Johns Hopkins Cancer Center

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.

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

Primary Location of GEJ Tumors Affects Treatment

) meeting.

“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.





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

).

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.”

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.



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 2013.4 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; 



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

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

Jean Wright, MD, director of the Breast Cancer Program, Department of Radiation Oncology and Molecular Radiation Sciences and associate professor of Radiation Oncology and Molecular Radiation Sciences at Johns Hopkins Medicine, discusses radiation considerations in breast cancer.

Radiation decisions in breast cancer are no longer viewed as a one-size-fits-all approach, says Wright. There is a lot of nuance, in terms of deciding the optimal fields that should be treated, the optimal dose and length of treatment, and whether patients really need radiation at all, adds Wright.

Additionally, it is important to raise awareness on the studies that are being conducted in this space. Although these trials are not available at every center, it is important to know whether they are available and to consider which patients are appropriate for them to help answer remaining questions in the field, concludes Wright.

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Jean Wright, MD, discusses radiation considerations in breast cancer.

Dr. Wright on Radiation Considerations in Breast Cancer

Additionally, it is important to raise awareness on the studies that are being conducted in this space. Although these trials are not available at every center, it is important to know whether they are available and to consider which patients are appropriate for them to helpanswer remaining questions in the field, concludes Wright.

Jean Wright, MD, discusses radiation considerations in breast cancer.

Nivolumab (Opdivo), when administered approximately 4 weeks prior to surgery in patients with Merkel cell carcinoma (MCC), was found to be tolerable and to induce pathological complete responses (pCRs) as well as radiographic tumor regressions in about half of treated patients, according to results from the phase 1/2 CheckMate-358 trial. 

"Neoadjuvant nivolumab therapy in high-risk resectable MCC mediated major pathologic and radiographic responses in approximately one half of patients, with significantly improved recurrence-free survival among responders," wrote the lead investigator, Suzanne L. Topalian, MD, of Johns Hopkins Medicine, and colleagues in the paper. "This treatment regimen seemed to be generally tolerable and should be further explored as a potentially beneficial adjunct to surgery in patients with MCC."

The study enrolled 39 patients with American Joint Committee on Cancer stage IIa-IV resectable MCC who received ≥1 nivolumab dose. Of these patients, 7.7% (n = 3) did not undergo surgery because of either tumor progression (n = 1) or adverse events (AEs; n = 2). Any-grade treatment-related AEs occurred in 46.2% of patients (n = 18), and grade 3 to 4 events were reported in 7.7% of patients (n = 3). No unexpected toxicities were observed.

Furthermore, among 36 patients who underwent surgery, 47.2% experienced a pCR (n = 17). Among 33 patients who underwent surgery and were radiographically evaluable, 54.5% (n = 18) experienced tumor reductions of ≥30%. At a median follow-up of 20.3 months, median RFS and overall survival (OS) had not yet been reached. Notably, investigators found that RFS significantly correlated with pCR and radiographic response at the time of surgery. Moreover, no patient with a pCR experienced tumor relapse during observation.

"In CheckMate-358, the efficacy of neoadjuvant anti—PD-1 did not correlate with baseline MCC viral status or PD-L1 expression," the authors wrote. "Also consistent with prior studies, Merkel cell polyomavirus (MCPyV)–positive tumors had low tumor mutational burden, suggesting that a limited number of strong viral antigens can serve as tumor rejection antigens in MCC and potentially in other virus-associated cancers. Multiplex markers may provide increased sensitivity and specificity for treatment outcomes."

In the multicenter, open-label, multicohort CheckMate-358 trial, investigators are evaluating the use of nivolumab monotherapy or nivolumab-based combination therapies in patients with virus-associated solid tumors in the recurrent/metastatic or neoadjuvant setting.

The primary end point of the study was the safety and tolerability of neoadjuvant nivolumab measured by treatment-related AEs (TRAEs) and surgical delays. Exploratory end points included pCR rate as assessed by investigators and an independent pathologist, radiographic response, RFS, OS, immunologic changes in blood and tumor, and association of tumor MCPyV status and PD-L1 expression with efficacy.

Between January 2016 and March 2019, 39 patients received nivolumab 240 mg intravenously on days 1 and 15, and then underwent surgery on day 29. Delayed administration of the second dose of the drug was considered to be acceptable up to day 22. In the neoadjuvant MCC cohort, eligible patients were ≥18 years of age with an ECOG performance score of 0 or 1. The median age of the participants was 68 years (range, 22-88 years).

Most patients had American Joint Committee on Cancer stage III disease at the time of study enrollment (66.7%). Among 35 patients with tumors evaluable for MCPyV status, 62.9% were found to be positive. Among the 27 patients who had quantifiable tumor cell PD-L1 expression, 25.9% (n = 7) had expression of ≥1%. A total of 36 out of 39 patients received both planned doses of nivolumab; 3 patients received only 1 dose.

Results showed that any-grade TRAEs were observed in 46.2% of all patients (n = 18/39). Only 7.7% of patients (n = 3) reported TRAEs that were grade 3 to 4 in severity. Additionally, no treatment-related deaths occurred. A total of 15.4% of patients (n = 6) experienced select TRAEs with potential immunologic cause; these included 2 grade 3 to 4 events (1 skin and 1 gastrointestinal). The most commonly observed any-grade select TRAE, were skin reactions (10.3%).

Of the 39 treated patients on the trial, only 3 did not undergo surgery. One patient discontinued following tumor progression, another withdrew consent because of grade 2 nausea that was not determined to be related to study treatment, and the last patient discontinued because of a treatment-related rash that was grade 3 in severity.

Among the 36 patients who underwent surgery, the median interval between the first dose of nivolumab and the procedure was 4.3 weeks (range, 2.9-15.0). One patient (2.6%) had surgery delayed >4 weeks because of treatment-related autoimmune colitis, with the procedure performed on day 105. Three patients (7.7%) had surgery delayed >7 days but ≤4 weeks due to administrative reasons; their surgeries were performed on days 37, 39, and 44, respectively. Six deaths occurred on study; 4 of them were because of disease progression and the other 2 were due to AEs unrelated to the study treatment, according to the investigators.

All 36 patients who underwent surgery were assessed for pCR via the study investigators; of these patients, 47.2% (n = 17) achieved a pCR. Definitive resection specimens obtained from 26 patients were examined as well. Results showed that 46.2% of patients (n = 12) experienced a pCR and 15.4% (n = 4) achieved a major pathologic response (MPR) to treatment; this yielded a pCR plus MPR rate of 61.5%.

Of those who underwent surgery, 33 were determined to be evaluable for radiographic response. Results showed that 87.9% of patients (n = 33) experienced a radiographic tumor reduction and 54.5% (n = 18) experienced a tumor reduction of ≥30%; specifically, the median change in tumor burden from baseline was —32.8%. Radiographic reduction of ≥30% was noted in patients whose tumors were MCPyV-positive or -negative, and PD-L1–positive or –negative. No trends were observed.

In the patients who underwent surgery, the median RFS was not reached. At 12 and 24 months postoperatively, RFS rates were 77.5% (95% CI, 58.4%-88.7%) and 68.5% (95% CI, 47.5%-82.6%), respectively. When comparing patients who achieved pCR versus those who did not via site review (n = 36), the RFS at 12 months was 100.0% compared with 59.6%, respectively, and 88.9% versus 52.2%, respectively, at 24 months (HR, 0.12; 95% CI, 0.01-0.93). Similarly, when comparing patients with pCR/MPR versus without pCR/MPR, the RFS at 12 months was 100.0% versus 50.0%, respectively; at 24 months, the rates were 88.9% versus 50.0%, respectively (HR, 0.09; 95% CI, 0.01-0.80).

Moreover, among the 33 radiographically evaluable patients, when comparing those with radiographic tumor reduction ≥30% versus those with reduction <30% or progression, the RFS at 12 months was 100.0% versus 56.5%, respectively, and 90.9% versus 48.5%, respectively, at 24 months (HR, 0.11; 95% CI, 0.01-0.87). The investigators noted that no substantial difference in RFS was identified between subgroups on the basis of tumor PD-L1 expression or MCPyV status.

Among the 39 treated patients, the median OS was not reached. At 12 and 24 months following the first dose of nivolumab, OS rates were 93.2% (95% CI, 75.5%-98.3%) and 79.4% (95% CI, 56.9%-91.0%), respectively. Among patients who underwent surgery and were considered evaluable for pathologic response (n = 36) or radiographic response (n = 33), 100.0% and 88.9% of patients with pCR via site review and all patients with radiographic tumor reduction of ≥30% were alive at 12 and 24 months, respectively.

The fact that no tumor relapses occurred after pCR/MPR suggested that standard adjuvant radiotherapy may not be required in responders, the investigators noted. However, relapses occurred among those without pCR/MPR, which suggests that a period of postoperative anti—PD-1 may be appropriate for some, they added.

"The possibility of tailoring the extent of surgery and/or administration of postsurgical therapy according to radiographic and pathologic response status after neoadjuvant anti—PD-1 should be examined in future MCC trials, which have the potential to be practice changing," the authors wrote.

Topalian SL, Bhatia S, Amin A, et al. Neoadjuvant nivolumab for patients with resectable Merkel cell carcinoma in the CheckMate 358 trial [published ahead of print on April 23, 2020]. 

Nivolumab, when administered approximately 4 weeks prior to surgery in patients with Merkel cell carcinoma, was found to be tolerable and to induce pathological complete responses and radiographic tumor regressions.

Neoadjuvant Nivolumab Shows Strong Clinical Activity in Merkel Cell Carcinoma

Jean Wright, MD, director of the Breast Cancer Program, Department of Radiation Oncology and Molecular Radiation Sciences and associate professor of Radiation Oncology and Molecular Radiation Sciences at Johns Hopkins Medicine, discusses proton versus photon radiotherapy in breast cancer.

Protons been available in radiation oncology for a few decades; however, they have recently garnered a lot of attention, says Wright. In the past, only 2 radiation oncology centers in the country had protons; now, over 20 of these centers exist and there are more to come, Wright adds.

In breast cancer, the main potential benefit of proton therapy is reducing the radiation exposure to the heart and lungs versus photon-based techniques, explains Wright. It is possible that proton therapy has somewhat different biological properties in the way that it interacts with tissues; however, most likely, it has a similar effect on the tissues as photon radiation, concludes Wright.

Jean Wright, MD, discusses proton versus photon radiotherapy in breast cancer.

Dr. Wright on Proton Versus Photon Radiotherapy in Breast Cancer

Available treatments for women with uterine serous carcinoma represent a significant unmet clinical need, said Amanda Nickles Fader, MD. For patients who overexpress HER2/neu, the addition of trastuzumab (Herceptin) to standard chemotherapy could provide a novel regimen with improved outcomes.

"Uterine serous carcinoma is a very rare subtype of uterine cancer, representing only about 5% to 10% of all uterine malignancies," explained Fader. "However, the disease accounts for about 40% of all uterine cancer deaths. It is an important group of women who we need to study to move the needle toward improved survival."

Updated findings from a phase II trial (NCT01367002)

, which were made available as part of the virtual platform for the 2020 SGO Annual Meeting, demonstrated a statistically significant improvement in survival with the addition of trastuzumab to carboplatin/paclitaxel versus chemotherapy alone for women with advanced or recurrent, HER2-positive uterine serous carcinoma.

The median overall survival (OS) was 29.6 months in the trastuzumab arm compared with 24.4 months in the chemotherapy-alone arm (HR, 0.58; 90% CI, 0.34-0.99; 

Notably, the OS benefit was extended among patients with newly diagnosed stage III/IV disease who received the combination of trastuzumab and chemotherapy up front. In these patients, the median OS had not yet been reached versus 25.4 months in those who received chemotherapy alone (HR, 0.49; 90% CI, 0.25-0.97; 

No significant improvement in OS was reported with the addition of trastuzumab to chemotherapy in patients with recurrent uterine serous carcinoma.

, Fader, an associate professor of gynecology and obstetrics, vice chair of Gynecologic Surgical Operations, director of the Kelly Gynecologic Oncology Service, director of the Center for Rare Gynecologic Cancers at The Johns Hopkins Hospital, and director of the F.J. Montz Fellowship Program in Gynecologic Oncology at Johns Hopkins Medicine, discussed the rationale for the phase II study and explained how the findings could open the door to other treatment options for women with uterine serous carcinoma.

OncLive: Why is HER2/neu a good target in uterine serous carcinoma?

 HER2/neu is a growth factor receptor (GFR) that is present in many human cells. [HER2/neu] is evident in many human cancers and is quite common in breast cancer, where it was first identified.

About 10% of women have HER2/neu overexpression in their tumors. As such, these patients are candidates for trastuzumab.

The addition of trastuzumab to [standard chemotherapy in] women whose tumors overexpress HER2 leads to improved outcomes and survival.

What is interesting is that in select uterine cancers, including uterine serous carcinoma, HER2/neu is also very commonly overexpressed. In fact, in uterine serous carcinoma, which is the tumor type that we studied in this randomized phase II trial, HER2/neu was overexpressed in up to 25% to 30% of cases. Even though uterine serous carcinoma is a rarer tumor subtype than breast cancer, HER2/neu is proportionally present in more cases.

We wanted to study the impact of adding trastuzumab, which is a monoclonal antibody, to standard chemotherapy in women with HER2-positive uterine serous carcinoma to determine whether it would improve outcomes.

Could you shed light on the current unmet need in this space?

While the incidence of many solid tumors, as well as mortality [from cancer] around the world, is either decreasing or plateauing, uterine cancer rates and mortality is on the rise. As such, it is important that we study uterine cancer to determine why this is happening. Why is the global phenomenon occurring? What types of uterine cancers are associated with the poorest prognosis? Uterine serous carcinoma represents one of those subtypes with historically poor prognosis.

As stated earlier, uterine serous carcinoma can overexpress the HER2/neu GFR in up to 25% to 30% of cases. When we look at outcomes in women with uterine serous carcinoma who are treated with standard therapies such as surgery followed by chemotherapy, individuals with early-stage disease can do OK, but even in that subgroup quite a few women experience recurrence, disease progression, and eventual death. For women with advanced-stage disease, that number is much higher.

What was the rationale for evaluating trastuzumab in combination with carboplatin/paclitaxel in this patient population?

Trastuzumab has been well studied in breast cancer and other types of HER2-positive tumors. We think that trastuzumab, and monoclonal antibodies in general, work better when they are used in concert with other therapies, including conventional cytotoxic chemotherapy.

From the phase III GOG-209 trial, we know that carboplatin/paclitaxel is 1 of the best chemotherapy regimens we have for the treatment of patients with advanced or recurrent uterine cancers. We were building upon that backbone [when designing this trial].

How was the trial designed, and what were the primary end points of the study?

This is a randomized, phase II trial that had a 2-arm design. One arm enrolled women with advanced-stage primary uterine serous carcinoma who had stage III or IV disease, were newly diagnosed, and [had] just had surgery. The other arm enrolled women with recurrent disease who were remote from having received primary treatment. All women had to have HER2 overexpression in their tumors.

Patients were randomized to receive standard chemotherapy with carboplatin/paclitaxel or carboplatin/paclitaxel plus trastuzumab. The primary end point was progression-free survival (PFS) with secondary endpoints for toxicity and OS. [The goal of the study was to] determine whether the addition of trastuzumab would improve outcomes for these women.

What were the preliminary results of the trial?

The preliminary results were published in the 

 a few of years ago and were previously presented at the 2017 SGO Annual Meeting. Those findings stated that the subgroup of women treated with chemotherapy plus trastuzumab had significantly improved PFS. Particularly, chemotherapy-naïve women with stage III/IV disease who received the combination up front did the best. However, we did see a statistically significant improvement in PFS in [the up front and recurrent settings].

When those data were presented, we did not have enough events to calculate a mature OS estimation. Therefore, OS was not reported in that first manuscript.

We also identified that there were no significant differences in toxicity between the 2 subgroups. This was important because the addition of any targeted therapy can increase toxicity for patients.

What did the updated survival data from this study show?

We were excited to see mature OS data. We recalculated the PFS after a median follow-up of almost 88 months. We showed that the PFS was still significantly improved in the cohort of patients who were treated with chemotherapy plus trastuzumab. Overall, this was almost a 5-month improvement in the overall cohort.

[As in the initial analysis], the biggest difference we saw [in outcomes] was in the women who were treated [with trastuzumab/chemotherapy] up front [versus in the recurrent setting]. The median PFS was 17.7 months in the trastuzumab group versus 9.3 months in the chemotherapy-alone group. That was interesting to see.

We also saw a significantly improved OS difference. The median OS was 29.6 months in the trastuzumab arm compared with 24.4 months in the chemotherapy-alone arm.

Again, the benefit was particularly striking in the subgroup of patients with stage III/IV disease who were treated upfront. In that subgroup, the median OS in the trastuzumab-treated arm has not yet been reached.

In 2019, the National Comprehensive Cancer Network guidelines for uterine cancer recognized the trastuzumab/chemotherapy as a preferred treatment regimen in this cohort of patients with HER2-overexpressing uterine serous carcinoma.

What did the OS analysis demonstrate in patients with recurrent disease?

Interestingly, we did not observe a survival benefit in patients with recurrent disease. We have to take this with a grain of salt because this cohort included 58 evaluable patients, which is not that many. That comes with the territory in rare tumor trials; you are going to have fewer patients that require smaller, more innovative, adaptive study designs in order to determine the optimal treatment.

We do have another large trial planned within the NRG Oncology Group that is currently under development. That trial will hopefully validate these results and allow us to further explore alternative HER2-directed therapies in addition to trastuzumab for patients with uterine serous carcinoma.

What might the OS disparity between women with newly diagnosed disease and women with recurrent disease be attributed to?

The reason we are seeing a more striking difference in the upfront setting compared with the recurrent setting is because most women with uterine serous carcinoma are treated up front with chemotherapy, most likely carboplatin/paclitaxel. The women who recur are already somewhat pretreated. It is possible that their tumors developed resistance to this cytotoxic regimen when they recur. We know that carboplatin/paclitaxel is not as effective in the recurrent setting as it is upfront.

It could be because the patient's tumor develops resistant cancer clones, that their bone marrow is more heavily pretreated, or that platinum-based resistance develops. There are many therapies that are postulated to be the reason that this occurs. However, it appears that the addition of trastuzumab in the recurrent setting may not be potent enough to overcome the potential resistance to cytotoxic chemotherapy.

Could this regimen be used in earlier lines of therapy?

Yes, we believe that these data do support using this regimen in the up-front setting to get the best result for patients with HER2-overexpressing uterine serous carcinoma.

Are there any remaining questions with this research? What next steps are planned?

There are many remaining research questions regarding this trial, and it seems like [the trial created] more questions than it answered. There are a variety of anti-HER2 therapies on the market now, many of which have already been explored in breast cancer, gastric cancer, and other tumor types. We are very excited to explore some of those in patients with uterine serous carcinoma.

I can't say much about the NRG trial other than [it is a trial in progress] that we are excited about. It is likely going to have 3 arms in which we will explore different anti-HER2 therapies in other HER2-positive uterine cancers beyond uterine serous carcinoma.

We're trying to [evaluate the benefit of anti-HER2 therapy] agnostic of tumor type because we think it is an important target to explore.

Amanda Nickles Fader, MD, discusses the rationale for a phase II study and explains how the findings could open the door to other treatment options for women with uterine serous carcinoma. 

Trastuzumab Combo Paves Way for Novel Regimens in HER2+ Uterine Serous Carcinoma

The addition of radium-223 dichloride (Xofigo) to sipuleucel-T (sip-T; Provenge) resulted in prolonged radiographic progression-free survival (PFS) in patients with bone-metastatic castration-resistant prostate cancer (CRPC), according to Emmanuel S. Antonarakis, MBBCh.

In a phase 2 study, patients with asymptomatic or minimally-symptomatic bone-predominant mCRPC were randomized 1:1 to receive treatment with sip-T alone or combined with 6 doses of radium-223. A total of 32 patients were enrolled to the trial, and the baseline characteristics in the single-agent and combination arms were matched with respect to age (median 70 vs 71 years, respectively), Gleason sum (69% vs 69%), prostate-specific antigen (PSA; median 33 ng/mL vs median 25 ng/mL), alkaline phosphatase (median 92 vs median 89 u/L) and ECOG scores (≥1: 19% vs 31%).

After a median follow up of 5.3 months, the median radiographic/clinical PFS was longer in the combination arm at 10.7 months versus 3.1 months in the single-agent arm (HR, 0.35; 95% CI, 0.15-0.81; 

 =.02). Outcomes were also better in the combination arm with respect to PSA responses. Specifically, those who received the sip-T/radium-223 experienced a PSA response of at 33% while those who received sip-T alone did not experience any PSA response (0%; P =.04). Outcomes regarding alkaline phosphatase responses also favored the combination, at 60% versus 7% (

 =.01). The time to radiographic PFS was a median of 9.3 months versus 3.1 months, with the combination versus the single agent, respectively (HR, 0.26; 

“Of course, this is a very small study and it is fraught with all the complications, nuances, and limitations of a randomized phase II study, but the level of activity was encouraging enough for us to begin to design further studies,” said Antonarakis. “We are now contemplating the design of a larger randomized phase II or even phase III study to test the combination of sip-T plus radium-223 compared with sip-T alone in a broader patient population with more follow-up.”

, Antonarakis, professor of oncology at Johns Hopkins Medicine, discussed the efficacy of radium-223 plus sip-T in patients with bone-metastatic CRPC and the next steps for research for this combination.

: Could you provide an overview of the trial examining sip-T and radium-223?

: At the 2020 Genitourinary Cancers Symposium, we presented a poster on a randomized phase II study of sip-T versus the combination of sip-T plus radium-223. I was delighted to present these data on behalf of the first author, my colleague Catherine H. Marshall, MD, MPH, of Johns Hopkins Medicine. In the study, we looked at a small population of about 30 patients with metastatic CRPC who were asymptomatic or minimally symptomatic were randomized to receive either standard sip-T alone or the combination of sip-T plus radium-223.

The combination group was a bit logistically challenging because they started off with the radium-223, which was given at an interval of once every 4 weeks; this is the FDA-approved dosage schedule. After 2 doses of radium-223, they then received sip-T, which was also given according to the dosage schedule of that drug at 3 doses every 2 weeks. Afterward, the patients received the third, fourth, fifth, and sixth dose of radium-223. The sip-T was essentially sandwiched in between the radium-223 injections.

The interesting thing about this study, which was a bit unanticipated, was that we saw evidence of synergy in the combination arm. The synergy was evidenced by PSA responses. We saw 5 out of 15 unconfirmed PSA responses; we did not see any PSA responses in the control group.

The more provocative part of this research was that we saw a prolongation of radiographic PFS. In the control arm, the radiographic PFS was about 3 months. In the combination arm, the radiographic PFS was over 9 months, and that was a statistical difference.

Will these agents be used in a triplet regimen in the future?

Yes, this brings up the question about whether or not radium-223 should be combined with a PD-1 or PD-L1 inhibitor. The [idea of a] triplet therapy is attractive although it could add logistical complexity. Could you use sip-T plus radium-223 plus pembrolizumab (Keytruda) or nivolumab (Opdivo)? This idea is theoretically attractive, but logistics need to be worked out. It probably would not be so easy to do; it would take some coordination.

Do you see this combination being utilized in other patient populations with prostate cancer?

Radium-223 is a bone-targeting alpha-particle, so this would not be for patients who do not have bone metastases; it would not be appropriate for the patients with nonmetastatic disease or rising PSA. Again, sip-T is also primarily approved for use in patients with metastatic CRPC.

One question is, “Could we give this combination in the nonmetastatic CRPC population to prevent bone metastases from occurring?” That would be a bit of a stretch because those patients do not have bone metastases, so radium-223 might not even [integrate] into the bone. You might be giving a drug, but that does not mean it would reach its intended target.

Marshall CH, Park JC, DeWeese TL, et al. Randomized phase II study of sipuleucel-T (SipT) with or without radium-223 (Ra223) in men with asymptomatic bone-metastatic castrate-resistant prostate cancer. 

. 2020;38(suppl 6; abstr 130). doi: 10.1200/JCO.2020.38.6_suppl.130

Emmanuel S. Antonarakis, MBBCh, discusses the efficacy of radium-223 plus sipuleucel-T in patients with bone-metastatic castration-resistant prostate cancer and the next steps for research for this combination.

Sipuleucel-T Plus Radium-223 Improves Clinical Outcomes in Bone-Metastatic CRPC

Amanda Nickles Fader, MD, an associate professor of Gynecology and Obstetrics, vice chair of Gynecologic Surgical Operations, director of the Kelly Gynecologic Oncology Service, director of the Center for Rare Gynecologic Cancers, at The Johns Hopkins Hospital, and director of the F.J. Montz Fellowship Program in Gynecologic Oncology at Johns Hopkins Medicine, discusses the utility of trastuzumab (Herceptin) plus chemotherapy in HER2-positive uterine serous carcinoma.  

Results from a randomized phase II clinical trial (NCT01367002) demonstrated an improvement in progression-free survival (PFS) and overall survival (OS) with the addition of trastuzumab to carboplatin/paclitaxel in patients with advanced or recurrent, HER2-positive uterine serous carcinoma. 

Findings revealed that patients with stage III/IV disease who received the triplet up front derived the greatest benefit in OS and PFS. At a median follow-up of 25.9 months, the median OS had not been reached compared with 25.4 months.  

 There are many theories as to why the patients who received the triplet up front tended to respond better than those who received it after recurrence, explains Fader. Women with recurrent disease had already been pretreated with carboplatin/paclitaxel, so they could have developed resistance to the regimen, says Fader. Moreover, data show that carboplatin/paclitaxel is not as effective in the recurrent setting compared with the upfront setting. 

While additional research is needed, these findings suggest that the addition of trastuzumab is not potent enough to overcome potential resistance to cytotoxic chemotherapy, concludes Fader.

Amanda Nickles Fader, MD, discusses the utility of trastuzumab plus chemotherapy in HER2-positive uterine serous carcinoma.

Dr. Fader on Trastuzumab/Chemo in HER2+ Uterine Serous Carcinoma

Amanda Nickles Fader, MD, an associate professor of Gynecology and Obstetrics, vice chair of Gynecologic Surgical Operations, director of the Kelly Gynecologic Oncology Service, director of the Center for Rare Gynecologic Cancers, at The Johns Hopkins Hospital, and director of the F.J. Montz Fellowship Program in Gynecologic Oncology at Johns Hopkins Medicine, discusses the rationale for utilizing HER2/neu as a target in uterine serous carcinoma.

As in breast cancer, HER2/neu is commonly overexpressed in select uterine cancers including uterine serous carcinoma, says Fader.

Though uterine serous carcinoma is a rare subtype of uterine cancer, a randomized phase II trial (NCT01367002) showed that up to 30% of the study population had HER2/neu overexpression, says Fader.

The study examined the efficacy of adding trastuzumab (Herceptin) to carboplatin/paclitaxel in patients with advanced or recurrent uterine serous carcinoma that overexpresses HER2/neu.

Findings from the study demonstrated that the addition of trastuzumab to chemotherapy improved progression-free survival and overall survival for patients compared with chemotherapy alone.

Amanda Nickles Fader, MD, discusses the rationale for utilizing HER2/neu as a target in uterine serous carcinoma.

Johns Hopkins Cancer Center

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Sipuleucel-T Plus Radium-223 Improves Clinical Outcomes in Bone-Metastatic CRPC

Dr. Fader on Trastuzumab/Chemo in HER2+ Uterine Serous Carcinoma

Dr. Fader on the Rationale for Targeting HER2/neu in Uterine Serous Carcinoma