effective at treating cancer, the improved survival rates have helped to unmask the cardiotoxic impact of some of the most common cancer therapies,” study coauthor Marielle Scherrer-Crosbie, MD, PhD, said in a statement.

“Our hope, in creating this risk score system, is to help clinicians identify patients with the highest risk for potential cardiac damage, so they can more closely monitor the patients via a multidisciplinary approach,” said Scherrer-Crosbie, director of the Cardiac Ultrasound Laboratory and a professor of cardiovascular (CV) medicine in the Perelman School of Medicine at the University of Pennsylvania in Philadelphia.

To examine these factors, investigators identified adults (≥18 years of age) treated with anthracyclines for newly diagnosed AML or ALL at the Hospital of the University of Pennsylvania between January 2004 and April 2018. In all, 450 patients with adequate baseline records who were followed for a median of 16 months (range, 1-132 months) were included in the analysis. The description of symptomatic HF was based on the 2017 Cardiovascular and Stroke Endpoint Definitions for Clinical Trials.

Among those in the study, symptomatic HF developed in 8.9% of the patients (n = 40), which included 1 patient with decompensated HF who died. The median time to development of HF was 10 months (range, 1-76). Death due to a noncardiac cause occurred in 47.8% of patients (n = 215).1

At baseline, 67% of patients in the study had AML (n = 301) and 33% had ALL (n = 149). Forty-eight percent of patients were male (average age, 51 years; ± 15). The most common baseline CV disease characteristics were current/previous smoking history (40%), having 2 or more CV risk factors (39%), hypertension (36%), and hypercholesterolemia (22%).

Investigators found that patients who developed HF were typically older and had a higher incidence of previous HF, atrial fibrillation, and preexisting CV diseases.

The scoring system assigns point values to 6 factors: baseline global longitudinal strain greater than —15%, left ventricular ejection fraction less than 50%, preexisting CV disease, AML, anthracycline dose of 250 mg/m

 or greater, and age greater than 60 years (

 Patients were then divided by scores into low (0-6 points), moderate (7-13 points), and high (14-21 points) risk groups.

Overall, the 1-year estimated cumulative incidence of HF for the low-, moderate-, and high-risk groups was 1.0%, 13.6%, and 35.0%, respectively.

Table. Variables Included to Predict the Risk of Heart Failure After Leukemia Therapy

For patients with ALL, investigators modified the risk score to exclude an AML diagnosis. Using a 17-point formula, investigators estimated the cumulative risk of HF incidence at 1 year in patients with ALL at less than 0.1% for the low-risk group, 3.6% for the moderate-risk group, and 17.0% for the high-risk cohort (

An exploratory analysis was also conducted to show the relationship between risk score and overall mortality. It was discovered that the risk score was associated with all-cause death (HR, 1.36; 95% CI, 1.23-1.50; 

 <.001). Patients in low-risk to moderate-risk groups had a greater overall survival time than high-risk patients (

 <.001). Only global longitudinal strain greater than —15% was found to be independently related to all-cause death (HR, 1.73; 95% CI, 1.30-2.31; 

Limitations of the study include the fact that it was conducted at a single center and that the score has not been validated in a separate cohort, investigators said. A large prospective, multicenter study is needed to further validate the formula.

The risk of HF and noncardiac mortality was found to be higher in patients with AML (11.6% and 52.8%, respectively) than in those with ALL (3.4% and 34.9%; 

<.001). Contributing factors to this finding included greater doses of anthracyclines in patients with AML and that patients in the AML group tended to be older. After adjusting for these risk factors, however, patients with AML still faced a greater risk of symptomatic HF (HR, 2.77; 95% CI, 1.01-7.63; 

Kang Y, Assuncao BL, Denduluri S, et al. Symptomatic heart failure in acute leukemia patients treated with anthracyclines. 

. 2019:1(2):208. doi:10.1016/j.jaccao.2019.10.008

Patients with acute leukemia who are treated with common therapy have increased risk for heart failure. New release. Philadelphia, PA: Penn Medicine; December 17, 2019. Accessed March 16, 2020. https://bit.ly/2w3mjPA

Articles

Baseline clinical characteristics coupled with measurable cardiac parameters can be used to predict the risk of heart failure among adults with acute leukemia who receive anthracycline-based therapy, according to recent study findings.

Scoring System Stratifies Risk of Heart Failure in Patients With Acute Leukemia

Treatment approaches are being refined by the primary location of gastroesophageal junction (GEJ) tumors, said Stephen C. Yang, MD, during the 

“The site does matter because it influences therapy,” said Yang, associate vice chair for faculty development, and professor of surgery and medical oncology at Johns Hopkins University School of Medicine in Baltimore, Maryland. “A multidisciplinary approach remains necessary for all of these tumors. It not only involves the esophageal group but also the gastric group at our institution.”

But Yang said there has been confusion about whether junction tumors should be treated as esophageal or gastric cancer. The confusion, he said, could be related to the fact that there are several ways to classify these tumors.

Classifying a Tumor: Gastric or Esophageal

The most commonly used classification for assessing and planning treatment of GEJ tumors is the Siewert classification, which has been used since the 1980s.

 Type I is similar to esophageal cancers by epidemiology and histology and type III is similar to distal gastric tumors with intestinal and diffuse histologic types and no association with reflux, Yang said. Type I GEJ tumors are 1 to 5 centimeters above the GEJ with type III starting 2 cm below the junction. Type II tumors begin 1 cm above the junction to 2 cm below the junction (

Less commonly used systems, Yang said, are the Union for International Cancer Control and Nishi’s Japanese Classification of Esophageal Cancer.

Yang noted in his presentation that the National Comprehensive Cancer Network had adopted the Siewert classification. The guidelines describe Siewert types I and II tumors as being esophageal and suggests clinicians follow recommendations for esophageal cancer. Siewert type III tumors are described as gastric cancer.

Yang suggested clinicians consider the molecular and genomic classifications, especially for gastroesophageal adenocarcinoma, which is the primary histologic cell type in GEJ tumors. He pointed to a recent study

 that found similarities between adenocarcinomas of the stomach and esophagus and their definitive distinction from squamous cell carcinomas of the esophagus. The authors suggest that a “single-target, single-drug” rationale has proved too simplistic for GEJ adenocarcinoma because of the genomic instability and heterogeneity of this disease.

“The gastroesophageal junction tumors are [characterized by] mostly chromosomal instability but also share other genomic characteristics similar to gastric cancer but are still primarily associated with esophageal cancer,” Yang said. “A small component has genomic stable types that have microsatellite instability and also a small percentage are associated with the Epstein-Barr virus.”

Table. Siewert Classification of Gastroesophageal Junction Tumors

“No trials have specifically addressed this for true type II GEJ tumors,” he said. Yang said that the histology of the stomach away from the tumor may be the key to determining which classification these borderline tumors fall under. It’s important to determine if the rest of the mucosa is healthy, noted Yang. If there is atrophy of the mucosa, the presence of 

, or the patient has a history of reflux, it likely that the tumor is primarily gastric cancer. On the other hand, if the mucosa is healthy and there is 

Another controversy, Yang said, is the surgical approach and whether surgery should take more of the esophagus or more of the stomach. He cited a 2015 study, a retrospective analysis of 266 patients with surgically resectable GEJ adenocarcinomas from 2003 to 2013.

 The analysis reported that a positive circumferential resection margin was more common with gastrectomy (29%) versus esophagectomy (11%; 

 = .025). Further, no significant differences in mortality, morbidity, or disease recurrence were found.

Yang said another question that remains is whether to use induction or adjuvant radiation. A retrospective data analysis from the Surveillance, Epidemiology, and End Results registry database showed that adjuvant radiation therapy was associated with a survival benefit as compared with neoadjuvant radiation therapy for the treatment of patients with type II GEJ cancer.

A total of 1497 patients with resectable GEJ cancer were identified, with 746 receiving adjuvant radiation therapy and 751 receiving neoadjuvant radiation therapy.

Adjuvant radiation had a significantly lower death risk (HR, 0.84; 95% CI, 0.73-0.97; 

 = .0168) as well as a significantly lower disease-specific death risk (HR, 0.84; 95% CI, 0.72-0.97; 

“The individualized surgical approach remains critical not only preoperatively but also intraoperatively for decision making,” Yang said.

Curtis N, Noble F, Bailey I, Kelly JJ, Byrne JP, Underwood TJ. The relevance of the Siewert classification in the era of multimodal therapy for adenocarcinoma of the gastro-oesophageal junction. 

 2013;109(3):202-207. doi:10.1002/jso.23484           

National Comprehensive Cancer Network. Clinical Practice Guidelines in Oncology. Esophageal and esophagogastric junction cancers (version 1.2020). Accessed April 20, 2020. https:// www.nccn.org/professionals/physician_gls/pdf/esophageal.pdf

Nagaraja A, Kikuchi O, Bass A. Genomics and targeted therapies in gastroesophageal adenocarcinoma. 

. 2019;9(12):1656-1672. doi:10.1158/2159-8290.CD-19-0487

Parry K, Haverkamp L, Bruijnen R, et al. Surgical treatment of adenocarcinomas of the gastro-esophageal junction. 

. 2015;22(2):597-603. doi:10.1245/s10434-014-4047-1

Miccio J, Oladeru O, Yang J. et al. Neoadjuvant vs. adjuvant treatment of Siewert type II gastroesophageal junction cancer: an analysis of data from the surveillance, epidemiology, and end results (SEER) registry.

. 2016;7(3):403- 410. doi:10.21037/jgo.2015.10.06

Yang said the variability of GEJ tumors has made treatment challenging. Controversies for GEJ tumors include the following: how best to stage these tumors, should induction or radiation be added to the regimen, what is the best surgical approach, and whether to add adjuvant therapies and under which situations.

Treatment approaches are being refined by the primary location of gastroesophageal junction tumors.

Primary Location of GEJ Tumors Affects Treatment

Therapeutic options for pretreated HER2-positive breast cancer now include tucatinib (Tukysa) as part of a triplet regimen with a tolerable safety profile that promises improved quality of life.

On April 17, 2020, the FDA approved tucatinib in combination with trastuzumab (Herceptin) and capecitabine (Xeloda) for adults with advanced unresectable or metastatic HER2-positive breast cancer, including patients with brain metastases, who have received at least 1 prior anti—HER2-based regimen in the metastatic setting. Tucatinib is a HER2-directed tyrosine kinase inhibitor.

The approval is based on findings from the phase 2 HER2CLIMB study (NCT02614794), which demonstrated the triplet’s capacity to improve survival in patients with and without brain metastases. In the overall population, the median progression-free survival (PFS) with the 3-agent approach was 7.8 months versus 5.6 months with trastuzumab and capecitabine alone. Among those with brain metastases, median PFS was 7.6 months in the tucatinib arm versus 5.4 months in the control group.

, Erika P. Hamilton, MD, director of the Breast Cancer and Gynecologic Research Program at Sarah Cannon Research Institute in Nashville, Tennessee, discussed the regimen’s potential in earlier lines of therapy and how HER2CLIMB’s inclusion of patients with brain metastases has the power to move the needle in clinical investigations of therapies in this subgroup.

What was noteworthy about the efficacy data?

HER2CLIMB had 4 end points looking at progression-free survival, overall survival, overall response rate, and then progression-free survival among patients with brain metastases. The trial met all 4 of these end points, so it was a win across the board.

The activity in the population of patients with brain metastases really stood out. We have a lot of good therapies for breast cancer, but many of them do not cross the blood-brain barrier, so patients with brain metastases comprise a very highrisk patient population that is known to have worse outcomes. To have a drug that not only [meets end points] across the board but also benefits patients with brain metastases is meaningful. There is a statistic from the trial that [shows] the progression-free survival at 1 year among patients with brain metastases was 0% if they were not receiving tucatinib [compared with] a quarter of patients with brain metastases who remained on the trial at 1 year and were [receiving tucatinib].

Why is HER2CLIMB’s inclusion of a broad population of patients with brain metastases important?

In oncology trials, we commonly allow patients with brain metastases only if they have been treated with local therapy, such as resection or radiation and are stable 4 weeks after they finish local treatment. This trial was very different. HER2CLIMB allowed 3 different populations of patients with brain metastases to enroll: this traditional population with stable, pretreated brain metastases; metastases that had never been treated; and metastases that were treated and had progressed after. It was a very high-risk population.

Right now, I think that there is a lot of talk about how important clinical trials are and many patients’ trouble accessing them. We know that the best treatment option for a patient is enrolling on a clinical trial. There is also a lot of talk about how our inclusion criteria are a little too [strict], maybe [stricter] than they need to be, and historically, there has been some fear from drug companies because they do not want to include patients who may be sicker, not have optimal organ function, or in this case, have actively progressing brain metastases and may not do as well on therapy.

I think it was progressive, wise, and brave to allow these patients on the trial, who probably stood to benefit the most. After this trial, because it is the first one to do so, I think there will be many more companies who will follow suit.

How well is the tucatinib triplet regimen tolerated?

We normally give HER2 therapy in conjunction with chemotherapy. Capecitabine is an oral chemotherapy that tends to be pretty well tolerated. It does not cause hair loss, and it also does not cause a patient’s [white blood cell] counts to drop [significantly], so it is a favored chemotherapy partner in breast cancer. Trastuzumab is our most widely used HER2 antibody, and we learned that having a dual HER2 blockade such as trastuzumab with pertuzumab [Perjeta] or in this case, trastuzumab and tucatinib, can [lead to] additive [efficacy]. It is a very good combination, and I think that what is unique about tucatinib is this [agent] does not add a whole lot of toxicity.

The most common adverse events we saw in the trial were diarrhea, hand-foot syndrome, nausea, and fatigue, and those are the most common side events of capecitabine as a single agent. The addition of tucatinib added some liver dysfunction, about a 5% grade 3 elevation in liver function tests that was reversible.

The most important [characteristic] of tucatinib that is unlike other HER2 [agents] that we are familiar with like lapatinib [Tykerb] and neratinib [Nerylnx] is that tucatinib is specific and only blocks HER2, which makes it better tolerated than some of our more traditional options for HER2-positive breast cancer. Lapatinib and neratinib not only block HER2, but they also block HER1, or EGFR, and toxicities of rash and diarrhea come from EGFR [inhibition].

What are the next steps for the use of this regimen?

Can we move tucatinib earlier [in the treatment paradigm]? There is a lot of excitement around the brain metastases data, but I do not see this as a drug that I would only use in patients with brain metastases because it is an active regimen for the 52% of patients on the trial who did not have brain metastases. Because our systemic therapies are effective for HER2-positive breast cancer, these women are living longer and longer. Up to 50% of people with this disease will eventually develop brain metastases, which is quite a bit higher than some other types of cancer, so using a drug like tucatinib, even in the absence of brain metastases—that can get into the brain and work&mdash;may prevent brain metastases. I think an important question to ask moving forward is if we use tucatinib earlier, could we prevent brain metastases?

Figure. Tucatinib in Combination With Trastuzumab and Capecitabine (Click to Enlarge)

I am currently enrolling [patients in] the HER2CLIMB-02 trial [NCT03975647] of tucatinib in combination with T-DM1 [Kadcyla; ado-trastuzumab emtansine] or T-DM1 alone in the second-line setting.

Tucatinib Approval Adds Impact to HER2+ Breast Cancer Paradigm

Investigators are changing the standard randomized controlled trial (RCT) design to more expeditiously identify experimental therapies for patients with glioblastoma (GBM), the deadliest form of brain cancer.

GBM kills 95% of patients within 5 years of diagnosis, with more than half of patients dying in the first 15 months; that prognosis makes a customary RCT structure that could span 1 to 4 years in length impractical. Investigators of the first global adaptive phase 2/3 GBM Adaptive Global Innovative Learning Environment (AGILE) platform trial (NCT03970447) are implementing a multiarm, 2-stage approach to concurrently evaluate single-agent and combination regimens.

“We felt that there needed to be a way to test multiple therapies in a randomized study, determine whether or not there are signals, confirm those signals, and move forward with new drug applications,” said Timothy F. Cloughesy, MD, global principal investigator of the GBM AGILE trial and director of the Neuro-Oncology Program of the Brain Research Institute at the University of California, Los Angeles.

GBM AGILE is recruiting 550 patients with 

 R132H wild-type newly diagnosed (ND) grade IV GBM or recurrent GBM (

). Investigators will stratify patients by 3 subtypes of GBM: ND methylated GBM, ND unmethylated GBM, or recurrent disease, and randomize them to a treatment arm in the trial’s first stage.

At present, GBM AGILE investigators are evaluating treatment interventions in patients either with ND unmethylated GBM or recurrent disease.

Figure. Multiple Regimens in Newly Diagnosed and Recurrent GBM Study (Click to Enlarge)

For those with recurrent disease, participants in the control arm will be treated with lomustine (Gleostine) started at 110 mg/m

 per day on day 1 of a 42-day cycle for a maximum of 6 cycles; in the experimental arm, patients with recurrent disease type will receive an investigtional therapy.

The first experimental agent to be tested is regorafenib (Stivarga), a multikinase inhibitor that the FDA has approved for metastatic colorectal cancer, metastatic gastrointestinal stromal tumor, and hepatocellular carcinoma. In the GBM AGILE trial, regorafenib will be administered at 160 mg daily for 3 weeks of every 4-week cycle.

As the study progresses, investigators will open additional treatment arms to explore other regimens. They also will assess patients for potential biomarkers that could be used to direct therapy. Across stages 1 and 2 of GBM AGILE, the primary end point of the study is overall survival (OS). Secondary end points include progression-free survival, tumor response, and duration of response.

GBM AGILE investigators will closely assess the anticancer activity of the control and experimental interventions in the ND and recurrent disease populations. In stage 1 of the study, investigators will stop enrolling patients in a treatment arm if the arm completes accrual (n ≤150) or if the arm’s therapy demonstrates futility or unacceptable toxicity.

In stage 1 of the GBM AGILE study, investigators will use a dynamic assignment strategy known as adaptive randomization to direct a higher proportion of new participants to the superior treatment arm.

“Adaptive randomization allows us to identify the therapies that are working best for patients. The randomization probabilities would adjust based on current data from the ongoing trial,” Cloughesy said.

This predefined algorithm will identify the treatments with the greatest efficacy based on the survival benefit that these therapies confer when compared with a common control. It will also select the GBM population for which these interventions are most promising. Those therapies deemed promising will “graduate” to stage 2.

For this stage, investigators will use fixed randomization to evaluate the efficacy of these therapies in the algorithm-defined population to confirm findings from the first stage of the trial. Each stage 2 cohort will enroll 50 patients.

The design of the 2-stage study supports swifter patient registration, as well as a more rapid regulatory review process and subsequent clinical adoption of the treatments that display signals in the second stage of the GBM AGILE study.

Equally important, GBM AGILE’s unique model means that investigators can more rapidly identify and expel the treatments that do not show signals indicative of therapeutic benefit than they would in traditional RCTs. “[Recognizing] early futility has huge value because if you find early futility and stop enrollment, you have determined that the therapy is not going to confer benefit, and you didn’t have to run a large, costly phase 3 study to get that answer,” Cloughesy said.

Of note, data from the treatments that do not demonstrate a sufficient survival advantage in the first stage to justify further study in stage 2, but nevertheless suggest a potential benefit, will become available to GBM specialists and can be used to support the development of biomarker hypotheses as well as further therapeutic investigations in the field.

“Our goal is to identify the effective drugs, get rid of the ineffective drugs, and also identify the drugs that have a signal, [but one] that isn’t quite as strong [as others],” Cloughesy said, adding that drug developers can draw upon data from the GBM AGILE study to determine whether they would like to appropriately power and pursue a trial of an agent that was found to have a more minimal signal in the phase 2/3 study.

The GBM AGILE study is a clinical endeavor that has been years in the making and owes its dynamic design to the collaborative interplay of more than 130 oncologists, pathologists, statisticians, imagers, neurosurgeons and academic, industry, and government researchers, who have worked collectively to cultivate this investigative model since 2015.

GBM AGILE is a “group effort” that was initiated in response to a series of unsuccessful clinical trials in GBM, according to Cloughesy. “The rationale for GBM AGILE comes from the setting of GBM, where in the [past] few years, there have been several negative phase 3 studies. They were expensive, costing several hundred million dollars, and it seemed that we weren’t [facilitating investigations] very well,” Cloughesy said. “Then, the disease gets the reputation that drugs can’t be developed in glioblastoma— that they’re just bound to fail.”

In ND GBM, the standard of care is temozolomide, which was approved for use in combination with RT and as a maintenance therapy in 2005.

 Existing data show that the median OS with temozolomide and concurrent RT is 14.6 months versus 12.1 months with RT alone, supporting the doublet regimen’s application in this setting.

Patients with ND GBM receive temozolomide with RT after maximal surgical resection, which rarely eradicates GBM tumor cells in their totality due to the invasive nature of the disease. Although adjuvant temozolomide and RT are administered to reduce the risk of disease recurrence, nearly all cases of GBM that initially respond to frontline treatment eventually recur.

In contrast to ND GBM, there is no established standard of care for recurrent disease. Interventions for recurrent GBM can include surgical resection, reirradiation, nitrosoureas, temozolomide rechallenge, or treatment with tyrosine kinase inhibitors or bevacizumab (Avastin).

Bevacizumab was indicated for use in patients with GBM in 2017, after findings from the phase 3 EORTC 26101 study (NCT01290939) showed that adding the VEGF inhibitor to lomustine reduced the risk of disease progression or death by 48%.8 Administering bevacizumab with lomustine extended the median progression- free survival versus single-agent lomustine (4.2 vs 1.5 months; HR, 0.52; 95% CI, 0.41-0.64) but notably did not result in a significant improvement in OS (HR, 0.91; 

The modest survival benefits that existing therapies afford patients with GBM, coupled with the lack of curative options, translate to a need for more efficacious treatment options for a disease that accounts for 45% of all malignant brain tumors and more than 12,000 cases annually in the United States.

GBM AGILE investigators and the trial’s broad network of clinical collaborators believe that the platform format of the study has the potential to not only identify better therapies for this deadly disease but also reduce the time and costs associated with their development around the world.

“We wanted to facilitate this evaluation in 1 environment to boost development in glioblastoma, and we also wanted to do this in multiple jurisdictions beyond the United States,” Cloughesy said. GBM AGILE is actively enrolling patients in the United States, and international locations in Canada, China, and Europe are also expected to open at a later date, according to Cloughesy.

Whereas the coronavirus disease 2019 (COVID-19) pandemic has prompted the suspension of many clinical trials across the nation, GBM AGILE has continued to accrue patients. “We have continued to add sites during this time and enrollment has remained steady, so we’ve been happy to see that,” Cloughesy said. “At their institutions, people [ask], what’s a necessary study going forward? Glioblastoma is almost 100% fatal. COVID-19 is incredibly serious, but glioblastoma will continue to be serious even after we’ve learned how to deal with COVID-19. We still need to learn how to deal with glioblastoma.”

Global Coalition For Adaptive Research. GBM AGILE website. Accessed April 13, 2020. bit.ly/2RU55M2         

Step 3: clinical research. US FDA website. Updated January 4, 2018. Accessed April 14, 2020. bit.ly/2KrezKs

A trial to evaluate multiple regimens in newly diagnosed and recurrent glioblastoma (GBM AGILE). ClinicalTrials.gov identifier: NCT03970447. Updated April 14, 2020. Accessed April 15, 2020. http://www.clinicaltrials.gov/ct2/show/NCT03970447 Alexander BM, Ba Sujuan, Berger MS, et al. Adaptive global innovative learning environment for glioblastoma: GBM AGILE. Clin Cancer Res. 2018;24(4):737-743. doi:10.1158/1078-0432.CCR-17-0764

Alexander BM, Ba Sujuan, Berger MS, et al. Adaptive global innovative learning environment for glioblastoma: GBM AGILE. 

. 2018;24(4):737-743. doi:10.1158/1078-0432.CCR-17-0764

Temodar. Package insert. Merck; 2019. Accessed April 15, 2020. https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/021029s033lbl.pdf

Stupp R, Mason WP, van dan Bent MJ, et al. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. 

 2005;352:987-996. doi:10.1056/NEJMoa043330

Shergalis A, Bankhead A, Luesakul U, Muangsin N, Neamati N. Current challenges and opportunities in treating glioblastoma. 

. 2018;70(3):412-445. doi:10.1124/pr.117.014944

Avastin. Package insert. Genentech Inc; 2019. Accessed April 15, 2020. https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/125085s331lbl.pdf

Wick W, Gorlia T, Bendszus M, et al. Lomustine and bevacizumab in progressive glioblastoma. 

. 2017;377(20):1954-1963. doi:10.1056/NEJMoa1707358

Patients with ND GBM who are randomized to the control arm will receive radiation therapy (RT) at 60 Gy in combination with temozolomide (Temodar) at 75 mg/m

 for 6 weeks, followed by maintenance temozolomide. The maintenance phase would begin 2 to 6 weeks after RT, starting with 150 mg/m

 on days 1 to 5 of a 28-day cycle, followed by 200 mg/m

 on days 1 to 5 of the second and subsequent cycles. In the experimental arm, patients with ND GBM will also be treated with RT and temozolomide but will receive the experimental regimen instead of maintenance temozolomide.

Investigators of the first global adaptive phase 2/3 GBM Adaptive Global Innovative Learning Environment platform trial are implementing a multiarm, 2-stage approach to concurrently evaluate single-agent and combination regimens in glioblastoma.

Chasing a Cure for GBM: Investigators Test Multiple Regimens in Novel Trial

The degree to which nature and nurture affect disease has long been debated in medicine, and it is an issue that esteemed breast cancer researcher and medical oncologist Joyce A. O’Shaughnessy, MD, has been working to unravel for her patients throughout a career that spans more than 30 years.

O’Shaughnessy’s care approach strives to consider the whole patient, from determining the importance of germline and somatic mutations and other molecular disease markers, to applying the ever-advancing knowledge at the bedside, to advocating for guidelines and policies that help improve overall quality of life and increase the chances of favorable long-term outcomes for patients and survivors. These efforts include advocating for insurance coverage of nutrition and exercise programs to help overcome treatment-related adverse events and reduce risk of recurrence.

Her endeavors have led to some encouraging outcomes, including for patients with unmet needs who would normally have a poor prognosis. O’Shaughnessy’s practice- changing work in oncology and efforts to educate other clinicians on advances in the field resulted in her becoming a recipient of the 2016 Giants of Cancer Care

 award in the community outreach/education category. She is the Celebrating Women Chair in Breast Cancer Research, Baylor University Medical Center, Texas Oncology, and chair, Breast Cancer Program, US Oncology Research.

After a burst of FDA approvals of novel drugs and formulations in less than 18 months, O’Shaughnessy is looking forward to integrating these advancements into clinical practice. Over the next few years, many additional new agents are expected to be approved for breast cancer, and others are likely to receive expanded indications, O’Shaughnessy said in an interview with 

“It’s truly an exciting and hopeful time in breast cancer because many of the novel agents recently approved and in late-stage development will ultimately improve the long-term outcomes of high-risk early-stage patients, thereby decreasing the global burden of metastatic breast cancer, and there’s no indication that the pace of discovery will slow down any time soon,” she said.

The nature of these emerging therapies and how they fit into the treatment paradigm are among the topics that O’Shaughnessy will tackle this year as she continues her role as a leading breast cancer physician-scientist and educator. She will serve as program chair and co-chair, respectively, for the 

International Congress on the Future of Breast Cancer

 (IBC), which will be held in New York City on July 17 and 18, 2020, (IBC East) and in San Diego, California, on July 31 and August 1, 2020, (IBC West).

The conferences, which are among many medical meetings with which O’Shaughnessy is involved, are hosted by Physicians’ Education Resource

). Each meeting features more than 25 sessions that will cover a broad range of novel and practical topics in breast cancer, including new risk-reduction strategies, new algorithms for treating hormone receptor—positive metastatic disease, and the potential emergence of HER2-low breast cancer as a unique subtype. (The meetings currently are scheduled as live events. For updates, visit GoToPER.com).

Additionally, in perhaps her most unusual education project, O’Shaughnessy will chair the 

, an intensive 3-day deep dive into the latest data and their clinical implications about breast cancer biology, diagnostics, prevention, and treatment. The program, also hosted by PER

, will take place November 5 through November 7, 2020, in Atlanta, Georgia.

The conference events are indicative of O’Shaughnessy’s standing among her peers. “It is always an absolute pleasure to work with Dr O’Shaughnessy on conferences like the Miami Breast Cancer Conference

 and IBC,” said Sara A. Hurvitz, MD, of the Ronald Reagan University of California Los Angeles Medical Center, in Santa Monica, who will co-chair the IBC West Conference. “She is a true leader in the field of breast cancer with a unique grasp on translational approaches that are moving the field forward and an extraordinary ability to clearly convey these results to clinicians and investigators alike.”

The Importance of Learning From Exceptional Responders: A Patient Story 

A patient who greatly influenced O’Shaughnessy’s translational and clinical research direction is a woman named Donna, now 68 years old, who was initially diagnosed with triple-negative breast cancer (TNBC) in 2008 at age 56.

As is characteristic of TNBC, Donna experienced multiple recurrences of treatment- refractory disease in her thoracic and supraclavicular lymph nodes. She had undergone several surgical resections and rounds of radiation therapy and had been treated with multiple cytotoxic agents, including taxanes, carboplatin, anthracyclines, alkylators, and antimetabolites. In 2011, she was referred to O’Shaughnessy to be considered for enrollment into a clinical trial. At that time, she had a 3-cm involved left supraclavicular lymph node and no other disease.

“We biopsied the lymph node and performed next-generation sequencing but didn’t find a specific mutation to target therapeutically. Her cancer contained an FOXM1 amplicon and somatic loss-offunction mutation in 

, which is part of the SWI/SNF family that is involved in double-strand DNA repair, among other things,” O’Shaughnessy said in an interview with 

Donna was enrolled into a clinical trial assessing dactolisib (BEZ235), an oral agent that inhibits PI3K, mTOR, and the DNA repair protein DNA-PK. “Her cancer responded with a decrease in the size of the left supraclavicular lymph node, but after approximately 6 weeks on therapy, the node began growing very rapidly. This was a definite change in the tempo of her disease, which heretofore had been growing slowly,” O’Shaughnessy said.

The enlarging supraclavicular lymph node was resected, as was a subpectoral lymph node a few months later, which was the patient’s only site of recurrent disease at that time. Shortly after the second resection, however, she developed very rapidly growing internal mammary lymph nodes, some of which were substernal and pushing her sternum out, causing considerable pain. “I treated her with 6 cycles of high-dose nab-paclitaxel [Abraxane] and cisplatin every 3 weeks and obtained a complete response [CR] on CT scan after 2 cycles of therapy. She has been without evidence of disease since 2012,” O’Shaughnessy said.

O’Shaughnessy has analyzed the molecular characteristics of Donna’s serial tumor specimens, including by reverse-phase protein arrays to understand protein pathway activation within her breast cancer. “I think what happened is that the BEZ235 remodeled her cancer by interrupting signaling through the PI3K pathway, inhibited DNA-PK, and shifted signaling in the cancer over to the highly proliferative MAP kinase, MEK/ERK-driven pathway. And BEZ235 increased the degree of homologous recombination deficiency in her breast cancer, which I think was present because of the somatic 

 loss-of-function mutation seen on next-generation sequencing. These changes likely increased the sensitivity of her cancer to DNA-damaging agents, including cisplatin. So, though Donna had never benefited from chemotherapy before, her remodeled tumor became exquisitely sensitive to cisplatin and nab-paclitaxel following treatment with BEZ235,” O’Shaughnessy explained.

O’Shaughnessy’s experience with Donna, an exceptional responder, shifted the direction of her research toward conducting small, translational pilot trials aimed at increasing 

ness in metastatic TNBCs, defined as disruptive DNA repair traits that sporadic cancers share with 

 The goal of increasing BRCAness is to enhance the effectiveness of DNA-damaging agents and checkpoint inhibitors. She currently has ongoing clinical trials using PI3K/ mTOR inhibitors, a combination of TAK-228 and TAK-117 called PIKTOR (NCT03193853) and LY3023414 (NCT04032080), to evaluate whether these agents can increase homologous recombination deficiency in patients with pretreated metastatic TNBCs.

How It All Started: O'Shaughnessy's Story

At the time, O’Shaughnessy was a student at the College of the Holy Cross in Worcester, Massachusetts, and, after her sister’s death, she decided that cancer research would become her life’s mission. Fortunately, the dean of Holy Cross was very supportive and provided her with funding for her initial study that summer, and she then spent much of her senior year in college studying tumor virology at the Worcester Foundation for Biomedical Research in nearby Shrewsbury, Massachusetts.

After graduating college, O’Shaughnessy went on to pursue her medical degree from Yale University Medical School in New Haven, Connecticut, where she conducted research and wrote her graduation thesis on the biochemical mechanisms of antileukemic agents under the mentorship of 2 very dedicated oncologists, Edwin C. Cadman, MD, and Christopher C. Benz, MD.

Although O’Shaughnessy was initially interested in hematological malignancies because of her sister, a post-fellowship opportunity to transition to the National Cancer Institute’s Clinical Breast Cancer Division to work with her mentor, Kenneth Cowan, MD, PhD, in 1990 cemented her focus on breast cancer. She has since made a considerable impact on the field.

Today, many patients with breast cancer, including those with metastatic disease and the aggressive subtypes, are experiencing improved survival rates due to the rapid pace of discovery, clinical development, and FDA approval of new agents.

O’Shaughnessy’s contributions to the breast cancer armamentarium include key research into the chemotherapeutics gemcitabine, capecitabine, and eribulin mesylate; the CDK4/6 inhibitors abemaciclib (Verzenio) and ribociclib (Kisqali); the immune checkpoint inhibitor pembrolizumab (Keytruda); and numerous targeted therapies including HER2 and PARP inhibitors.

Unlike in the past, when researchers searched for broad-spectrum cancer therapies, today’s treatments are increasingly targeting molecular markers in well-defined breast cancer subtypes. O’Shaughnessy shared her insights on some of the emerging therapies on the horizon that are likely to reshape breast cancer care.

Neratinib (Nerlynx) is an orally available tyrosine kinase receptor inhibitor of EGFR, HER2, and HER4.

 On February 25, 2020, the drug received FDA approval for a new indication as a combination therapy with capecitabine for adult patients with advanced or metastatic HER2-positive breast cancer who have received 2 or more previous anti-HER2—based regimens in the metastatic setting.4 It was previously approved in 2017 as a single agent for the extended adjuvant treatment of adults with early-stage HER2-positive breast cancer following adjuvant trastuzumab (Herceptin)-based therapy.

Neratinib’s new indication was approved based on data from the multicenter, openlabel NALA trial (NCT01808573), which randomly assigned patients 1:1 to receive neratinib 240 mg orally once daily on days 1 to 21 with capecitabine 750 mg/m

 given orally twice daily on days 1 to 14 for each 21-day cycle (n = 307) or to lapatinib (Tykerb) 1250 mg orally once daily on days 1 to 21 with capecitabine 1000 mg/m

 given orally twice daily on days 1 to 14 for each 21-day cycle (n = 314).

 The primary end points were progression-free survival (PFS) and overall survival (OS), whereas secondary end points included objective response rate and response duration. Primary and secondary outcome measures were improved with neratinib plus capecitabine versus lapatinib plus capecitabine (

“One year of neratinib is a very important therapy for patients with high-risk estrogen receptor—positive breast cancer in the adjuvant setting. I offer it in combination with endocrine therapy following neoadjuvant pertuzumab [Perjeta] and adjuvant T-DM1 [ado-trastuzumab emtansine; Kadcyla], as it substantially reduces the risk of breast cancer recurrence. In my practice, I have seen that neratinib plus capecitabine is an effective combination for patients with HER2-positive brain metastases,” O’Shaughnessy said.

Table 2. Select Trials of Promising Regimens in the Breast Cancer Pipeline (Click to Enlarge)

In the intention-to-treat analysis, 112 patients had a response to therapy (60.9%; 95% CI, 53.4-68.0), with a CR rate of 6.0% and a partial response rate of 54.9%. The median duration of response was 14.8 months (95% CI, 13.8-16.9), and the median duration of PFS was 16.4 months (95% CI, 12.7-not reached).

Several phase 3 trials are ongoing, including DESTINY-Breast02 (NCT03523585), which is evaluating trastuzumab deruxtecan versus the investigator’s choice in patients with HER2-positive, unresectable, or metastatic breast cancer previously treated with standard-of-care HER2 therapies, including T-DM1; DESTINY-Breast03 (NCT03529110), which is comparing trastuzumab deruxtecan versus T-DM1 in patients with HER2-positive, unresectable, or metastatic breast cancer previously treated with trastuzumab and a taxane; and DESTINYBreast04 (NCT03734029), which is assessing trastuzumab deruxtecan versus the investigator’s choice for HER2-low breast cancer that has spread or is unresectable. All 3 trials are currently recruiting patients.

O’Shaughnessy said she is excited about the potential for trastuzumab deruxtecan, which may redefine how women with HER2-low—expressing breast cancers (1+/2+ on immunohistochemistry) are treated if it receives an expanded indication.

“Trastuzumab deruxtecan represents an exciting new strategy because the antibody against HER2, trastuzumab, binds to the breast cancer cells even in the setting of low HER2 expression, enabling the powerful chemotherapy drug, deruxtecan, to be delivered to these and even neighboring HER2-negative cells—the so-called bystander effect,” O’Shaughnessy said. “If the phase 3 DESTINY-Breast04 trial is positive, and the early phase 1/2 data do appear promising, we will have a new subtype of breast cancer, HER2-low, to target with this new agent,” she said.

Approval of trastuzumab deruxtecan in the setting of HER2-low expression would potentially affect a large number of patients, as this group has been estimated to be 2.5 times that of the current HER2- positive population.

Sacituzumab govitecan-hziy (Trodelvy) gained an accelerated approval on April 22, 2020, for the treatment of patients with metastatic TNBC who have received 2 or more prior therapies for metastatic disease.

 It is an antibody-drug conjugate that combines a humanized monoclonal antibody with SN-38 in a way that enables high concentrations of SN-38 to be delivered to tumors.

In a phase 1/2 multicenter trial (NCT01631552) that included 108 patients, investigator assessment showed an objective response rate of 33.3%, with 3 CRs and 33 partial responses. The median duration of response was 7.7 months. Post hoc assessment by independent central review showed a response rate of 34.3% and median duration of response of 9.1 months. The clinical benefit rate was 45.4%, the median PFS was 5.5 months (95% CI, 4.1-6.3), and the median OS was 13.0 months (95% CI, 11.2-13.7).

Sacituzumab govitecan is being assessed in the phase 3 ASCENT study (NCT02574455) in patients with relapsed or refractory metastatic TNBC who have been treated with 2 or more anticancer agents. The study, which has an estimated enrollment of 529 patients, is randomizing participants 1:1 to receive either sacituzumab govitecan (10 mg/kg on days 1 and 8 of a 21-day cycle) or physician’s choice of chemotherapy (eribulin, capecitabine, gemcitabine, or vinorelbine).

In the phase 2 HER2CLIMB trial (NCT02614794), the PFS rate at 1 year was 33.1% among those who received the tucatinib-containing regimen versus 12.3% for participants who took placebo, trastuzumab, and capecitabine; the median PFS was 7.8 months (95% CI, 7.5-9.6) and 5.6 months (95% CI, 4.2-7.1), respectively, (HR, 0.54; 95% CI, 0.42- 0.71; 

At 2 years, the OS rate was 44.9% in the tucatinib group and 26.6% in the comparator arm; the median OS was 21.9 months (95% CI, 18.3-31.0) and 17.4 months (95% CI, 13.6-19.9), respectively, (HR, 0.66; 95% CI, 0.50-0.88; 

 = .005). Among the patients with brain metastases, PFS at 1 year was 24.9% in the tucatinib-combination group and 0% in the placebo-combination group, and the median PFS was 7.6 months (95% CI, 6.2-9.5) and 5.4 months (95% CI, 4.1-5.7), respectively.

HER2CLIMB is the first completed randomized trial to include and show benefit in patients with HER2-positive breast cancer and brain metastases.

Novel Therapies in Late-Stage Development 

Margetuximab is being assessed in the phase 3 SOPHIA trial (NCT02492711), which is comparing this agent in combination with chemotherapy versus trastuzumab plus chemotherapy in patients with HER2-positive metastatic breast cancer previously treated with anti—HER2– targeted therapies. Margetuximab is a crystallizable fragment-engineered anti-HER2 monoclonal antibody that is similar to trastuzumab, targeting the same epitope and exerting similar antiproliferative effects but with enhanced immune activity against HER2-expressing tumor cells.

The second interim OS analysis, which was planned after 270 deaths (cutoff September 2019), showed a median OS of 21.6 months (95% CI, 18.86-24.05) for the margetuximab-containing regimen versus 19.8 months (95% CI, 17.54-22.28) for trastuzumab-based therapy plus chemotherapy, a finding that did not reach statistical significance (stratified log-rank 

 The final prespecified OS analysis is planned after 385 deaths and projected to occur in the second half of 2020.

However, exploratory analysis of patients carrying a specific genotype of CD16A, the CD16A 158F allele, had a larger OS benefit with margetuximab. In the second interim analysis, their median OS was prolonged by 4.3 months versus trastuzumab (23.7 vs 19.4 months, respectively; HR, 0.79; 95% CI, 0.61-1.04; nominal 

 = .087). Approximately 85% of participants in the SOPHIA trial had the CD16A 158F allele, which represents its prevalence in the general human population.

 In contrast, the patients who did not have the CD16A 158F allele (15%) had a better survival outcome with the trastuzumab combination.

On December 19, 2019, based on the SOPHIA data, margetuximab’s manufacturer, MacroGenics, announced it had submitted a biologics license application to the FDA.

 It previously received fast-track designation for margetuximab on January 23, 2018.

Neoadjuvant and First-Line Metastatic Settings

Pembrolizumab, a humanized, anti—PD-1 monoclonal antibody, is showing promise when added to chemotherapy in the neoadjuvant and first-line metastatic settings for women with TNBC or hormone receptor–positive/HER2-negative disease.

In February 2020, both the phase 2 adaptively randomized I-SPY2 trial (NCT01042379) and the phase 3 randomized KEYNOTE-522 trial (NCT03036488) reported positive results in the neoadjuvant setting,

Vol. 21/No. 10 | Oncology Live®

Scoring System Stratifies Risk of Heart Failure in Patients With Acute Leukemia

Primary Location of GEJ Tumors Affects Treatment

Tucatinib Approval Adds Impact to HER2+ Breast Cancer Paradigm

Chasing a Cure for GBM: Investigators Test Multiple Regimens in Novel Trial

Looking Forward to a New Wave of Breast Cancer Therapies

MRD in Acute Lymphoblastic Leukemia: Why, How, When, and Whom to Test?

Community Oncology Practices Offer Telehealth Tips

Oncology Clinical Trials Should Reflect Molecular Advances, Real-World Patients