 mutational status and geographical region were associated with time on treatment (TOT), and body mass index (BMI) and age were linked with overall survival (OS) in patients with metastatic colorectal cancer mCRC) being treated with second-line cetuximab (Erbitux) after irinotecan or oxaliplatin-based regimens, according to data from a real-world retrospective analysis presented at the 2021 ASCO Annual Meeting.

Results, indicated that the median TOT in patients who received second-line cetuximab was 3.94 months (median interquartile range [mIQR], 3.51-4.40), while the median OS was 14.36 months (mIQR, 13.01-15.70).

Moreover, receiving second-line treatment with cetuximab plus FOLFIRI (median TOT = 4.43 months; mIQR, 3.71-5.36), having 

 wild-type status, and receiving second-line cetuximab following frontline capecitabine plus oxaliplatin (CAPOX), were all associated with a longer median TOT. Moreover, residing in the South region vs the Midwest of the United States was linked with a shorter median TOT.

Having a higher BMI was associated with a longer median OS (obese vs underweight HR, 0.46; 95% CI, 0.32-0.66), while receiving treatment with second-line cetuximab plus 5-fluorouracil, leucovorin, and oxaliplatin (FOLFOX) was linked with a shorter median OS (10.97 months; mIQR, 5.55-14.06). Additionally, being older than 65 years was also linked with a shorter median OS (≥65 years vs <65 years; HR, 1.24; 95% CI 1.05-1.46).

Anti-epidermal growth factor receptor drugs are being increasingly utilized in later lines of therapy in patients with mCRC, but the real-world TOT and OS of patients who receive cetuximab in second-line setting has not been examined. As such, investigators set out to examine characteristics linked with TOT and OS using retrospective observational data.

Between January 2013 and August 2020, 1011 patients were selected from the nationwide Flatiron electronic health record database. Patients were included in the analysis if they had a mCRC diagnosis, received second-line treatment with a cetuximab-based regimen, and had progressed on oxaliplatin/irinotecan-based regimens in the frontline.

Investigators defined TOT as the time from start of cetuximab in the second line to the last date of evidence of administration. Moreover, end of treatment was defined if patients progressed to a third line of therapy or if they had a death record. Additionally, OS was calculated from index date to the date of death or censored to the last visit date available.

Among the 1011 patients included in the analysis, more than half were younger than 65 years (58%) and male (60%). Additionally, most patients had a median BMI of 26.6 kg/m², had previously received FOLFOX regimens in the first-line setting (61%), and received treatment in the community setting (96%). The most frequently used second-line treatment regimens were cetuximab plus FOLFIRI (46%) and cetuximab plus irinotecan (29%).

Gathirua-Mwangi W, Yang T, Khan T, et al. Real-world time on treatment and overall survival in patients with metastatic colorectal cancer receiving cetuximab in second line after failing irinotecan or oxaliplatin-based regimens. 

. 2021;39(suppl 15):e15568. doi:10.1200/JCO.2021.39.15_suppl.e15568

Articles

KRAS mutational status and geographical region were associated with time on treatment (TOT), and body mass index (BMI) and age were linked with overall survival (OS) in patients with metastatic colorectal cancer mCRC) being treated with second-line cetuximab (Erbitux) after irinotecan or oxaliplatin-based regimens.

Patient Characteristics Linked to Time on Treatment and Survival in Patients With mCRC Receiving Cetuximab

Screenings for breast cancer, colorectal cancer (CRC), and prostate cancer declined sharply from March to May 2020 vs the same time span in 2019, suggesting that public health efforts, such as increased use of screening modalities that do not require a procedure, are needed to address the deficit caused by the COVID-19 pandemic, according to findings from a study that were published in 

Within the 3-month period in 2020, the sharpest decline in screening for breast cancer, CRC, and prostate cancer was observed in April 2020 compared with the same month in 2019; screenings declined by 90.8%, 79.3%, and 63.4% in breast cancer, CRC, and prostate cancer, respectively.

Compared with April 2019, the incidence of breast cancer screenings in April 2020 declined from 4287 per 100,000 individuals (95% CI, 4258-4316) to 394 per 100,000 individuals (95% CI, 385-403). The incidence of CRC screenings declined from 2073 per 100,000 individuals (95% CI, 2058-2087) to 430 per 100,000 individuals (95% CI, 423-436). The incidence of prostate cancer screenings declined from 4025 per 100,000 individuals (95% CI, 3993-4057) to 1474 per 100,000 individuals (95% CI, 1454-1493).

Notably, near complete recovery in monthly screening rates were observed by July 2020 for patients with breast cancer and prostate cancer.

"Unfortunately, by causing cancellations of appointments and cancer screenings, COVID will indirectly cause an increase in cancer deaths—another negative consequence of COVID that has not yet received much public attention," said lead study author Ronald C. Chen, MD, MPH, the Joe and Jean Brandmeyer Endowed Chair in the Department of Radiation Oncology at the University of Kansas Medical Center.

The COVID-19 pandemic significantly affected all elements of health care, including cancer treatment and screening, across the United States in 2020, Chen and co-authors wrote.1 Stay-at-home orders and safety guidelines issued by the CDC to minimize COVID-19 transmission resulted in a significant decline in non-emergency clinical visits, particularly among older, high-risk patients, explained Chen and co-authors.

The study evaluated 3 distinct cohorts of patients from the HealthCore Integrated Research Database, which comprises single-payer administrative claims data and enrollment information from about 60 million patients in Medicare Advantage and commercial insurance plans across the United States. The cohorts included women with breast cancer, men and women with CRC, and men with prostate cancer.

Cancer screenings were evaluated from 2018 to 2020. Evaluable individuals for breast cancer screening or CRC screening were aged 50 to 79 years, and evaluable individuals for prostate cancer screening were aged 50 to 69 years. Individuals had to have at least 2 years of continuous enrollment before the first day of the index month. Restrictions based on medical claims and personal history codes for cancers of interest further refined the evaluable population.

“Excluding individuals with a history of the cancer of interest allowed us to more accurately assess cancer screening,” wrote Chen and co-authors.

Additional results from the study revealed that despite the rebound in monthly cancer screening rates, a deficit in total cancer screenings from January to July 2020 remained compared with January to July 2019. This translated to a United States–population deficit in breast cancer, CRC, and prostate cancer screenings of approximately 3.9 million women, 3.8 million men and women, and 1.6 million men, respectively. Moreover, the total deficit in cancer screenings was estimated at 9.4 million individuals in 2020 compared with 2019.

By geographic region, the Northeastern United States reported the sharpest decline in cancer screenings in March, April, and May for all 3 cancer types. The Western region had a slower recovery in screening during June and July compared with the Midwest and South regions.

Regarding socioeconomic status, prior to the pandemic, screening rates were higher for all 3 cancer types in the highest 2 socioeconomic index quartiles compared with the lower 2 socioeconomic index quartiles. However, the highest socioeconomic index quartile reported the largest decline in screening for all 3 cancer types from January to July 2020 compared with the same period in 2019. Moreover, the decline narrowed the gap in screening rates across the quartiles in 2020 vs 2019.

Other key findings from the study showed that increasing age was associated with less screening in all 3 cancer types. Individuals in the higher quartiles were screened less for breast cancer and CRC in April 2020 compared with individuals in the lower quartiles.

Notably, individuals who utilized telemedicine services had higher rates of cancer screening across the 3 cancer types evaluated.

“Telehealth has a measurable positive effect on whether patients get their cancer screenings,” Chen said.2 “This study also justifies a continued use of telehealth even after the pandemic.”

Chen and co-authors reported that analyzing only insured individuals, the lack of racial/ethnic diversity in the study population, the use of nonspecific codes for screening, and the inclusion of individuals without a history of cancer were limitations of the study.

“As a physician, I wasn’t surprised to see that screenings had declined, but this study measures by how much. There needs to be a concerted public health educational campaign across the country to reinforce the importance of cancer screening. Hospitals across the country also need to devote effort to contact patients to reschedule canceled screening tests, in order to minimize the delay in screening and cancer diagnoses from the missed tests,” concluded Chen.2

Chen RC, Haynes K, Du S, et al. Association of cancer screening deficit in the United States with the COVID-19 pandemic. 

. Published online April 29, 2021. Accessed May 13, 2021. doi:10.1001/jamaoncol.2021.0884

Massive negative impact of COVID-19 on cancer screenings quantified in KU Medical Center faculty study published in JAMA Oncology. News release. April 29, 2021. Accessed May 13, 2021. https://bit.ly/3ojB2fJ.

This article was originally published on OncLive as, "

Routine Screening Rates for Breast, Colorectal, and Prostate Cancers Decline During COVID-19 Pandemic

Public health efforts must address new methods of cancer screening, an expert says.

Routine Cancer Screening Declined During the COVID-19 Pandemic

The FDA approved adjuvant nivolumab (Opdivo) for the treatment of completely resected esophageal or gastroesophageal (GEJ) cancer with residual pathologic disease in patients who have previously had neoadjuvant chemoradiation treatment, according to Bristol Myers Squibb, the manufacturer of the immunotherapy agent.

"Esophageal and GEJ cancer patients with residual pathologic disease following neoadjuvant CRT and complete resection face a high risk of disease recurrence; however, the predominant option for these patients has been surveillance,” said Adam Lenkowsky, senior vice president and general manager, U.S. Cardiovascular, Immunology and Oncology, Bristol Myers Squibb in a statement. “Today’s news marks an important step for patients as well as meaningful progress toward our commitment to pioneering immunotherapy treatment options in earlier stages of disease where there is the potential to reduce the risk of recurrence.”

The approval is based on findings from the phase 3 CheckMate-577 trial (NCT02743494), which involved 794 patients with stage II esophageal or GEJ cancer, adenocarcinoma or squamous cell carcinoma. To be eligible, patients had to have undergone neoadjuvant chemoradiation and surgical resection and have residual pathologic disease and an ECOG performance score of 0 to 1.

Study participants were randomized 2:1 to receive either 240 mg of nivolumab once every 2 weeks for 16 weeks then 480 mg once every 4 weeks; or placebo once every 2 weeks for 16 weeks and then once every 4 weeks. Treatment continued for up to 1 year.

Trial results proved that nivolumab led to a clinically meaningful improvement in disease-free survival (DFS) compared with placebo, 22.4 months versus 11.0 months, respectively in patients with resected esophageal or GEJ cancer after neoadjuvant chemoradiation.

There was also a 31% reduced risk of disease recurrence or death with nivolumab compared to placebo.

While patients were stratified based on histology (squamous or adenocarcinoma) pathologic lymph node status, and PD-L1 expression, benefit with nivolumab treatment was seen across all subgroups, also including age, sex, race, ECOG performance status, disease stage at initial diagnosis, and tumor location.

“Locally advanced esophageal and gastroesophageal junction cancers are aggressive tumor types that often require multiple approaches to address the disease, including chemotherapy, radiation and surgery,” said Ronan J. Kelly MD, MBA, director, Baylor Scott & White Charles A. Sammons Cancer Center, and W.W. Caruth Jr. Endowed Chair of Immunology at Baylor University Medical Center.

While the majority of patients on nivolumab experienced an adverse event (AE) of any grade, far fewer 33% had a severe (grade 3 or 4) AE. Two percent of more of patients receiving nivolumab experience pneumonitis. One patient died of myocardial infarction while taking nivolumab.

Common AEs that were reported in 20% or more of patients were fatigue (34%), diarrhea (29%), nausea (23%), rash (21%), musculoskeletal pain (21%), and cough (20%).

“Even after neoadjuvant CRT followed by surgery, there may be a high risk of recurrence for patients who do not achieve a pathologic complete response.2,3,7 In the CheckMate -577 trial, we saw a doubling in median disease-free survival compared to placebo, which suggests that 

 could become a new standard of care for these patients.1,9 This is exciting news, providing renewed hope,” Kelly said.

Bristol Myers Squibb. U.S. Food and Drug Administration Approves Opdivo® (nivolumab) as Adjuvant Treatment of Completely Resected Esophageal or Gastroesophageal Junction Cancer in Patients who have Received Neoadjuvant Chemoradiotherapy. May 20, 2021. 

https://news.bms.com/news/details/2021/U.S.-Food-and-Drug-Administration-Approves-Opdivo-nivolumab-as-Adjuvant-Treatment-of-Completely-Resected-Esophageal-or-Gastroesophageal-Junction-Cancer-in-Patients-who-have-Received-Neoadjuvant-Chemoradiotherapy/default.aspx

The FDA approved adjuvant nivolumab for the treatment of patients with resected esophageal or gastroesophageal (GEJ) cancer who have previously had neoadjuvant chemoradiation treatment. 

FDA Approves Adjuvant Nivolumab for Resected Esophageal and GEJ Cancer

The United States Preventive Services Task Force (USPSTF) now recommends colorectal cancer (CRC) screening to begin at 45 years of age, rather than the previous recommended age of 50. These new recommendations, which were published in 

 now align with those of the American Cancer Society.

These recommendations finalize draft guidelines that were issued in October 2020, and, in doing so, will mandate insurance coverage for CRC screening (colonoscopies and stool tests) in adults starting at age 45.

Nurses should encourage all eligible patients to get screened, especially those who are at increased risk.

“We know that black adults get colorectal cancer more often and are more likely to die from colorectal cancer than people of other races and ethnicities,” said John B. Wong, MD, interim chief scientific officer at Tufts Medical Center, primary care physician, and member of the USPSTF said.

“Clinicians, nurses, physicians, and others should reach out to their black patients to help make sure they get screened… What’s really important [to take home] is that colorectal cancer screening helps people ages 45 to 75 liver longer and healthier lives.”

The guidelines come after a concerning increase in CRC incidence in people under the age of 50. While this has been a trend since the mid 1990s, researchers are still unsure why younger adults are seeing higher CRC rates, especially since CRC diagnoses have been going down in the over-50 population due to modifying risk behaviors.

“Our recommendation calls out for additional research to try to understand better what the causes are, and to see if we can find [out] because once you find and determine the cause, then maybe we can do something to prevent that from happening going forward,” Wong said.

Most young-onset CRC diagnoses and deaths occur in people between the age of 45 and 49–so there is hope that the new recommendations will catch cancers earlier and decrease the number of CRC fatalities.

However, the rate of young-onset CRC is actually growing most in individuals who are even younger. Colon cancer incidence is increasing by about 2% every year in the 20- to 29-year-old cohort, compared to 1.3% in the 40- to 49-year-old cohort. Similarly, rectal cancer is also increasing at a steeper rate in the 20- to 29-year-old group than the 40- to 49-year-old group, at 3.2% yearly and 2.3% yearly, respectively.

“We are now seeing patients even younger than 45–in their 20s and 30s–who are being diagnosed with this cancer and often at very late stages,” said Kimmie Ng, MD, MPH, guideline author, in a statement. “Clearly the USPSTF recommendation to start screening at age 45 will not be enough to catch those young people who are being diagnosed.”

The USPSTF will continue to analyze data and update recommendations, if needed.

“As part of our normal process at the USPSTF, we want our recommendations to be as up-to-date as possible. So roughly every 5 years, we re-examine the evidence, look for new research, look to see if there are any changes in the evidence that might alter the recommendations we make,” Wong said.

US Preventive Services Task Force. Screening for Colorectal Cancer: US Preventive Services Task Force Recommendation Statement. May 18, 2021.

The United States Preventative Services Task Force now recommends colorectal cancer screening to start at 45 years old. 

USPSTF Lowers CRC Screening Age, Forcing Insurance Coverage

One in 6 patients with colorectal cancer (CRC) harbor genetic changes that substantially increase their risk for cancer, especially in those who are younger at the time of diagnosis, according to the data from a prospective, multicenter study published in 

A total of 361 patients with CRC enrolled on the study and underwent germline genetic testing with a panel that included approximately 80 genes known to increase risk for cancer.

 Results showed that these cancer-linked genetic changes were detected in 15.5% of patients with CRC (n = 56). Moreover, these changes predominantly occurred in high-penetrance cancer susceptibility genes like 

. A younger age at diagnosis was also linked with increased likelihood of genetic changes associated with increased susceptibility to cancer.

“Colorectal cancer is one of the most common types of cancer. Recently, we've seen an unfortunate increase in incidence among people younger than 50-years-old. Improving our understanding of who is at risk and implementing appropriate screening strategies is essential to ensuring these cancers are caught and treated earlier when outcomes are typically better,” Robert Nussbaum, MD, chief medical officer of Invitae Corporation, stated in a press release. “Access to information about inherited risk factors is also important after diagnosis, not only for the patients themselves…but also in alerting other family members of the need to be tested to see if they are also at increased risk and need more intensive surveillance to catch cancer early and prevent more serious disease.”

Hereditary factors are key players in the risk of developing several cancers. The detection of a germline predisposition can impact treatment decisions, risk-reducing interventions, cancer screening, and testing, in patients and their relatives. The impact of broad-based testing for inherited germline variants in patients with cancer vs traditional strategies of selection for genetic testing remains an open question.

In this study, investigators sought to examine the occurrence of pathogenic and likely pathogenic germline variants (PGVs) in inherited cancer susceptibility genes identified by a broad universal testing approach vs a targeted approach based on clinical guidelines. Investigators also wanted to evaluate the link between universal genetic testing and clinical management and the proportion of families who receive cascade family variant testing (FVT) when available at no cost.

For the prospective study, investigators enrolled patients with solid tumors who were receiving care at any of the 3 Mayo Clinic Cancer Centers or the Mayo Clinic Health System from April 2018 to March 2020. Patients were between 18 years and 85 years of age, had a new or active cancer diagnosis, confirmed pathologic diagnosis of carcinoma, and received treatment in medical oncology, radiation oncology, dermatology, or surgical clinics. Those with malignant hematologic cancers and those who were under surveillance following curative cancer, were not included in the study.

Participants were selected for cancer type, disease stage, family history of cancer, race/ethnicity, or age. All had undergone germline testing with a next-generation sequencing platform that tested for 83 genes; as of July 2019, it tested for 84 genes. Test results were analyzed by a certified genetic counselor; those with PGVs were offered genetic counseling. PGVs were classified as either high, intermediate, or low penetrance or recessive actionable variants; relative risk in these subsets was greater than 4, between 2 and 4, and less than 2, respectively.

“A PGV was considered incremental if it was detected based on the universal testing performed in this study and would not have been identified in targeted testing approaches recommended by published guidelines,” the study authors noted.

Additionally, free cascade FVT was offered to all blood relative of participants with PGVs within a 90-day window of the final test results. Patients were educated about the FVT program during genetic counseling; they were also provided assistance in relaying this information to their relatives via a letter and online video that detailed the benefits and risks of genetic testing.

The final analytic cohort included 2984 patients, who had a median age of 61.4 years; 53% of the patients were male. Additionally, at the time of genomic analysis, 18.6% (n = 535) of patients had stage 0/I disease, 16.7% (n = 477) had stage II disease, 20.7% (n = 593) had stage III disease, and 43.9% (n = 1257) had stage IV disease. Just over 5% (5.3%; n = 159) of patients were Hispanic/Latino, 3.7% were African American (n = 110), and 1.8% were Asian (n = 53). Moreover, 34.1% (n = 1019) of patients had a family history of cancer in a first-degree relative.

Of the 2984 total patients, 13.3% (n = 397) were found to harbor 426 PGVs. In 27 patients, more than 1 PGV variant was identified; 2 of these patients had 3 variants detected. Moreover, 149 of the PGVs had high penetrance, 133 had moderate penetrance, and 65 had low penetrance. Fifty patients were noted to harbor variants linked with recessive syndromes.

. Approximately 47% of patients (n = 1415), variants of uncertain significance. The incidence of PGVs in different cancer types ranged; the incidence was 20.6% for ovarian cancer, 15.9% for pancreatic cancer, 15.3% for colorectal cancer, 13.7% for prostate cancer, 14.7% for lung cancer, 14.5% for cholangiocarcinoma, 13.3% for endometrial cancer, and 14.2% for bladder cancer.

Notably, the variant rate by cancer stage was found to be similar; this rate was 13.7% in stage 0 to II disease and 13.1% in stage III to IV disease (

 = .24). Patients who had a family history of cancer in the same organ system were found to have a high rate of PGVs of 21.8%.

Additional data indicated that 192 cases had incremental findings that would not have been identified via phenotype or family history–based testing criteria using established guidelines; this accounted for 6.4% of the overall cases and 48.4% of the 397 patients with PGVs. Of these 192 patients, 18.2% (n = 35) had high-penetrance PGVs, 43.2% (n = 83) had low-penetrance PGVs, and 17.2% (n = 33) had recessive-penetrance PGVs. Of the 149 patients with high-penetrance PGVs, 28.2% (n = 42) experienced clinically actionable management and treatment adjustments indicated by the PGVs that were identified.

Additionally, 17.6% (n = 70) of patients with PGVs had relatives that accepted and underwent FVT within a 3-month window of their test result. Forty-five percent (n = 79) of the 176 family members had positive results.

Data from logistic regression analyses indicated that younger age at the time of cancer diagnosis was linked with a higher likelihood of having a PGV (odds ratio [OR], 1.38; 95% CI, 1.06-1.78). Although patients who had CRC, pancreatic cancer, or prostate cancer were noted to have comparable PGV prevalence vs those with breast cancer, those with melanoma were observed to have a significantly lower likelihood of having PGVs (OR, 0.58; 95% CI, 0.32-1.00).

“In this large, prospective multisite cohort study with a broad mixture of cancer types and stages, a variety of academic and community cancer practices, and patients unselected for family cancer history, universal multigene panel testing was associated with increased detection of clinically actionable, heritable variants over the predicted yield by targeted testing based on clinical guidelines,” the study authors concluded. “This study offers significant insight into the performance of multigene panel testing and has broad implications for its wide clinical implementation and acceptance in oncology practice.”

Samadder N, Johnson D, Boardman L, et al. Comparison of universal genetic testing vs guideline-directed targeted testing for patients with hereditary cancer syndrome. 

. 2021;7(2):230-237. doi:10.1001/jamaoncol.2020.6252

Study finds risk-causing genetic changes in nearly 1 in 6 patients with colorectal cancer. News release. Invitae Corporation. April 15, 2021. Accessed April 23, 2021. 

Universal Genetic Testing Reveals Variants Linked With Increased Cancer Risk in CRC.

Genetic Changes Linked to Increased CRC Risk

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. 

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

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.

Gastrointestinal Cancer