While some people face barriers to colorectal cancer screening, at-home fecal immunochemical tests (FIT) can help. For this episode, we heard from Diann Boyd, BSN, RN, OCN, a nurse navigator at the Penn Medicine Abramson Cancer Center. Boyd specializes in GI oncology and has a passion for ensuring that everyone completes the screening.

Boyd recently presented at the ONS Annual Congress about how to increase screening rates in Black and underserved communities. In doing so, the medical community has the opportunity to potentially catch cancers in earlier stages and improve patient outcomes.

Podcasts

While some people face barriers to colorectal cancer screening, at-home fecal immunochemical tests (FIT) can help. 

Overcome Screening Barriers in CRC

Offering patients with metastatic gastroesophageal tumors a more personalized and adaptable treatment approach using monoclonal antibodies matched to genetic profiles in combination with chemotherapy may result in higher rates of survival compared with historic controls, according to the results from the phase 2 PANGEA study (NCT02213289).

A 1-year overall survival (OS) rate of 66% (95% CI, 54%-76%) was reported in the 68 patients who comprised the intent-to-treat population, meeting the primary efficacy end point of the trial (one-sided, 

 = .0024). The median OS was 15.7 months (95% CI, 13.4-17.7) in these patients; the median time to treatment failure (TTF) was 13.6 months (95% CI, 11.3-15.8). Moreover, the 2-year OS rate in this population was 29%, the 3-year rate was 14%, and the 5-year rate was 11%. The 1-year OS rate in the non-ITT population (n = 12) was 33.3%, with a 2-year rate of 8% and a median OS of 9.0 months (95% CI, 4.6-20.3).

“At first there was only chemotherapy for HER2-negative tumors in the first-line setting, but now other targeted therapies are coming out, including anti–PD-1, anti-FGFR2 and anti-claudin,” Daniel Catenacci, MD, an associate professor of medicine and director of the Gastrointestinal Oncology Program at the University of Chicago, as well as the assistant director of Translational Research in the Comprehensive Cancer Center, stated in a press release.

 “How does a physician decide which treatment to prescribe when a patient might be eligible for multiple options given known overlap in a tumor of the predictive biomarkers for each of these therapies? This study shows that using an algorithm such as ours could help with that prioritization to direct optimal care and may potentially lead to better outcomes for patients.”

Although advances made in genetic testing have created opportunities to better inform treatment strategies, heterogeneity can cause difficulties in identifying the best targeted therapy for each individual patient. To address this unmet need, investigators developed a new treatment strategy for this patient population.

The goal of the study was to optimize survival in patients through the use of sequential doublet chemotherapy in combination with an individually matched monoclonal antibody at baseline diagnosis, then again serially over up to 3 lines of therapy.

To account for the potential of several therapeutic approaches because of concurrent molecular alterations in a given patient’s sample, a predefined prioritized biomarker and treatment assignment algorithm was applied at each line of therapy. Investigators hypothesized that the individualized treatment approach, which comprised 8 biological subsets with 6 matched monoclonal antibodies, could address formidable hurdles presented by molecular heterogeneity, resulted in improved outcomes over historical controls.

From June 2015 through May 2019, investigators enrolled 80 eligible patients. The median age of the study population was 61 years (range 28-81), the majority of whom were male (80%; n = 64). Of the 80 total patients enrolled to the study, 43% (n = 34) had esophageal tumors and 30% (n = 24) and gastroesophageal junction tumors. Seventy-four percent of patients (n = 59) had signet ring cells absent.

In the total patient population, baseline metastases were noted in the lymph nodes (63%; n = 50), peritoneum (38%; n = 30), liver (36%; n = 29), lung (8%; n = 6), bone (5%; n = 4), adrenal gland (4%; n = 3), or another location (1%; n = 1). Additionally, 40 patients (50%) had a performance status of 0, 33 (41%) had a status of 1, and 7 (9%) had a status of 2.

The biomarker prioritization and treatment assignment algorithm utilized by investigators placed patients in 1 or 8 treatment arms based on genetic testing results:

PD-L1 IHC combined positivity score of over 10, who were microsatellite instability–high, had a tumor mutation burden less than 15 mutations/mb, and/or Epstein–Barr virus–positive received anti-PD-1 nivolumab (Opdivo)

-amplified received trastuzumab (Herceptin)

-amplified received anti-MET (no agents available)

In the ITT population, all patients received a first-line therapy, 87% (n = 53/61) went on to receive a second-line therapy, and 42% (n = 60) progressed and received a third-line therapy. Those who progressed on all 3 lines of therapy in the PANGEA study went on to receive a fourth line of therapy (12%; n = 8). No fifth-line or later therapies reported.

During the first cycle of treatment, 41.2% (n = 28) of patients in the ITT population received modified oxaliplatin, levofolinate, 5-fluorouracil (5-FU), and bevacizumab (Avastin; mFOLFOX7) without 5-FU bolus while the remainder were given leucovorin, 5-FU, and oxaliplatin (mFOLFOX6) with 5-FU bolus. Through the duration of their treatment, 20.6% of patients received palliative radiotherapy to the primary tumor, all of which were proximal esophagogastric junction tumors (28%; n = 14/50).

Additional findings indicated that 79% (n = 54) of patients in the ITT population and 83% (n = 10) of those in the non-ITT population had measurable disease. Four patients (7.4%) in the ITT population had a complete response (CR), 36 (66.7%) had a partial response (PR), 13 (24.1%) had stable disease, and 1 (1.9%) had progressive disease. No patients (0%) within the non-ITT population experienced a CR. However, 4 (40%) patients in the non-ITT population achieved a PR, 3 (30%) had stable disease, and 3 (30%) had progressive disease.

No diagnostic or treatment-related deaths were reported on the study, and only 1 patient required overnight monitoring due to abdominal pain following a baseline ultrasound-guided biopsy of a peritoneal nodule. The most frequent grade 3 or higher hematologic treatment-related adverse effects (TRAEs) reported across all lines of therapy included neutropenia (18%; n = 12), anemia (16%; n = 11), and white blood cell decrease (9%; n = 6). Other grade 3 or higher TRAEs included fatigue (13%; n = 9), as well as nausea and vomiting (9%; n = 6).

In the first-line setting, the most common high-grade hematologic toxicities included anemia (10%; n = 7), neutropenia (9%; n = 6), and thrombocytopenia (6%; n = 4), with other TRAEs including nausea and vomiting (6%; n = 4) and fatigue (4%; n = 3). Patients in the second-line setting experienced some neutropenia (8%; n = 4), fatigue (6%; n = 3) and diarrhea (6%; n = 3). Lastly, in the third-line setting, the most common TRAE was fatigue (16%; n = 4) with hematologic TRAEs including neutropenia (12%; n = 3), anemia (12%; n = 3), and thrombocytopenia (12%; n = 3).

“During the study, we learned that not only is it common to see genetic heterogeneity between the primary and metastatic tumor — about 40% of the time, the metastatic tumor differed substantially from the primary tumor — but also that about 45 or 50% of the time, patients had their therapies changed as the disease evolved,” Catenacci added. “By going after the metastatic site at the start of treatment, reassessing the tumor if and when there was clinical disease progression, and using the algorithm to prioritize therapy each time, the survival outcome was substantially higher than would be expected using standard therapies.”

Catenacci DVT, Moya S, Lommnicki S, et al. Personalized antibodies for gastroesophageal adenocarcinoma (PANGEA): a phase II study evaluating an individualized treatment strategy for metastatic disease. 

. Published online November 20, 2020. doi:10.1158/2159-8290.CD-20-1408

Dynamic, personalized treatment approach may improve outcomes in gastroesophageal cancers. News Release. University of Chicago Medicine. January 21, 2021. Accessed January 22, 2021. 

This article was originally published on OncLive as, "

Personalized, Adaptable Treatment Strategies May Improve Survival in Metastatic Gastroesophageal Cancer

Articles

Personalized and adaptable treatment regimens seem to be the way forward in treating gastroesophageal cancer.

Individualized Treatment May Improve Outcomes in Gastroesophageal Cancer

The Food and Drug Administration (FDA) granted an accelerated approval to pembrolizumab (Keytruda) plus trastuzumab, fluoropyrimidine- and platinum-containing chemotherapy for the frontline treatment of patients with locally advanced unresectable or metastatic HER2-positive gastric or gastroesophageal junction (GEJ) adenocarcinoma.

The approval was based on interim findings from the ongoing multicenter, randomized, double-blind, placebo-controlled KEYNOTE-811 trial. The trial included 264 patients with HER2-positive advanced gastric or GEJ adenocarcinoma who had not previously received systemic therapy for metastatic disease. Half the patients received 200 mg of pembrolizumab every 3 weeks in combination with trastuzumab and either fluorouracil plus cisplatin or capecitabine plus oxaliplatin.

The overall response rate, as assessed by a blinded independent review committee, was 74% in the pembrolizumab arm, and 52% in the placebo arm. Average duration of response was 10.6 months (range 1.1 months to 16.5 months) for the immunotherapy agent, compared with 9.5 months (range, 1.4 months to 15.4 months) for the placebo arm.

Researchers said that the adverse event profile observed in KEYNOTE-811 is consistent with the known safety profile of the drug.

The recommended dosing for this patient population is 200 mg of pembrolizumab every 3 weeks or 400 mg every 6 weeks.

FDA. FDA grants accelerated approval to pembrolizumab for HER2-postive gastric cancer. May 5, 2021. 

https://www.fda.gov/drugs/drug-approvals-and-databases/fda-grants-accelerated-approval-pembrolizumab-her2-positive-gastric-cancer?utm_medium=email&utm_source=govdelivery

The FDA granted an accelerated approval to pembrolizumab plus trastuzumab, fluoropyrimidine- and platinum-containing chemotherapy for the frontline treatment of patients with locally advanced unresectable or metastatic HER2-positive gastric or gastroesophageal junction adenocarcinoma. 

FDA Approves Frontline Pembrolizumab for HER2+ Gastric, GEJ Cancer

Certain factors such as being younger in age, having more comorbidities and having had a higher number of prior cancer treatments all contribute to higher levels of sleep disturbance in patients with gastrointestinal (GI) cancers, according to Yufen Lin MSN, RN, of the Duke University School of Nursing.

At this year’s Oncology Nursing Society’s Annual Congress, Lin explained that chemotherapy is a common primary treatment for various GI cancers, and sleep disturbance is a frequent and distressing symptom that patients experience as a result of treatment. These disturbances often lead to a decrease in patients’ functional status, treatment responses and quality of life (QOL).

Previous studies have focused on various aspects of sleep disturbance and its impact on patients with cancer, including risk factors, but few have looked at sleep characteristics or combined all of this information into one study.

“Most studies have focused on patients with breast cancer, lung cancer and prostate cancer. Less is known about sleep disturbance in patients with GI cancer,” Lin said in her presentation.

Therefore, Lin and her team took a “person-centered approach” to identify the subsets of patients with GI cancers with distinct sleep disturbance profiles and evaluate the differences among these subgroups in demographic, clinical, and sleep characteristics, co-occurring symptoms, as well as QOL outcomes.

To do so, 405 participants were asked to complete questionnaires 6 times over 2 cycles of chemotherapy. Levels of sleep disturbance were evaluated using the General Sleep Disturbance Scale (GSDS). This was also the first study to use latent profile analysis (LPA) to identify subgroups of patients with GI cancers with distinct sleep disturbance profiles.

In this analysis, researchers evaluated the differences in demographic, clinical, and sleep characteristics, co-occurring symptoms, and QOL outcomes among the subgroups, using parametric and non-parametric analyses.

In total, 3 different sleep disturbance classes were identified across the six assessments: Low (35.8%), High (48.6%), and Very High (15.6%). When compared to patients in the Low class, those in the High and Very High classes were significantly younger, had more comorbidities, had a higher number of prior cancer treatments, were less likely to be married or partnered, and were less likely to exercise on a regular basis.

Compared to the Low class, patients in the Very High sleep disturbance class were less likely to be employed and had a diagnosis of back pain, while patients in the Very High class were more likely to report having childcare responsibilities.

Among all 3 sleep disturbance classes, significant differences that gradually increased in each group were found for comorbidity burden, occurrence of depression, and the GSDS subscale and total scores. Additionally, patients in the Very High class reported higher levels of anxiety, depressive symptoms, morning and evening fatigue, and pain, and lower levels of attentional function and QOL scores at enrollment.

According to Lin, these findings provide new insights into the risk factors and co-occurring symptoms that could lead to higher levels of sleep disturbance in patients with GI cancers, which can, in turn, help health care providers identify and address these problems before they start.

“Clinicians can use common and distinct factors to identify high-risk patients with sleep disturbance, and also initiate appropriate sleep hygiene education and referrals,” Lin said.

Additionally, these findings highlighted the need for further research into the underlying mechanisms that contribute to the development of sleep disturbance, and could prompt providers to develop personalized symptom management interventions to reduce symptom burden and improve QOL.

Yufen L., Bailey D., Docherty S. Distinct Sleep Disturbance Profiles in Patients with Gastrointestinal Cancers Receiving Chemotherapy. Presented at: Oncology Nursing Society 46th Annual Congress; April 20, 22, 27, and 29, 2021. Late-Breaking Abstract #5.

Factors such as being younger in age, having more comorbidities, and more prior cancer treatments all contribute to higher levels of sleep disturbance in patients with gastrointestinal cancers.

Factors Correspond With Higher Levels of Sleep Disturbance in Patients with GI Cancers

With immunotherapy options expanding for patients with a range of gastrointestinal cancers to include combination strategies with chemotherapy, their use in the treatment course should come sooner rather than later for those with high PD-L1 expression, explained Aravind R. Sanjeevaiah, MD.

“We should be looking at PD-L status upfront, just like we already knew, but we should also be looking at PD-L1, and if [the combined positive score is (CPS)] greater than 5, we should introduce immunotherapy sooner rather than later,” Sanjeevaiah said. “Previously we used to order the PD-L1 [testing] later because it was only approved in the third-line setting, but the paradigm has [since] shifted.”

In January 2021, nivolumab (Opdivo) was granted priority review status for use as an adjuvant treatment for patients with resected esophageal or gastroesophageal junction (GEJ) cancer following neoadjuvant chemoradiation. The FDA will make a decision on the supplemental biologics license application (sBLA) by May 20, 2021.

Also that month, the FDA granted a priority review to an sBLA for nivolumab (Opdivo) in combination with a fluoropyrimidine- and platinum-containing chemotherapy for use in patients with advanced or metastatic gastric cancer, GEJ cancer, or esophageal adenocarcinoma.The agency is expected to make a decision by May 25, 2021.

® during a 2021 Institutional Perspectives in Cancer Webinar on gastrointestinal malignancies, Sanjeevaiah, an assistant professor in the Department of Internal Medicine at UT Southwestern Medical Center, discussed how immunotherapy has altered treatment for patients for gastrointestinal cancers, both as monotherapy and in combination with chemotherapy.

How has the addition of immunotherapy impacted the way you treat your patients with gastrointestinal cancers?

: Many immunotherapy agents have been studied in gastrointestinal cancers, not just nivolumab, but also pembrolizumab [Keytruda], durvalumab [Imfinzi], atezolizumab [Tecentriq], and others. The first major study was the phase 2 KEYNOTE-059 [NCT02335411] trial, in which there was clear evidence of benefit with immunotherapy in metastatic gastroesophageal cancers.

The benefit appeared to be mostly in PD-L1-positive cancers in the third-line setting, and that is where it was approved and has lived, so to speak, for the last 2 to 3 years. Now, we have phase 3 data from CheckMate-649 [NCT02872116], which shows that, in patients with a CPS of 5 or higher, the introduction of nivolumab plus 5-fluorouracil [5-FU], leucovorin, and oxaliplatin [FOLFOX] would result in significant clinical benefit in terms of overall survival [OS]. That has been practice changing. There are further studies that are looking to see if that space can be further elaborated on, but the best evidence we have right now is from CheckMate-649.

How do you explain the discordant results between the CheckMate-649 and KEYNOTE-062 [NCT02494583] trials?

Let’s look at the differences between these 2 studies. Of course, the immunotherapy agent being used was different. In KEYNOTE-062, we used pembrolizumab, while in CheckMate-649 we used nivolumab. There was also a difference in the chemotherapy regimens. CheckMate-649 used FOLFOX, whereas KEYNOTE-062 used 5-FU and cisplatin.

Additionally, the sample sizes were different. CheckMate-649 was a larger study with about 790 patients in each arm, [while] KEYNOTE-062 had about 240 patients. That might have been a factor. Also, we need to gather more data about how many of the patients who progressed after chemotherapy [crossed over to receive] immunotherapy. We still do not have data regarding the crossover that influenced the survival in those patients.

How would you describe the clinical implications of the phase 3 CheckMate-577 (NCT02743494577) trial?

This is probably the most important study in the gastrointestinal cancer space. What the study did was examine patients who received chemoradiation followed by surgery. For patients who had residual disease after chemoradiation therapy, they were given adjuvant nivolumab. [There were] approximately 532 patients in that arm [with nivolumab], which was a 2:1 randomization, and [patients received] nivolumab every 2 weeks for 16 weeks, followed by 418 mg every 4 weeks for 1 year, or placebo.

CheckMate-577 showed that survival was drastically different for patients who received adjuvant nivolumab, and the median disease-free survival was 22 months compared with 11 months [for placebo]. That is impressive. There are other studies being conducted right now to answer the same question—whether there is a role for immunotherapy in the perioperative setting. In particular, the phase 2/3 EA2174 [NCT03604991] study [is looking at this question with] nivolumab and ipilimumab. That will be another study to look out for in the next few years.

What emerging agents in this space are of interest?

There are all sorts of studies looking into the use of immunotherapy agents along with docetaxel, oxaliplatin, leucovorin, and 5-FU [FLOT], which is not a standard perioperative chemotherapy. Those recent studies should be looked at going forward and could show that we can improve upon the current success rate in curing patients with resectable gastroesophageal cancers.

PD-1 Regimens Lead Charge Against Gastrointestinal Cancers

With immunotherapy options expanding for patients with a range of gastrointestinal cancers to include combination strategies with chemotherapy, their use in the treatment course should come sooner rather than later for those with high PD-L1 expression.

Immunotherapy Regimen Continues to Improve GI Treatment

The FDA has authorized the marketing of the first device that utilizes artificial intelligence (AI) based on machine learning to help clinicians detect lesions like polyps or suspected tumors in the colon in real time during a colonoscopy.1

The device, dubbed the GI Genius, is comprised of hardware and software that was developed to highlight portions of the colon where the device identifies a possible lesion. By using AI algorithm techniques, the device is able to reveal regions of interest.

During the colonoscopy, the system produces markers that look like green squares and are accompanied by a short, low-volume sound. These markers are superimposed on the video from the endoscope camera when a possible lesion is identified. When this happens, it signifies that a further assessment may be needed, whether that be closer visual inspection, tissue sampling, testing or removal, or ablation of the lesion.

“AI has the potential to transform healthcare to better assist healthcare providers and improve patient care. When AI is combined with traditional screenings or surveillance methods, it could help find problems early on, when they may be easier to treat,” Courtney H. Lias, PhD, acting director of the GastroRenal, ObGyn, General Hospital and Urology Devices Office in the FDA’s Center for Devices and Radiological Health, stated in a press release.

Colorectal cancer (CRC) is the third leading cause of death from cancer in the United States, according to the National Institutes of Health. Colonoscopies are performed to identify any changes or abnormalities in the lining of the colon and rectum. The GI Genius was developed to have compatibility with several FDA-authorized standard video endoscopy systems.

The safety and effectiveness of the GI Genius was examined through a multicenter, prospective, controlled study done in Italy, which enrolled a total of 700 patients who were aged between 70 years and 80 years who were undergoing a colonoscopy for CRC screening, surveillance, and who had positive results from a prior fecal immunochemical test for blood in the stool or gastrointestinal symptoms of possible CRC.

The primary analyses that were done had been based on a subgroup of 263 patients who underwent screening or surveillance every 3 years or more. Patients were randomized to receive either white light standard colonoscopy with the GI Genius (n = 136) or white light colonoscopy alone (n = 127). The primary end point of the trial was to compare how often colonoscopy plus GI Genius was able to identify a patient with at least 1 lab-confirmed adenoma or carcinoma vs standard colonoscopy alone.

Results indicated that the system identified laboratory-confirmed adenomas or carcinomas in 55.1% of patients vs 42.0% identified with standard colonoscopy; this translated to an observed difference of 13%. The device resulted in more biopsies conducted, but no perforations, infections, or bleeding was observed with the additional tests. However, investigators noted a slight increase in the number of lesions biopsied that did not turn out to be adenomas.

Importantly, the system is not supposed to characterize or classify a lesion, and it should not replace laboratory sampling as a means of diagnosis. “The device does not provide any diagnostic assessments of colorectal polyp pathology, nor does it suggest to the clinician how to manage suspicious polyps,” according to a statement issued by the FDA.

The system identifies areas of the colon within the field of view of the endoscope where a colorectal polyp could potentially be and allows for more extended examination in real time during the colonoscopy. The clinician must determine whether the region identified actually does have a suspected lesion and how that lesion should be managed and processed per standard guidelines.

The GI Genius was reviewed through the De Novo premarket review pathway.

“Medtronic is committed to preventing CRC and improving patient outcomes with disruptive technologies that aid screening, increase patient compliance, and improve treatment,” Giovanni DiNapoli, president of the Gastrointestinal business, which is part of the Medical Surgical Portfolio at Medtronic, stated in a press release.2 “With FDA de novo clearance for the GI Genius and its AI capabilities, we expect to enhance and improve colonoscopies and polyp detection. By introducing AI technology into the colonoscopy market, we anticipate improving colonoscopy detection rates and reducing variability in patient outcomes.”

FDA authorizes marketing of first device that uses artificial intelligence to help detect potential signs of colon cancer. News release. FDA. April 9, 2021. Accessed April 12, 2021. 

US FDA grants de novo clearance for first and only artificial intelligence system for colonoscopy; Medtronic launches GI Genius intelligent endoscopy module. News release. Medtronic plc. April 12, 2021. Accessed April 12, 2021. 

FDA Authorizes Marketing of First AI Device to Detect Signs of Colon Cancer

The FDA has authorized the marketing of the first device that utilizes artificial intelligence based on machine learning to help clinicians detect lesions like polyps or suspected tumors in the colon in real time during a colonoscopy.

FDA Authorizes Marketing for AI Colon Cancer Detection Device

The FDA has approved a new biweekly dosing regimen of 500 mg/m2 as a 120-minute intravenous infusion for cetuximab (Erbitux) for patients with KRAS wild-type, EGFR-expressing colorectal cancer (CRC) or squamous cell carcinoma of the head and neck (SCCHN).

With this regulatory decision, a biweekly dosing option is now available in addition to the weekly dosage regimen that had previously been approved for all approved indications when the agent is used either as a monotherapy or it is combined with chemotherapy.

The approval was based on findings from population pharmacokinetic modeling analyses that compared the predicted exposures of cetuximab delivered at a biweekly dose of 500 mg vs observed exposures in patients who received the agent at a weekly dose of 250 mg.

The application was also supported by data from pooled analyses of overall response rates, progression-free survival, and overall survival (OS) from published literature of cetuximab in patients with CRC and SCCHN. OS analyses that comprised real-world findings in patients with metastatic CRC who received either the weekly or biweekly dosing regimens was also used to support the decision.

In these exploratory analyses, the efficacy data proved to be consistent across dosage regimens examined and served to further support the data reported in the population pharmacokinetic modeling analyses.

The most common frequently reported toxicities with cetuximab include cutaneous adverse reactions such as rash, pruritus, and nail changes. Other adverse effects experienced with the agent include headache, diarrhea, and infection.

FDA approves new dosing regimen for cetuximab. News release. FDA. April 6, 2021. Accessed April 6, 2021. https://bit.ly/3mpj2Qj

The FDA has approved a new biweekly dosing regimen of 500 mg/m2 as a 120-minute intravenous infusion for cetuximab (Erbitux) for patients with KRAS wild-type, EGFR-expressing colorectal cancer or squamous cell carcinoma of the head and neck.

FDA Approves Additional Cetuximab Dose for KRAS Wild-Type, EGFR-Expressing CRC, Head and Neck Cancer

Optimizing first- and second-line therapy, understanding the role of maintenance therapy for patients with 

-positive disease, and developing improved therapeutic options for elderly patients has become a priority for research in metastatic pancreatic cancer, said Steven J. Cohen, MD, medical director of the Asplundh Cancer Pavilion, chief of the Medical Oncology and Hematology Division, and vice chair of the Department of Medical Oncology at Sidney Kimmel Cancer Center at Abington-Jefferson Health.

In the frontline setting, FOLFIRINOX or gemcitabine plus nab-paclitaxel (Abraxane) remain standard of care options for patients with metastatic pancreatic cancer; however, as the therapies have not been compared head-to-head, data cannot inform whether one regimen is preferred over the other.

“There is no clear, ‘best’ regimen, but in practice, most of us…give FOLFIRINOX for [patients] who are younger and otherwise healthy, gemcitabine and nab-paclitaxel [for those patients who are] a little bit older and not quite as [fit], and single-agent gemcitabine when there is a reason to worry about performance status or lab [results],” said Cohen, who is also a professor of medical oncology at Thomas Jefferson University, in a virtual presentation during an 

®Institutional Perspectives in Cancer webinar on gastrointestinal malignancies.

The phase 2/3 PRODIGE 4/ACCORD 11 trial randomized patients with metastatic pancreatic cancer to FOLFIRINOX (n = 171) or gemcitabine (n = 171).1 Findings from the study demonstrated a median progression-free survival (PFS) of 6.4 months with FOLFIRINOX vs 3.3 months with gemcitabine (HR, 0.47; 95% CI, 0.37-0.59; 

 < .001). Additionally, the median overall survival (OS) was improved with FOLFIRINOX at 11.1 months compared with 6.8 months with gemcitabine (HR, 0.57; 95% CI, 0.45-0.73; 

Similarly, the phase 3 MPACT trial randomized patients with metastatic pancreatic cancer to gemcitabine plus nab-paclitaxel (n = 431) compared with gemcitabine alone (n = 430).2 In this study, the median OS was 8.5 months with the addition of nab-paclitaxel vs 6.7 months with gemcitabine alone (HR, 0.72; 95% CI, 0.62-0.83; 

Despite the lack of comparative data in the metastatic setting, during the 2020 ASCO Virtual Scientific Program, findings from the randomized phase 2 SWOG S1505 trial were presented, revealing a 2-year OS rate of 43.1%, and a median OS of 22.4 months, with modified FOLFIRINOX compared with 46.9%, and a median OS of 23.6 months, with gemcitabine plus nab-paclitaxel in patients with resectable pancreatic cancer.3 Moreover, post-resection disease-free survival was 10.9 months vs 14.2 months, respectively. Both perioperative options induced adequate safety and high rates of resectability but did not appear to improve OS compared with the historic standard.

“We all tend to [utilize FOLFIRINOX] compared with gemcitabine and nab-paclitaxel in the frontline [setting]. [Now there are] some data suggesting there may not be much of a difference, at least in advanced or localized settings,” Cohen said.

Additionally, for the overall pancreatic cancer population, updated findings from a phase 1/2 study of liposomal irinotecan plus 5-FU/LV and oxaliplatin, (NALIRIFOX), which were presented during the ESMO World Congress on Gastrointestinal Cancer 2020 virtual meeting, demonstrated a tolerable safety profile with promising antitumor activity when used as frontline therapy for patients with locally advanced or metastatic pancreatic cancer.8

“We will see if NALIRIFOX can also show some benefit in the frontline setting, but we certainly have a lot newer approaches and targets, particularly in elderly patients,” said Cohen.

Moreover, the study served as a precursor to the ongoing phase 3 NAPOLI-3 trial (NCT04083235), which is evaluating NALIRIFOX vs gemcitabine/nab-paclitaxel in the frontline setting for patients with metastatic pancreatic cancer.

To potentially extend frontline responses, the phase 3 POLO trial evaluated the PARP inhibitor olaparib (Lynparza) as maintenance therapy in patients with metastatic pancreatic cancer who harbored germline 

 mutations and had not progressed during first-line platinum-based chemotherapy. Patients were randomized 3:2 to receive maintenance olaparib (n = 92) or placebo (n = 62).4

During the 2021 Gastrointestinal Cancers Symposium, results from the final OS analysis of the POLO trial were presented. The data failed to show a statistically significant OS benefit with maintenance olaparib compared with placebo (HR, 0.83; 95% CI, 0.56-1.22; 

 = .3487); however, primary PFS and other key secondary end points support the use of maintenance olaparib in this patient population.5

More patients remained on olaparib treatment at 3 years compared with placebo (17.2% vs 3.3%, respectively). Additionally, 21.5% of patients remained free of subsequent cancer therapy with olaparib compared with 3.6% of patients with placebo (HR, 0.44; 

 < .0001). At 3 years, 33.9% of patients on the olaparib arm were alive vs 17.8% of patients on the placebo arm.

“Olaparib clearly has a role [as maintenance therapy]…but there is no survival benefit,” said Cohen. “The way [the POLO trial] was designed was tricky [because] we don’t stop chemotherapy completely. In the real world, we might drop oxaliplatin and continue FOLFIRI. Many of us would bring in [olaparib] at some point, but when [that] perfect time [is] has to [be] gauged with each patient.”

“It is easier to justify [adding olaparib in patients who obtained] deep responses [with chemotherapy]. If someone has almost a complete response [to frontline therapy], switching to an oral agent and stopping chemotherapy makes sense. If [the patient has] stable disease or liver disease, we worry a bit more,” Cohen added.

For patients who do progress following frontline or maintenance therapy, second-line treatment options remain sparse and ultimately, the standard of care is to give whichever regimen was not utilized as frontline therapy, explained Cohen. Patients who received up-front FOLFIRINOX should receive a gemcitabine-based regimen upon progression. Patients who received gemcitabine plus nab-paclitaxel as first-line therapy should receive a 5-fluorouracil (5-FU)–based regimen, such as FOLFOX or 5-FU plus liposomal irinotecan, in the second-line setting.

However, second-line therapies confer more modest benefit [than frontline options] and data have not demonstrated a clear benefit to giving FOLFIRINOX or gemcitabine plus nab-paclitaxel in this setting, Cohen explained.

One significant addition to the paradigm emerged from the phase 3 NAPOLI-1 trial, which demonstrated an OS advantage with liposomal irinotecan plus 5-FU and leucovorin (5-FU/LV) vs 5-FU/LV alone in patients with metastatic pancreatic cancer who progressed on prior gemcitabine-based therapy.6 PFS, objective response rate, and disease control rate also favored the addition of liposomal irinotecan.

Although frontline, maintenance, and second-line regimens are established for all patients with metastatic pancreatic cancer, older patients are historically underrepresented in clinical trials but are commonly seen in clinical practice, Cohen highlighted. As such, ongoing clinical trials, such as the phase 2 GIANT trial (NCT04233866), are evaluating standard frontline options specifically in elderly patients with pancreatic cancer.7 Moreover, the GIANT trial will evaluate geriatric factors and biomarkers of ageing to identify potential predictors of treatment response and tolerance in older patients with metastatic pancreatic cancer.

The GIANT study is enrolling patients with untreated metastatic pancreatic cancer who are over the age of 70 years and have an ECOG performance status between 0 and 2. These patients are considered vulnerable, meaning that they are unfit, frail and can have any mild to moderate geriatric assessment abnormalities. Patients will be randomized to modified gemcitabine/nab-paclitaxel every 2 weeks vs dose-reduced 5-FU plus liposomal irinotecan every 2 weeks.

Conroy T, Desseigne F, Ychou M, et al. FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. 

. 2011;364(19):1817-1825. doi:10.1056/NEJMoa1011923

Von Hoff DD, Ervin T, Arena FP, et al. Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine. 

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Sohal D, Duong MT, Ahmad SA, et al. SWOG S1505: results of perioperative chemotherapy (peri-op CTx) with mfolfirinox versus gemcitabine/nab-paclitaxel (Gem/nabP) for resectable pancreatic ductal adenocarcinoma (PDA). 

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Comparing two treatment combinations, gemcitabine and nab-paclitaxel with 5-fluorouracil, leucovorin, and liposomal irinotecan for older patients with pancreatic cancer that has spread. ClinicalTrials.gov. Posted January 18, 2020. Updated June 25, 2020. Accessed March 10, 2021. 

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Ongoing Research Is Slated to Optimize Sequencing With Current Standards in Pancreatic Cancer.

Optimizing first- and second-line therapy, understanding the role of maintenance therapy for patients with BRCA-positive disease, and developing improved therapeutic options for elderly patients has become a priority for research in metastatic pancreatic cancer.

Research Will Reveal Optimal Drug Sequencing in Pancreatic Cancer

The introduction of immunotherapy to the treatment paradigms of esophageal and gastric cancers has been an exciting advance, said Namrata (Neena) Vijayvergia, MD, who added that although agents, such as nivolumab (Opdivo), are not yet approved by the FDA in the adjuvant or metastatic settings, they should be considered for use based on National Comprehensive Cancer Network (NCCN) recommendations.

“Experts put out these guidelines for a reason,” said Vijayvergia. “There are phase 3 data supporting [the use of immunotherapy in esophageal and gastric cancers].”

On January 20, 2021, the FDA granted a priority review to a supplemental biologics license application (BLA) for adjuvant nivolumab (Opdivo) in patients with resected esophageal or gastroesophageal junction (GEJ) cancer following neoadjuvant chemoradiation treatment.

Also, on January 20, 2021, the FDA granted a priority review to a supplemental BLA for nivolumab in combination with a fluoropyrimidine- and platinum-containing chemotherapy for use in patients with advanced or metastatic gastric cancer, GEJ cancer, or esophageal adenocarcinoma.

® during an Institutional Perspectives in Cancer webinar on gastrointestinal malignancies, Vijayvergia, assistant chief of Gastrointestinal Medical Oncology, assistant professor in the Department of Hematology/Oncology, and medical director of Medical Oncology at Fox Chase Cancer Center Partners, of Fox Chase Cancer Center, discussed the emerging role of immunotherapy in resectable and metastatic esophageal and gastric cancers, as well as key nuances that could complicate these agents’ utility in clinical practice.

®:How do the results of the CheckMate-577 trial support the use of nivolumab as adjuvant treatment for patients with esophageal cancer?

:The CheckMate-577 study was very exciting in terms of adjuvant therapy for patients with esophageal cancer. [The results support the use of] adjuvant therapy with nivolumab [for these patients].

[CheckMate-577] compared nivolumab with placebo in patients who had treatment for their esophagus cancer and, at the time of surgery, did not have a complete pathological response. Giving those patients nivolumab in the adjuvant setting for up to 1 year led to an improvement in progression-free survival [PFS]. The disease-free survival was 22 months for the nivolumab group compared with 11 months for the placebo group. The curves started separating at around 3 months, and at around 6 months, they separated further. The separation continued for a long time, which is a really exciting finding. [Nivolumab] is something that is going to hopefully get [FDA] approval in [the adjuvant] setting soon. Interestingly, this study included patients with squamous and adenocarcinoma, so [adjuvant nivolumab] works for both [patient populations].

Should chemoimmunotherapy be considered for patients with metastatic esophageal cancer?

In [the metastatic] setting, esophageal and gastric cancer are differentiated from each other.

There are new data [regarding] the role of adding immunotherapy with pembrolizumab [Keytruda] to chemotherapy for patients with esophageal cancer. The KEYNOTE-590 trial [enrolled] patients with locally advanced and unresectable metastatic esophageal adenocarcinoma or squamous cell carcinoma. Patients were randomized to receive chemotherapy, which was cisplatin and 5-fluorouracil, with pembrolizumab or placebo. The primary end point was overall survival [OS] and PFS.

Interestingly, in this study, most patients, not just those who had a CPS greater than 10, benefited from the addition of pembrolizumab to chemotherapy with a hazard ratio [HR] of 0.73. Obviously, the extent of benefit improved in patients who had squamous cell carcinomas, as well as those who had PD-L1 [expression] greater than 10%.

What data support the use of immunotherapy in metastatic gastric cancer?

In terms of gastric cancer, we had the CheckMate-649 study that was presented at [the 2020] ESMO [Virtual Congress] that suggested the addition of nivolumab to chemotherapy in patients with a CPS greater than 5 was associated with an improvement in OS and response rate. The OS was 11 months [with chemotherapy alone] vs 14 months [with nivolumab/chemotherapy], favoring the combination arm. The study’s primary end point was to look at patients with a CPS of greater than 5 for PD-L1 [expression], but when [the investigators] looked at the entire population, the benefit was maintained [with nivolumab] in all patients. However, that was not the primary end point. The outcome of the study was that adding nivolumab to oxaliplatin-based chemotherapy was beneficial in patients who have a CPS greater than 5.

Apart from [CheckMate-649], there were 2 other studies that complicated the picture a little bit. There was the ATTRACTION-4 trial, as well as the KEYNOTE-062 trial, which had suggested that the benefit of immunotherapy was not that [significant]. In the KEYNOTE-062 trial, some benefit [was observed] in PFS, but not much in OS, meaning there wasn’t much benefit to adding pembrolizumab to chemotherapy.

However, in patients who had a CPS greater than 10, pembrolizumab alone was very effective. Unfortunately, this was not a primary end point of the study and this was more of a secondary analysis. Hence, we cannot take [pembrolizumab monotherapy] to the frontline [setting], but it is beneficial. In patients who are frail and cannot get chemotherapy [but] have a CPS greater than 10, using single-agent pembrolizumab is absolutely reasonable and should be considered.

What could explain the conflicting results observed in the KEYNOTE-062, ATTRACTION-4, and CheckMate-649 trials?

Trying to understand why one [immunotherapy] worked and one didn’t is a little confusing, but patient selection is very important. Interestingly enough, if we look [at the data] and compare these 3 trials, the KEYNOTE-062 trial compared with the ATTRACTION-4 trial and the CheckMate-649 trial used a cisplatin-based regimen rather than oxaliplatin. [The discrepancy] could be that the chemotherapy backbone was different.

Second, the primary study population in ATTRACTION-4 included all-comers, and only 16% of patients were PD-L1 selected. In CheckMate-649, 60% of patients had a CPS greater than 5, so [the population] was more selected for PD-L1 positivity [compared with ATTRACTION-4]. In the KEYNOTE-062 trial, only 36% of patients had a CPS greater than 10.

Also, the [study] locations [were different]. The ATTRACTION-4 trial was done in Asia, [whereas] the KEYNOTE-062 and CheckMate-649 studies were done worldwide.

There were a lot of differences in these studies and people are attributing [the conflicting results] to the chemotherapy backbone in the KEYNOTE-062 trial vs the nivolumab studies. Also, the higher enrichment of PD-L1 in the CheckMate-649 study [may have contributed] to the overall benefit; 82% of patients had a CPS greater than 1 and 60% had a CPS greater than 5 in that study.

Having seen these data, do you adhere to the NCCN guidelines that recommend immunotherapy?

Absolutely. Even though these agents are not approved by the FDA, they are under review by the FDA. The NCCN guidelines recommend nivolumab as a category 1 indication in the adjuvant setting for [patients with] esophagus cancer. For patients with gastric cancer who are HER2 negative and have a CPS greater than 5, adding nivolumab [to chemotherapy] is recommended. Similarly, adding immunotherapy for patients with esophageal cancer [is recommended].

Could there be any overlap between biomarkers such as PD-L1 and microsatellite instability status that could be used identify a specific population of patients that benefit most from immunotherapy?

Interestingly, the KEYNOTE-062 trial tried to do this testing. In the study, about 5% of patients in the pembrolizumab alone–arm were MSI-high [(MSI-H) vs], about 7% in the chemotherapy-alone arm, and about 8% in the pembrolizumab plus chemotherapy arm. A very interesting finding showed that there was a collection of MSI-H tumors that were enriched for PD-L1. If we look at the benefits of therapy in those patients, there is a clear benefit to pembrolizumab plus chemotherapy vs chemotherapy alone. The HRs were in the range of 0.2 to 0.3, [representing] very significant benefit in that area. Patients with MSI-H disease tend to enrich PD-L1 scoring.

There are some data in early-stage disease that patients with MSI-H disease may not respond very well to chemotherapy. That would even extend into the metastatic setting too, but we will see. At this point in time, I would definitely recommend pembrolizumab with or without chemotherapy for patients who are MSI-H.

Beyond immunotherapy, what other advances appear promising in gastric cancer?

There is also a lot of excitement around HER2-directed therapy. A study that was presented during the [2021 Gastrointestinal Cancers Symposium evaluated] 

-altered gastric cancer. [The data showed that] the addition of an FGFR inhibitor to FOLFOX chemotherapy improved outcomes.

Therefore, not only is immunotherapy buzzing in this space, a lot of targeted therapy options [are emerging]. Data with ZW25 [zanidatamab] were presented during the [2021 Gastrointestinal Cancers Symposium]. At the same time, [fam-trastuzumab deruxtecan-nxki (Enhertu)] was approved for second- and third-line HER2-positive gastric cancer.

testing become a standard marker to test for in practice?

 testing] is available, but we typically didn’t test for it because there were no therapies suggesting benefit until now. We’re still awaiting the phase 3 study to [reveal] more data, but it is something we can all work toward easily to figure how to [best identify 

US Food and Drug Administration accepts for priority review application for Opdivo® (nivolumab) as adjuvant therapy for patients with resected esophageal or gastroesophageal junction cancer. News release. Bristol Myers Squibb. January 20, 2021. Accessed March 12, 2021. http://bit.ly/3qDi6bT.

US Food and Drug Administration accepts for priority review application for Opdivo® (nivolumab) combined with chemotherapy as first-line treatment in metastatic gastric cancer, gastroesophageal junction cancer and esophageal adenocarcinoma. News release. Bristol Myers Squibb. January 20, 2021. Accessed March 12, 2021. http://bit.ly/3a4b6OL.

Immunotherapy Makes Waves in Gastroesophageal and Gastric Cancers

Namrata (Neena) Vijayvergia, MD, discusses the emerging role of immunotherapy in resectable and metastatic esophageal and gastric cancers, as well as key nuances that could complicate these agents’ utility in clinical practice.

Immunotherapy Enters Gastroesophageal and Gastric Cancers

Circulating tumor DNA (ctDNA) and total neoadjuvant therapy (TNT) are reshaping the landscape of early-stage colorectal cancer (CRC), explained Tony Philip, MD, who added that the paradigm shift in the advanced setting came from moving less-intensive treatment to the first-line setting.

“We should keep an eye on what’s going to come out with ctDNA, because it’s exciting stuff. It’s nice to have these new toys to play with. We’ve just got to figure out how and when to use them,” said Philip. “Total neoadjuvant therapy for rectal cancer is really changing the landscape. For patients who have distal rectal cancers, we really should think about nonoperative management. How do we [avoid] a permanent colostomy [in some patients]? How can we preserve organ function for some of those patients?”

In the advanced setting, the addition of trifluridine/tipiracil (TAS-102; Lonsurf) to bevacizumab (Avastin) led to an improvement in overall survival (OS) vs capecitabine/bevacizumab in the frontline treatment of patients with unresectable metastatic CRC who are not eligible for standard chemotherapy, according to data from the phase 2 TASCO1 trial. In results presented during the 2021 Gastrointestinal Cancers Symposium, patients in the TAS-102/bevacizumab arm had a median OS of 22.31 months (95% CI, 18.00-23.69) vs 17.67 months (95% CI, 12.58-19.81) in the capecitabine/bevacizumab arm (HR, 0.78; 95% CI, 0.55-1.10).

“Based on the TASCO1 trial, we do have options for patients that are not able to get aggressive treatment,” said Philip.

® during an Institutional Perspectives in Cancer webinar on gastrointestinal malignancies, Philip, a medical oncologist at Monter Cancer Center of the North Shore, LIJ Cancer Institute, and an assistant professor of medicine at Hofstra-North Shore LIJ School of Medicine and New York Institute of Technology College of Osteopathic Medicine, provided insight into the utility of ctDNA in the early-stage setting, trials that could determine its role in clinical practice, and detailed the shift toward nonoperative and less-intensive interventions in the early-stage and advanced settings, respectively.

®: What is the role of ctDNA in early-stage CRC, and how could it be used to detect MRD and inform a patient’s risk of recurrence?

: Some of the data that was presented at [the 2021 Gastrointestinal Cancers Symposium] suggests that ctDNA may be able to pick up disease recurrence approximately 8 months prior to traditional methods, such as carcinoembryonic antigen tumor markers, or even CT scan. It lays the groundwork for some interesting data and may change how we do things moving forward. However, we definitely need a lot more clinical trials to validate whether that’s truly the case and how to use it in a day-to-day setting.

Several clinical trials are ongoing [in that regard]. Some of the trials are looking at [ctDNA] in stage II/III disease and [are studying] whether giving chemotherapy and changes in ctDNA validate its use [as] both a predictive test and a prognostic test. BEACON and COBRA are some of the trials that are ongoing, amongst many others.

How have the RAPIDO and OPRA trials contributed to our understanding of how to manage patients with locally advanced rectal cancer?

[It’s] interesting timing for RAPIDO because in the COVID-19 environment that we’re in currently, the ability to do short-course radiation might reduce patients’ time in the hospital or clinic. The outcomes for response to treatment might be preserved, so that’s one benefit.

In terms of OPRA, as we evolve the nonoperative management of distal colorectal cancers, [the data] suggest that the nonoperative management route, which was not even considered many years ago, of up-front chemoradiation followed by chemotherapy may be a better strategy.

What research is being done to improve care for patients who aren’t eligible for intensive therapy?

The TASCO1 trial is interesting because we normally think of TAS-102 as one of the last resorts of treatment. The drug is generally thought to be fairly well tolerated, but traditionally, given its approval in the fourth- or fifth-line setting, people don’t think of it as effective. However, when we look at this drug for patients that have disease, but are not really eligible for aggressive treatment, this presents an option and may be better than what we perceive to be some of the standards before, without any added toxicity. It allows us to treat some of those patients that can’t get more aggressive chemotherapy. It gives them those options as well. Many trials are ongoing, trying to figure out how to harness immunotherapy for MSS [microsatellite stable] CRC and other treatment options.

What ongoing efforts have the potential to impact practice?

Ongoing trials looking at ctDNA are really going to change practice. In trying to figure out for patients that have stage II/III disease that we think based on traditional markers of risk recurrence make them high risk, [we’ll ask whether we] can we tease out patients that may be cured from just surgery alone and don’t need chemotherapy. That would be a great practice changing result from all of this [research].

For those who we think may be cured from surgery, but truly aren’t: Should those patients benefit from chemotherapy and prevent metastatic disease from developing down the road? That’s one of the more exciting things: How do we better determine who should get adjuvant therapy and who shouldn’t? Clearly, we’re not there yet, but this lays some of the groundwork for that.

Tony Philip, MD, provides insight into the utility of ctDNA in the early-stage setting, trials that could determine its role in clinical practice, and detailed the shift toward nonoperative and less-intensive interventions in the early-stage and advanced settings, respectively.

Gastrointestinal Cancer