2021 Research Round Up: Brain Tumors and Gastrointestinal Cancers

September 30, 2021
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In today’s episode, Cancer.Net Associate Editors discuss new research in brain tumors and gastrointestinal cancers presented at the 2021 ASCO Annual Meeting, held virtually June 4-8.  First, Dr. Glenn Lesser will discuss new research in 2 types of brain tumors, craniopharyngioma and glioblastoma. Next, Dr. Jeffrey Meyerhardt will discuss new research in esophageal and colorectal cancer. 



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The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. Guests on this podcast express their own opinions, experience, and conclusions. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement. Cancer research discussed in this podcast is ongoing, so the data described here may change as research progresses.

In the Research Round Up series, members of the Cancer.Net Editorial Board discuss the most exciting and practice-changing research in their field and explain what it means for people with cancer. In today’s episode, Cancer.Net Associate Editors discuss new research in brain tumors and gastrointestinal cancers presented at the 2021 ASCO Annual Meeting, held virtually June 4-8.

First, Dr. Glenn Lesser will discuss new research in 2 types of brain tumors, craniopharyngioma and glioblastoma.

Dr. Lesser is the Louise McMichael Miracle Professor and Associate Chief in the section on Hematology and Oncology in the Department of Internal Medicine at Wake Forest University, and is the Director of Medical Neuro-Oncology at the Atrium Health Wake Forest Baptist Comprehensive Cancer Center. He is also the Cancer.Net Associate Editor for central nervous system tumors.

View Dr. Lesser’s disclosures at Cancer.Net.

Dr. Lesser: Hello. My name is Glenn Lesser, and I'm a professor of medical oncology and the Director of Medical Neuro-oncology at the Wake Forest Baptist Comprehensive Cancer Center in Winston-Salem, North Carolina. I'm also the editor of the brain tumor section for ASCO's Cancer.Net. And today, I would like to briefly discuss 2 clinically relevant research studies involving patients with brain tumors that were presented at this year's ASCO's Virtual Scientific Program. I have no disclosures or relationships relevant to the second abstract I'll be discussing today. But by way of full disclosure, I have enrolled patients and I'm a co-investigator on the first study I'll describe.

As an introduction to those listeners not familiar with the current treatment options for patients with brain tumors, it's important to remember that patients with primary tumors of the brain have not seen the recent rapid advances in effective treatment strategies that patients with other malignancies have experienced. Thus, those of us who treat these patients really actively await the research results, which are presented and highlighted annually in several of our key national meetings, including ASCO, or the American Society of Clinical Oncology, Annual Meeting, which was, again, held virtually this year in light of the pandemic. I have selected several abstracts whose results, I believe, have immediate clinical relevance and can be used to modify our current standard of care therapies for the subgroups studied.

First abstract of interest was the presentation by Dr. Brastianos, who is the principal investigator of the Alliance A071601 study, which is a phase II trial of BRAF/MEK inhibition in patients with a tumor called a newly diagnosed papillary craniopharyngioma. A craniopharyngioma's a very uncommon tumor that can occur in both adults and children. And it typically arises in the region of the optic chiasm, a very important structure related to vision, and the pituitary gland, which is responsible for the production of a variety of hormones or compounds which stimulate other glands in the body to produce key hormones. These tumors often have cystic and solid components. And, as they grow, they compress the optic chiasm and the pituitary gland to produce symptoms, including loss of bilateral peripheral vision. Standard therapy for these lesions has included 1 or more surgeries and treatment with radiation therapy, including both external beam radiation and stereotactic radiosurgery. 

Although these tumors are generally not felt to be malignant, their continued growth and compression of surrounding structures leads to significant morbidity and symptoms, which dramatically worsen the quality of life of patients who have them and which, rarely, can be fatal. In adults, the most common variant of these tumors is called a papillary craniopharyngioma. And Dr. Brastianos and others have previously shown that these papillary tumors almost always have a driver mutation known as a BRAF V600E mutation. Now, a driver mutation is a specific mutation in the DNA, the instruction manual of the tumor cells, that gives those cells a selective growth advantage and, thus, promotes the cancer's development and spread.

In contrast, passenger mutations are mutations that may be present in the cancer cells but don't directly promote their growth or survival. The tumors that contain these driver mutations have the potential to be selectively targeted and effectively controlled by drugs which have been developed against that particular characteristic mutation. So this study builds on earlier case reports showing fairly dramatic regressions of these tumors with the use of agents that have been developed to target the BRAF V600E mutation, which is a characteristic of the more common aggressive melanoma skin cancer.

Over the last decade, 3 sets of drugs have been developed and brought to market, which have great efficacy in killing cells with this specific mutation. These drugs include a BRAF inhibitor, which targets the BRAF gene, and a MEK inhibitor, which essentially blocks an escape mechanism that the tumor cells try to use when confronted by the BRAF inhibitor. This is the only example I know of in oncology where giving 2 drugs leads to actually fewer side effects than if only the BRAF inhibitor was given by itself. But this trial had 2 cohorts of patients, 1 where it involves 16 patients with newly diagnosed craniopharyngiomas and a second arm enrolled patients whose craniopharyngioma recurred after radiation plus or minus surgery. The drugs used in this trial were vemurafenib and cobimetinib. And the goal was to give patients at least 4 months of this oral combination therapy. Dr. Brastianos presented the results of the newly diagnosed cohort, or Cohort A, at this year's ASCO. Remarkably, 15 of the 16 treated patients, or 94% of those treated, had a volumetric response, meaning a significant shrinkage of the tumor based on a central, independent review of their brain MRI scans. In fact, the only patient who didn't respond only received 2 days of treatment before they had to stop the medications due to some drug-related toxicity. So not only did these patients respond, but the median reduction in their tumor size was about 91%. And, furthermore, these responses appeared to last a long time, with only 1 patient recurring at the time the data was analyzed for ASCO.

The estimated overall survival of the patients on Cohort A at 2 years was 100%, while their estimated progression-free survival at 2 years was 93%. Phenomenal results. These drugs do have a variety of side effects which can occur to someone commonly and may lead to drug discontinuation in as many as a third of patients, although not nearly that many discontinue these drugs due to toxicity on this particular trial. These results, I believe, really establish combination-drug therapy with BRAF and MEK inhibitors as an effective standard-of-care option for selected patients with these newly diagnosed papillary craniopharyngiomas that contain a BRAF mutation. We're anxiously awaiting both longer-term follow-up of this study to determine the durability of these responses as well as the presentation of the results of Cohort B, which treated patients with recurrent disease after radiation.

The second study I'd like to highlight was presented in the oral poster session by Dr. Domenech on behalf of her colleagues in the GEINO, the Spanish Neuro-oncology Cooperative Group Trial 14-01. She presented the long-term results of this prospective trial, which randomized patients with newly diagnosed glioblastoma to 6 cycles of adjuvant temozolomide versus continuing the temozolomide for up to 12 monthly cycles of therapy. But since the publication of Dr. Roger Stupp's landmark trial in the New England Journal of Medicine in 2005, the standard therapeutic approach around the world for patients with newly diagnosed glioblastoma has included concurrent radiation and temozolomide chemotherapy for about 6 weeks, so both given at the same time, followed by monthly adjuvant temozolomide for 6 to 12 months with the drug being given for 5 days in a row each month. We have learned much about the molecular subgroups of glioblastoma and the characteristic molecular findings that may predict a given patient's responsiveness to this therapy since this publication. To date, however, clinical trials have not convincingly determined whether the benefits seen by adding chemotherapy to radiation stem from the concurrent phase of therapy, the adjuvant or post-radiation phase of therapy, or the entirety of the concurrent followed by adjuvant temozolomide. Furthermore, although the initial pivotal study described only 6 months of adjuvant monthly temozolomide to patients, many practitioners have felt that, frankly, more is better, particularly with a well-tolerated drug like temozolomide. And many physicians routinely give up to 12, or even more, monthly cycles of the drug.

As a result, many clinical trials over the last 15 years have allowed investigators to treat to the duration of their choice. Those in favor of this approach believe that more anti-cancer therapy is better, while those who limit temozolomide to only 6 months cite the increased cost, the increased rate of side effects or toxicities, as well as the mutational stress that prolonged alkylating therapy might put on tumors, which can theoretically lead to a more resistant tumor at the time of recurrence.

GEINO 14-01, which enrolled 159 patients, is the only large, prospective attempt to randomize patients to 6 or 12 cycles of adjuvant temozolomide therapy. The presented findings clearly show that adding 6 cycles of temozolomide after the first 6 adjuvant cycles produced no additional benefit in overall survival. With a median follow-up of about 20 months, there was no difference in the percent of patients surviving at 2 years between the arms, nor was there a difference in the percent of long-term survivors defined as survival of at least 30 months from the diagnosis. Patients in the extended therapy arm did experience an increase in hematologic or blood count toxicities in addition to the added cost and additional doctor visits the extended treatment generated. The authors, somewhat respectfully, concluded that the results of this trial should be corroborated in a prospective phase III trial. However, it's unlikely that such a trial will ever be mounted. And these results are likely going to be the best data we have to guide our approach in the future. Although more data will be provided in the full publication of the results of this trial, the presented results indicate that in most patients with newly diagnosed glioblastoma, the standard of care should involve a maximum of 6 months of adjuvant temozolomide chemotherapy.

In conclusion, the investigative teams behind both of these studies I've just described are to be commended on their efforts, which provide guidance on how best to care for patients with craniopharyngiomas and newly diagnosed glioblastoma. These studies are also outstanding examples of why well-done clinical trials that carefully test and evaluate the beneficial effects, as well as the toxicities of new cancer treatments, are critical to our goal of optimizing the treatment of our patients with cancer. Thanks so much for listening today.

ASCO: Thank you Dr. Lesser.

Next, Dr. Jeffrey Meyerhardt will discuss new research in esophageal and colorectal cancer. Dr. Meyerhardt is the Douglas Gray Woodruff Chair in Colorectal Cancer Research, Clinical Director and Senior Physician at the Gastrointestinal Cancer Center at the Dana-Farber Cancer Institute, Deputy Clinical Research Officer at the Dana-Farber Cancer Institute, and Professor of Medicine at Harvard Medical School. He is also the Cancer.Net Associate Editor for gastrointestinal cancers.

View Dr. Meyerhardt’s disclosures at Cancer.Net.

Dr. Meyerhardt: My name is Jeffrey Meyerhardt. I'm a gastrointestinal oncologist at the Dana-Farber Cancer Institute in Boston, Massachusetts. I'm an Associate Editor of Cancer.Net, ASCO's patient information site. Today, I'm going to discuss research on gastrointestinal cancers that were presented at the 2021 ASCO Annual Meeting. I do not have any relationships to disclose related to these studies. I'm going to focus on some studies related to esophageal and gastric cancer as well as studies in colorectal cancer. For esophageal and gastric cancer, we saw a variety of studies for immunotherapy in different settings. I think some important background information in considering esophageal and gastric cancer is that there are similarities and differences between the 2 cancers. Esophageal cancers can be squamous cell or adenocarcinomas. Gastric cancers that'll be discussed here are adenocarcinomas. In between the esophagus and the stomach is the gastroesophageal junction, one of the cancers with increasing incidence overall. They are also typically adenocarcinomas. For non-metastatic disease, the location of disease is treated differently. But for metastatic disease, most standard chemotherapy trials lump all of these sites together and have mixed squamous cell carcinoma and adenocarcinoma of the esophagus together. However, with immunotherapy, there are differences emerging to rethink this concept. While there are challenges in finding reliable markers to determine efficacy of immunotherapy in all cancer types, 2 markers have emerged relevant to gastro and esophageal cancer, PD-L1, or the combined positive score, and tumor mutational burden, which signals immunogenicity of a cancer.

While there were a wealth of studies of immunotherapy, 1 study that was noteworthy at this year's ASCO was CheckMate 648. The CheckMate studies have focused on the PD-1 inhibitor nivolumab. Checkmate-648 was a randomized study comparing unresectable advanced, recurrent, or metastatic esophageal squamous cell carcinoma, previously untreated, randomized to 1 of 3 treatments. Nivolumab with 2 standard chemotherapies, 5-FU and cisplatinum, versus nivolumab and ipilimumab, a no-chemotherapy, just-immunotherapy arm, or chemotherapy only with 5-FU and cisplatinum. Nivolumab and ipilimumab was superior to chemotherapy only alone for overall survival and progression-free survival, particularly in patients with PD-L1 scores greater than or equal to 1%. Of note, there are some patients that don't benefit early on, which has been seen in other studies comparing chemotherapy to immunotherapy. There was similar overall and progression-free survival for immunotherapy alone compared to nivolumab, 1 immunotherapy with chemotherapy. More immunotherapy-related toxicities were seen with the combined immunotherapy arm, but more GI toxicities were seen with nivolumab plus chemotherapy. Overall, this study provides a non-chemotherapy option for patients as initial therapy for esophageal squamous cell carcinoma.

Turning to colorectal cancers, there are 2 studies that I wanted to highlight. The first study was the DESTINY-CRC01 study. This was a phase II study of trastuzumab deruxtecan, T-DXd, which is an antibody-drug conjugate of humanized anti-HER2 antibody bound to a chemotherapy, a topoisomerase I inhibitor. A phase II study means all patients got the same drug. The study focused on a limited population of metastatic colorectal cancer patients who overexpressed a protein called HER2. As with other cancer types, it is important to have molecular testing of colorectal cancer that may determine certain treatment options for patients. The several molecular features in colorectal cancer that are proven most important in treatment decisions include microsatellite instability, a feature that predicts effectiveness of immunotherapy; KRAS and RAS mutations that the lack of efficacy of a class of drugs called epidermal growth factor inhibitors like cetuximab and panitumumab; BRAF, which has specific drugs that target this mutation; and HER2. HER2 overexpression was first targeted in breast cancer. And there are also overexpressing stomach cancers that benefit from HER2-directed therapy. Approximately 3 to 4 percent of metastatic colorectal cancers overexpressed HER2. The DESTINY trial focused on patients who had progressed on at least 2 prior lines of therapy. So a heavily-pretreated population, 45% of patients with significant overexpression had a response to therapy. And 83% had disease control with a median of greater than half a year.

Interestingly, the drug was meaningfully active in patients who had prior HER2-directed therapy. While the drug had some expected toxicities, 9% of patients also experienced something called interstitial lung disease, inflammation of the lungs, which would need to be monitored. However, this drug does show promise in the armamentarium of targeted therapies for metastatic colorectal cancer.

The last trial I wanted to focus on is FOCUS4. This trial compared maintenance therapy with capecitabine, an oral form of 5-FU, versus active monitoring for patients with metastatic colorectal cancer. This is a topic that I found so important over the years and have not received as much attention I think it deserves. Fortunately, there are multiple trials in this field. And I think it's important to highlight them when new ones result. The basic principle is that when treating colorectal cancer these days with combinations of different chemotherapies, it is not uncommon to have a patient experience good disease control for prolonged periods of time. Initially, trials for metastatic colorectal cancer decades ago just continued therapy for as long as the disease was controlled for undue toxicities. However, with more effective therapies, there also have been increasing cumulative toxicities that catch up with patients over time. And there has been interest in continuing and considering changing at some point from multiple combination regimens to either maintenance therapy, some people call “chemotherapy light,” or giving a full holiday off therapy. And there have been multiple trials over the years that have looked at these strategies. What is clear from those trials is that patients don't do better just staying on combination therapy. However, maintenance therapy is still chemotherapy. And a key to understand, is that even necessary? Are patients compromising outcomes by taking periods off of treatment?

FOCUS4 was a trial in the U.K. that randomized patients with metastatic colorectal cancer whose disease was controlled after 16 weeks of first-line combination therapy. They received either capecitabine with a usual 2 weeks of pills followed by 1-week break--or active monitoring with scans every 8 weeks. While the time till this tumor grew was shorter fully off of chemotherapy, the overall survival was not different between the 2 arms. This lack of overall survival has proven out in other trials. It was recently seen in a meta-analysis published in the Journal of the American Medical Association of Oncology recently. Active monitoring may not be the best option for every patient. But I think it is an important discussion between patients and their oncologists to balance quality of life and continued disease control.

Thank you for listening to this brief summary of new research in gastrointestinal cancers from the 2021 ASCO Annual Meeting.

ASCO: Thank you, Dr. Meyerhardt. You can find more research from recent scientific meetings at www.cancer.net. And if this podcast was useful, please take a minute to subscribe, rate, and review the show wherever you listen to podcasts.

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