The FDA has granted a priority review to a supplemental biologics license application for nivolumab (Opdivo) in combination with a fluoropyrimidine- and platinum-containing chemotherapy for use in patients with advanced or metastatic gastric cancer, gastroesophageal junction (GEJ) cancer, or esophageal adenocarcinoma.

The application was based on data from the phase 3 CheckMate-649 trial, which showed that nivolumab plus leucovorin, 5-fluorouracil, and oxaliplatin (FOLFOX) or capecitabine and oxaliplatin (CapeOX) significantly improved survival in treatment-naïve patients with PD-L1—positive advanced gastric cancer, GEJ cancer, and esophageal adenocarcinoma compared with chemotherapy alone.

At a minimum follow-up of 12 months, the median overall survival (OS) with nivolumab/chemotherapy was 14.4 months (95% CI, 13.1-16.2) versus 11.1 months with chemotherapy alone (95% CI, 10-12.1) in patients who had a PD-L1 combined positive score (CPS) of 5 or greater (HR, 0.71; 98.4% CI, 0.59-0.86; P < .0001); this translated to a 29% reduction in the risk of death with nivolumab/chemotherapy. Moreover, the combination also reduced the risk of disease progression or death by 32% versus chemotherapy alone (HR, 0.68; 95% CI, 0.56-0.81; P <.0001).

Under the Prescription Drug User Fee Act, the FDA must make a decision by May 25, 2021.

“Today’s filing acceptance by the FDA marks important progress for the gastrointestinal cancer community and builds on our momentum of advancing immunotherapies to help improve the lives of those with advanced gastric and esophageal tumors,” Ian M. Waxman, MD, development lead, gastrointestinal cancers, at Bristol Myers Squibb, stated in a press release. “The positive results of the CheckMate-649 trial are potentially practice-changing, and we look forward to working with the FDA to possibly bring the first immunotherapy-based treatment option to front-line patients, for whom no novel therapies have been made available in the last decade.”

In the CheckMate-649 trial, total of 1581 participants were randomized in a 1:1 fashion to receive either nivolumab at a dose of 360 mg plus CapeOX every 3 weeks or nivolumab at a dose of 240 mg with FOLFOX every 2 weeks (n = 789) versus CapeOX or FOLFOX alone (n = 792). More than half of patients, or 60%, had a PD-L1 CPS of 5 or greater. The co-primary end points of the trial were OS and progression-free survival (PFS), while key secondary end points were OS in all randomized patients and those with a PD-L1 CPS of 1 or greater.

Additional results revealed that the median OS in the combination arm was 14 months in those with a PD-L1 CPS of 1 or greater compared with 11.3 months in the chemotherapy arm (HR, 0.77; 99.3% CI, 0.64-0.92; P = .0001). Moreover, the median OS with the combination versus chemotherapy alone was 13.8 months and 11.6 months, respectively, among all patients who underwent randomization (HR, 0.80; 99.3% CI, 0.68-0.94; P = .0002).

The safety profile of the nivolumab/chemotherapy combination was as expected, and no new signals were observed. Any-grade treatment-related toxicities reported in the subset of patients with a PD-L1 CPS of 5 or greater were reported in 95% of those on the investigational arm (n = 468) versus 88% of those on the control arm (n = 465). Grade 3 or 4 treatment-related adverse effects (TRAEs) occurred in 59% of those who received nivolumab/chemotherapy versus 44% of those who received chemotherapy alone.

More patients on the investigational arm discontinued treatment because of treatment-related toxicities compared with the control arm, at 38% versus 25%, respectively. Eight patients on the combination arm died because of a TRAE versus 4 patients on the chemotherapy arm.

The CheckMate-649 trial is also evaluating the combination of nivolumab plus ipilimumab (Yervoy); those in this arm were given nivolumab at a dose of 1 mg/kg plus ipilimumab at a dose of 3 mg/kg every 3 weeks for 4 cycles followed by nivolumab at a dose of 240 mg every 2 weeks. Data for this arm of the trial will be reported at an upcoming medical conference.

1. 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 January 20, 2021. http://bit.ly/3a4b6OL.

2. Moehler M. Shitara K, Garrido M, et al. Nivolumab (NIVO) plus chemotherapy (chemo) versus chemo as first-line (1L) treatment for advanced gastric cancer/gastroesophageal junction cancer (GC/GEJC)/esophageal adenocarcinoma (EAC): first results of the CheckMate 649 study. Ann Oncol. 2020;31(4):S1191. doi:10.1016/j.annonc.2020.08.2296

This article was originally published on OncLive as, "

FDA Grants Priority Review to Nivolumab/Chemo for Frontline Metastatic Gastric, GEJ, and Esophageal Cancer

Articles

Nivolumab/Chemo Granted Priority Review for Frontline Metastatic Gastric, GEJ, and Esophageal Cancer

Mean daily step count during the first 2 weeks of treatment with SM-88 (racemetyrosine) was found to correlate with overall self-reported quality of life (QoL) in patients with metastatic pancreatic cancer, according to the results from a preliminary exploratory analysis from part 2 of the phase 2/3 TYME-88-Panc trial (NCT03512756) presented during the 2021 Gastrointestinal Cancers Symposium.

All patients who enrolled on the trial and received treatment with SM-88 were given wearable devices to passively capture biometric data. Of these patients, 16 were synchronized on C1D1, 20 had available data that was synchronized within the first 2 weeks, and 1 patient did not have the technical support available to collect information.

The median baseline daily step count during the first 2 weeks of treatment with SM-88 was 3993.8 in patients who were alive (IQR, 2745.6-5078) versus 689.3 in patients who died (IQR, 630.0-2083.6) among those determined to be evaluable who had available data. Moreover, passively acquired mean heart rate during the third week of the trial among patients who died early was 89.3 (standard deviation [SD], 10.5) compared with 78.0 (SD, 9.2) in patients who were still alive. The medians were 87.0 and 79.2 for each cohort, respectively (P = NS).

When patients were asked question 29 (Q29) from the European Organization of Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ), which focused on overall health, during the second cycle, a median score of 3 was reported in patients who experienced early death versus 4.5 in those who were still alive. Moreover, mean steps during the first 2 weeks was found to be correlated with EORTC Q30 responses (r = 0.71; P = .01). From cycle 1 to cycle 2, patients who experienced early death had a median weight decrease of 2.5 lbs compared with 0.5 lbs in those who were still alive.

“Median daily baseline step counts were calculated for the first 2 weeks of treatment,” Vincent Chung, MD, an associate clinical professor in the Department of Medical Oncology & Therapeutics Research and director of the Phase I Program at City of Hope, said during a presentation at the meeting. “Even though the eligible patients enrolled had an ECOG performance status of 0-1, the subjects who died early had step counts that were 5 times less than that of the comparator group.”

SM-88 is an investigational dysfunctional tyrosine derivative that is given with 10 mg of methoxsalen (Oxsoralen), 50 mg of phenytoin (Dilantin), and 0.5 mg of sirolimus (Rapamune). The agent was developed to interrupt protein synthesis machinery, induce oxidative stress, and alter both autophagy and immune function.2 Thus far, the agent has been shown to have a survival benefit with favorable tolerability in heavily pretreated patients with pancreatic ductal adenocarcinoma (PDAC) who had achieved stable disease (HR, 0.08; P = .02).

Additionally, circulating tumor cells (CTCs) have demonstrated prognostic value in identifying a subgroup of patients with PDAC who may be more likely to glean benefit from SM-88. In a preliminary radiomic analysis, the largest metastases at baseline reportedly correlated with baseline CTCs.

The prospective, open-label, randomized TYME-88-Panc trial is currently enrolling patients with histologically or cytologically confirmed PDAC who have received at least 2 prior lines of systemic therapy and have acceptable adequate organ function.

Patients will be randomized 1:1 to receive either SM-88 (n = ~125) or investigator's choice of therapy (n = ~125). Patients will receive treatment until intolerable toxicity, progressive disease, or until any treatment discontinuation criteria are met.

The primary end point of the study is overall survival, with key secondary end points consisting of progression-free survival, clinical benefit rate, and QoL. Additionally, key exploratory end points include a biomarker analysis, which is comprised of CTCs and wearable device data.

The goal of the preliminary analyses of the randomized portion of the trial was to examine the potential role of SM-88 in the treatment of patients with metastatic disease through the use of CTC analysis and biometrics data that had been passively collected through a wearable device with data available as of September 15, 2020.

In total, 27 patients had available CTC data. Investigators collected isolated CTCs on the first day of each treatment cycle. Four phenotypic CTCs were noted by investigators, including epithelial cell surface marker Epi-positive, green fluorescent labeled CAM (GCAM)-positive, Epi-positive floating fraction, and GCAM-positive floating fraction.

Biometrics data were available for 20 patients. These data were also passively collected and included information on total number of steps taken per day and heart rate. This information was collected through wearable technology, such as a Fitbit, that was continuously worn by patients. Investigators examined patients who died early during the trial; this was defined as those who passed away within 3 months of randomization versus those who did not.

Additionally, patients were asked 2 global questions from the EORTC QLQ-C30 to determine a correlation with biometric parameters. One was Q29, which was "How would you rate your overall health during the past week?” The other was Q30, which was "How would you rate your QoL during the past week?"

Patients enrolled on the study had a mean age of 65 years (range 48-86) and a mean body mass index of 24.6 (range 18.8-38.7). Of the patients enrolled, 39.5% were female and 60.5% were male. The majority of patients were white (76.3%) and 15.8% were Asian. Moreover, patients had a mean CA 19.9 of 23,678.2 (range, 2.9-422,000.4) and a mean albumin of 3.8 g/dL (range, 2.7-4.6).

As of September 15, 2020, 67 patients consented to treatment, 38 of whom were randomized and considered evaluable. Roughly half, or 52.6%, (n = 20/38) of all patients were randomized to receive 920 mg of daily SM-88, while the remainder (47.4%; n = 18/38) were treated with standard of care.

Additional data revealed that the 4 CTC subpopulation phenotypes identified by investigators, defined by GCAM positivity, EPI positivity, and cluster status, were enumerated and correlated with one another (r = 0.03-0.71). At least 1 CTC subpopulation was identified at baseline in patients who had available data (n = 27), at a mean of 33.8 cells/2 mL. It was also revealed that the longest metastatic lesion diameter at baseline correlated with baseline CTCs (Epi-positive cluster, r = 0.55; P = 0.05; GCAM-positive cluster, r = 0.52; P = .07). Investigators were able to successfully separate and enumerate CTCs at each subsequent treatment cycle for further evaluation.

Notably, 166 adverse effects (AEs) were reported in 25 of the 38 patients enrolled on the trial, of whom 14 (56.0%) were treated with SM-88 and 11 (44.0%) with standard of care. Among these AEs, 6.02% (n = 10) were determined to be serious, having been reported by 4 patients on each respective arm of the study.

Of the reported AEs, 25.7% were determined to potentially be related to SM-88, while the majority were considered to be possibly be related to the standard-of-care chemotherapy (50.8%; P = .001). All AEs possibly related to treatment with SM-88 were grade 1 or 2 in severity with the exception of 4 hematologic events, 1 liver function test (LFT), and 1 case of abdominal pain.

The most common AEs associated with SM-88 were gastrointestinal (GI; 26.9%), dermatologic (19.2), and LFTs (19.2%), while the most frequent AEs observed in the standard-of-care arm were GI (48.5%), hematologic (24.2%), and dermatologic (15.2%).

Investigators concluded that biometrics can be passively collected and that they appeared to correlate with traditional clinical trial outcomes. CTC collection and enumeration also demonstrated feasible correlation with traditional clinical trial outcomes.

Moreover, possible important predicators of CTCs could include radiologic feature analysis due to the fact that the longest patient lesion diameter appeared to correlate with CTCs at baseline. The agent was also found to be well tolerated within this population, having elicited no grade 4 or 5 AEs.

1. Chung V, Oberstein PR, Lim KH, et al. Phase 2/3 study of SM-88 in patients with metastatic pancreatic cancer. Poster presenter at: 2021 Gastrointestinal Cancers Symposium; January 15-17, 2021; Virtual. Accessed January 15, 2021. Abstract #437. http://bit.ly/3nN1fkY

2. Fernandez-Zapico M, Kim DW, Philip P, et al. Therapeutic potential of targeting amino acid metabolism in pancreatic cancer. Cancer Res. 2019;79(suppl 24):B15. doi:10.1158/1538-7445.PANCA19-B15

3. Noel M, Wang-Gillam A, Ocean A, et al. SM-88 therapy in high-risk poor prognosis pancreatic cancer (PDAC). Ann of Oncol. 2019;30(suppl 4):IV16. doi:doi.org/10.1093/annonc/mdz155.058

4. Ocean A, Noel M, Wang-Gillam A, et al. Phase II monotherapy efficacy of cancer metabolism targeting SM-88 in heavily pre-treated PDAC patients. Ann Oncol. 2019;30(suppl 5):V275. doi:10.1093/annonc/mdz247.046

This article was originally publisjed on OncLive as, "

Mean Daily Step Count While Receiving SM-88 Correlates With Patient-Reported QoL in Metastatic Pancreatic Cancer.

Mean daily step count during the first 2 weeks of treatment with SM-88 (racemetyrosine) was found to correlate with overall self-reported quality of life (QoL) in patients with metastatic pancreatic cancer.

Step Count May Boost QOL in Patients Receiving SM-88

The FDA approved fam-trastuzumab deruxtecan-nxki (Enhertu) for the treatment of patients with locally advanced or metastatic HER2-postive gastric or gastroesophageal (GEJ) adenocarcinoma who previously received a trastuzumab-based regimen, according to the agency.

The FDA based its approval on findings from the multicenter, open-label, randomized DESTINY-Gastric01 trial (NCT03329690), which involved 188 patients with metastatic gastric or GEJ adenocarcinoma who progressed on at least 2 prior regimens: trastuzumab, a fluoropyrimidine-, or a platinum-containing chemotherapy.  Participants were randomized 2:1 to receive either 6.4 mg/kg of fam-trastuzumab deruxtecan-nxki every 3 weeks or physician’s choice of either irinotecan or paclitaxel.

Overall survival (OS), a co-primary end point, was higher in the fam-trastuzumab deruxtecan-nxki arm compared with the physician’s choice arm (12.5 months vs. 8.4 months, respectively.) Fam-trastuzumab deruxtecan-nxki also bested physician’s choice in objective response rate (ORR), the other co-primary end point. Confirmed ORR was 40.5% in the fam-trastuzumab deruxtecan-nxki arm, compared with 11.3% in the irinotecan or paclitaxel monotherapy arms.

Average progression-free survival (PFS) was also better with the fam-trastuzumab deruxtecan-nxki arm, at 5.6 months, compared to 3.5 months in the physicians’ choice arm. Average duration of response was 11.3 months in the experimental arm, compared with 3.9 months in the physcians’ choice arm.

Common adverse events, including laboratory abnormalities, that occurred in 20% or more of patients were: anemia, leukopenia, neutropenia, lymphocytopenia, thrombocytopenia, nausea, decreased appetite, increased aspartate aminotransferase, fatigue, increased blood alkaline phosphatase, increased alanine aminotransferase, diarrhea, hypokalemia, vomiting, constipation, increased blood bilirubin, pyrexia, and alopecia.

Nurses and other providers should note that the prescribing information for fam-trastuzumab deruxtecan-nxki includes a boxed warning regarding interstitial lung disease and embryo-fetal toxicity.

The FDA approved fam-trastuzumab deruxtecan-nxki (Enhertu) for the treatment of patients with locally advanced or metastatic HER2-postive gastric or gastroesophageal (GEJ) adenocarcinoma who previously received a trastuzumab-based regimen.

FDA Approves Fam-Trastuzumab Deruxtecan-nxki for HER2+ Gastric Adenocarcinomas 

The management of patients with colorectal liver metastases is complicated and requires careful assessment from a multidisciplinary tumor board—especially in light of recent advances made with chemotherapy, according to Michael J. Cavnar, MD. Now, efforts are being made to confirm the benefit of using hepatic artery infusion pumps to further improve outcomes.

“With the increasing efficacy of chemotherapy, more patients who once would have strictly received palliative therapy can now undergo surgery,” said Cavnar. “I also believe that we’re going to have level-one evidence illustrating the benefits of hepatic artery infusion pumps in the not-so-distant future. I have seen patients start off with high disease burden and, over time, become disease free.

Of course, this isn’t the case for everyone; some may progress on this or experience complications. However, I truly believe aggressive treatments such as this one are going to move the dial in metastatic colon cancer.”

 during the 2020 Institutional Perspectives in Cancer webinar on Gastrointestinal Cancers, Cavnar, an assistant professor of surgery at the University of Kentucky Markey Cancer Center, highlighted the role of surgery in colon cancer, the role of tumor sidedness in informing surgical decisions, and research efforts that are being done to evaluate the utility of hepatic artery infusion pumps.

 What are some of the key components of surgical care in CRC that everyone should be aware of?

 I'm a surgical oncologist, so the treatments I provide generally focus on surgery. However, for this disease process, we need to look at much more than surgery. When treating patients with colon cancer, we must collaborate with colleagues across many specialties, particularly those in medical oncology.

It’s also important to be aware of the historical aspects of liver metastases, which are largely surgical. Notably, several advances have also been made with chemotherapy, which is used around the time of surgery for after resection of liver metastases. We also [consider] palliative chemotherapy, which is given to [those with] unresectable disease.

In addition, [another topic of interest has to do with] the hepatic artery infusion pump, which is one of my areas of specialty. At the University of Kentucky, we have a clinical trial that has been ongoing for about 6 months now; this is an effort that I am actively working on.

Tumor sidedness is another key component to consider when selecting the appropriate treatment approach for patients with this disease. What are some of the factors that you use to inform surgical decisions?

The right side of the colon is the easiest to remove surgically. As such, if someone has a right-sided cancer, unless it's very bulky or advanced, we typically perform the surgery laparoscopically. A hospital stay for that type of operation could be several days, and recovery is typically quick. Left-sided disease, depending on where it is, can be more complicated. If the tumor is in the upper part of the left colon, we call this a descending or sigmoid colon. Those [cases], surgically, are fairly straightforward and usually don't involve a diverting ileostomy. As you get down into rectal cancer, which technically would fall under a left-sided disease, the surgical management is much more complicated and often involves neoadjuvant radiation. The anastomosis is much higher risk and is frequently protected with a diverting ileostomy, which later requires another surgery to reverse.

If a patient just has a primary tumor, the surgical aspects are the dominant factor because up-front surgery for primary colon cancer is the standard of care. If the patient has synchronous metastatic disease, meaning they have metastatic disease that is diagnosed at the same time as their primary tumor, then the left- versus right-sidedness helps guide the selection of chemotherapy; that is an evolving practice.

A typical first-line chemotherapy regimen for either a left- or right-sided colon cancer would be something like FOLFOX/bevacizumab [Avastin], which both should respond to. If you get into a situation where a patient could not receive bevacizumab, maybe due to some cardiovascular issues, then we consider adding other biologics. If [we are dealing with] a KRAS mutant left-sided tumor, then that patient would not receive an EGFR inhibitor.

What is your approach for treating liver metastases in practice? How has this evolved in recent years?

The standard of care largely depends on the burden of the disease. A patient with confined liver metastases and only 1 or 2 small lesions can be managed with a minimally invasive procedure. In my practice, smaller lesions are typically done with a laparoscopic or robotic approach, which consists of small incisions and a 1-2 day hospital stay. Almost all patients with metastatic colon cancer receive some type of perioperative chemotherapy. Although there are some variations to this, giving 6 months of chemotherapy both before and after surgery is fairly standard. As the number and the complexity of the metastases increases, things become more complicated.

Notably, there is this concept of a future liver remnant, which I believe is a major advancement in liver surgery. We used to be under the impression that, in order to do surgery on the liver, we had to do a major hepatectomy—either a left hepatectomy, which involves removing about 40% of the liver, or a right hepatectomy, which involves removing about 60% of the liver. These are major operations and about 5 years ago, they carried over a 5-year mortality rate. As the understanding of liver surgery and the biology of colon cancer has evolved, it's now understood that [the goal is focused] not so much about getting a wide margin, but about taking out the metastasis and leaving as much healthy liver as possible. Historically, major hepatectomies accounted for most surgeries performed; however, now they are the minority.

What data have been reported regarding the utility of hepatic artery infusion pumps?

Hepatic artery infusion pumps have been around since the 1970s. They basically capitalize on the fact that liver metastases obtain their blood supply from the artery that feeds the liver. Ultimately, the liver has a dual inflow of blood; about one-third is from the hepatic artery and about two-thirds is from the portal vein. For whatever reason, colorectal liver metastases only obtain blood flow from the artery, which has been demonstrated for many years.

In the 1970s, they started infusing chemotherapy directly into the liver. The dose that you would need to put into [a patient’s] veins to achieve that level would be incredibly toxic to the body. Instead, we can achieve a dramatic response by [infusing] a small amount [of chemotherapy] at a high concentration directly into theliver. Although this sounds great conceptually, we need to prove this. To this end, so much work has been conducted at Memorial Sloan Kettering Cancer Center; this is where I did all of my training and learned about the artery pump; it’s truly one of the biggest programs in the country and in the world.

Could you expand on some of these efforts?

Many clinical trials have been conducted over the years, with the early trials focused on how this [approach] could be [used] safely. [Investigators] generally started with patients who had high disease burden, along with those who had unresectable disease. These patients were initially given hepatic artery chemotherapy through the pump. However, early on, it was learned that although this controlled liver disease, patients could still develop lung metastases. They learned that you could safely give regular chemotherapy, along with pump chemotherapy; as such, this became the standard. They then played around with different regimens, determining which would be the best to give.

The biggest bulk of data are focused on adjuvant pumps; this means that patients who undergo complete resection of liver metastases have a pump implantation at the same time of their surgery, so they leave their operating room with a pump. Then, a few weeks after surgery, they start chemotherapy into the liver remnant.

This process has been studied in a randomized trial, which was first [published] in 1999 in the New England Journal of Medicine; there was follow-up [information that was released] later on. [The approach was found to] unequivocally lower recurrence within the liver. The randomized study compared patients who had resection and just received adjuvant fluorouracil [5-FU] versus that plus a hepatic artery pump. The study showed that, initially, the OS was significantly longer in patients who received the pump. At the 10-year follow-up, that statistical difference drifted a little bit. If you look at the graph, the curves are still different, but the P value is 0.1, which led many to believe that the pump did not work.

What is being done to settle the debate of whether the pump should be utilized in practice?

A trial examining today’s modern chemotherapy, with or without the pump, has not been done.

This is a very difficult study to set up because those who believe in the pump, like myself, believe in it strongly, while others really do not. That being said, I'm actually involved in a multinational consortium on the hepatic artery pump, which just started. We recently had a Zoom call with about 50 different surgeons from all over the world; it was impressive to see these people all together. We're in the early stages of developing [such a] clinical trial, [and] we believe we could prove [the effectiveness of] this [approach].

In the meantime, the group at Memorial Sloan Kettering Cancer Center has come out with really powerful support of this [approach in the form of] retrospective data. They had a paper published in 2016 in the Journal of Clinical Oncology that included about 2000 patients who had liver resection in result of CRC liver metastases.

All patients received modern chemotherapy, typically FOLFOX. They looked at the patients who received pumps and compared them with those who did not. They used propensity matching, which basically compares apples to apples and oranges to oranges, and the survival difference was dramatic. A 10-year survival of approximately 40% was reported [with the pump], which is essentially a cure, versus about 23% [in those without it]—almost a doubling of survival. We, in this consortium, mark that date as the time when the game started to change again.

Aggressive Treatment Approaches May Move Dial in Metastatic Colon Cancer.

The management of patients with colorectal liver metastases is complicated and requires careful assessment from a multidisciplinary tumor board&mdash;especially in light of recent advances made with chemotherapy, according to Michael J. Cavnar, MD. 

Team Up, Be Aggressive: Improving Outcomes for Metastatic Colon Cancer

Opioid misuse may lead to an increased risk of pancreatic cancer, according to recent research published in 

Scientists already know that certain lifestyle factors, such as smoking and alcohol use, may contribute to the development of pancreatic cancer, but while these risk factors have been decreasing over the years at a population level, pancreatic cancer instances have been rising. So, the researchers sought out to determine if opioid use — which has also been increasing – and pancreatic cancer have any kind of correlation.

“While opium use is not a common recreational habit in the US, opioid use has been rising remarkably over the past decade,” the researchers wrote. “In fact, opioid misuse and overdose have evolved into a public health crisis.”

Previous studies have shown that opioids may have “a potential to promote cancer progression and metastases in multiple different types of cancers…” researchers noted, supporting their reasoning for investigating any potential relationship between opioid use and pancreatic cancer.

The researchers used national databases to analyze pancreatic cancer incidence rates from 1999 to 2016 and opioid death rates (which points toward opioid misuse) between 1999 and 2016. Overall, there were 700,300 incident cases of pancreatic cancer and 351,630 opioid overdose deaths.

This data was analyzed on both a state and national level.

Increased opioid-related deaths had a statistically significant association with increased pancreatic cancer rates (p<.0001), as well as with alcohol use (p=.0007). Interestingly, there was no statistically significant correlation between obesity rates and pancreatic cancer incidence, (p=.493), though there was a correlation between obesity and risk of dying from the disease (p=.0002).

“Although the overall trend in [pancreatic cancer] rates is increasing across the states, the rate of the increase is larger for those states starting at lower opioid levels and lower for those that started with higher levels of opioid usage,” the researchers wrote.

The researchers explained that this study found that opioid use may be a risk factor for pancreatic cancer, laying the groundwork for future, larger studies to better understand the correlation between the two, if there is any.

If these findings are confirmed in future researchers, nurses and health care professionals nationwide may want to think twice before prescribing or administering this type of drug.

“Once confirmed, implications of the opioids on [pancreatic cancer] development are clinically significant given the widespread opioid usage in the country,” the researchers wrote. “Furthermore, opioids are widely used for pain management in pancreatitis, an established precursor to [pancreatic cancer], as well as in the cancer itself.”  

Opioid-Free Regimen Is Feasible After Laparoscopic Surgery

Patients’ Opioid Self-Management Poses Risks

Barlass U, Deshmukh A, Beck T, Bishehsari F. Opioid use as a potential risk factor for pancreatic cancer in the United States: An analysis of state and national level databases. PLOS One. Jan. 2021. 

https://doi.org/10.1371/journal.pone.0244285

Recent research found that there may be a correlation between opioid use and pancreatic cancer risk.
 

Opioid Use May Increase Pancreatic Cancer Risk

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The FDA has granted priority review to a new supplemental biologics license application for pembrolizumab (Keytruda) in combination with platinum- and fluoropyrimidine-based chemotherapy as a first-line treatment in patients with locally advanced unresectable or metastatic esophageal and gastroesophageal junction (GEJ) cancer.

The application is based on data from the phase 3 KEYNOTE-590 trial (NCT03189719), which showed that the frontline regimen significantly improved overall survival (OS), progression-free survival (PFS), and objective response rate (ORR) vs chemotherapy alone in this patient population.

Results presented during the 2020 ESMO Virtual Congress showed that the median OS with the chemoimmunotherapy regimen was 12.4 months vs 9.8 months with chemotherapy alone (HR, 0.73; 95% CI, 0.62-0.86; P <.0001).2 The OS rate at 12 months in the investigative arm was 51% vs 39% in the control arm; these rates were 28% vs 16%, respectively, at 24 months.

Additionally, the median PFS months per investigator assessment and RECIST v1.1 criteria was 6.3 months and 5.8 months with pembrolizumab/chemotherapy and chemotherapy alone, respectively (HR, 0.65; 95% CI, 0.55-0.76; P <.0001). The 12-month PFS rates were 25% vs 12% in the investigative and control arms, respectively; the rates at 18 months were 16% vs 6%, respectively.

Under Prescription Drug User Fee Act, the FDA must make a decision by April 13, 2021.

“Patients with newly diagnosed esophageal and GEJ cancer face an aggressive disease with a poor prognosis, despite the currently available treatment options,” Vicki Goodman, MD, vice president of clinical research at Merck Research Laboratories, stated in a press release. “We look forward to working with the FDA to bring a new option to patients in the first-line setting.”

In the randomized, double-blind, placebo-controlled phase 3 trial, investigators evaluated pembrolizumab in combination with chemotherapy compared with placebo plus chemotherapy in the first-line treatment of patients with advanced esophageal cancer.

To be eligible for participation, patients had to be treatment naïve, an ECOG performance status of 0-1, and measurable disease in accordance with RECIST v1.1 criteria. Patients also needed to have locally advanced resectable or metastatic esophageal cancer, ESCC, or advanced/metastatic esophagogastric junction Siewert type 1 adenocarcinoma.

Study participants were stratified based on several factors, including region (Asia vs non-Asia), disease (ESCC vs esophageal), and performance status (0 vs 1). Patients were randomized 1:1 to receive either intravenous (IV) pembrolizumab at a dose of 200 mg every 3 weeks for up to 35 cycles in combination with chemotherapy comprised of IV 5-fluorouracil at 800 mg/m2 on days 1-5 every 3 weeks for up to 35 cycles and IV cisplatin at 80 mg/m2 every 3 weeks for up to 6 cycles (n = 370) or just the chemotherapy agents plus placebo (n = 370).

The primary objectives of KEYNOTE-590 were OS and PFS per RECIST v1.1 criteria and investigator assessment. With regard to OS, the following patient subsets were evaluated: those with ESCC and a PD-L1 combined positive score (CPS) or 10 or higher, those with ESCC, those just with a PD-L1 CPS of 10 or higher, and the entire study population. PFS was evaluated in the following subgroups: those with ESCC, those with a PD-L1 CPS of 10 or higher, and all study participants. The secondary objective of the trial was ORR per RECIST v1.1 criteria and investigator assessment. Investigators evaluated patients for tumor response at week 9 of treatment and every 9 weeks thereafter.

Regarding safety, treatment-associated toxicities were experienced by 98.4% of patients who received pembrolizumab/chemotherapy vs 97.3% of those who received placebo/chemotherapy. Grade 3 or higher effects were reported in more patients who received the chemoimmunotherapy vs those who just received chemotherapy, at 71.9% vs 67.6%, respectively.

Toxicities determined to be related to treatment and led to discontinuation were reported in 19.5% of those given pembrolizumab/chemotherapy compared with 11.6% of those who received chemotherapy alone. Additionally, slightly more patients in the investigational arm experienced treatment-related adverse effects that resulted in death compared with those in the control arm, at 2.4% vs 1.4%, respectively.

Almost 26% of patients who received the chemoimmunotherapy regimen experienced immune-mediated toxicities vs 11.6% of those who received chemotherapy alone; these effects were grade 3 or higher in 7.0% vs 2.2% of patients, respectively.

Pembrolizumab was approved by the FDA in July 2019 for use as a single agent in the second-line treatment of patients with recurrent locally advanced or metastatic squamous cell carcinoma of the esophagus whose tumors have a PD-L1 CPS of 10 or higher.

The decision was based on data from the phase 2 KEYNOTE-180 and the phase 3 KEYNOTE-181 trials. In KEYNOTE-180, the agent was found to induce an ORR of 14% with a median duration of response that had not been reached in third-line patients with ESCC and tumors with a PD-L1 CPS of 10 or higher.3 In KEYNOTE-181, pembrolizumab monotherapy resulted in a median OS of 10.3 months vs 6.7 months with chemotherapy (HR, 0.64), an ORR of 22% vs 7%, respectively, and a median DOR of 9.3 months vs 7.7 months, respectively, in second-line patients with ESCC and a CPS of 10 or higher.

The agent was also approved in this indication in China and Japan.

1. FDA grants priority review to Merck’s supplemental biologics license application for Keytruda (pembrolizumab) plus chemotherapy as first-line treatment for locally advanced unresectable or metastatic esophageal and gastroesophageal junction cancer. News release. Merck. December 17, 2020. Accessed December 17, 2020. http://bwnews.pr/3ar7EQ1.

2. Kato K, Sun J-M, Shah MA, et al. Pembrolizumab plus chemotherapy versus chemotherapy as first-line therapy in patients with advanced esophageal cancer: the phase 3 KEYNOTE-590 study. Ann Oncol. 2020;31(suppl 4):S1192-S1193. doi:10.1016/j.annonc.2020.08.2298

3. Shah MA, Kojima T, Hochhauser D, et al. Efficacy and safety of pembrolizumab for heavily pretreated patients with advanced, metastatic adenocarcinoma or squamous cell carcinoma of the esophagus: the phase 2 KEYNOTE-180 study. JAMA Oncol. 2019;5(4):546-550. doi:10.1001/jamaoncol.2018.5441

4. Shah MA, Adenis A, Enzinger PC, et al. Pembrolizumab versus chemotherapy as second-line therapy for advanced esophageal cancer: phase 3 KEYNOTE-181. J Clin Oncol. 2019;27(suppl 15):4010. doi:10.1200/JCO.2019.37.15_suppl.4010

5. Pembrolizumab prescribing information. 2020. Merck Sharp & Dohme Corp. Kenilworth, NJ. Accessed December 16, 2020.

This article originally appeared on OncLive as, "

FDA Grants Priority Review to Frontline Pembrolizumab/Chemo for Locally Advanced Unresectable or Metastatic Esophageal/GEJ Cancer.

The FDA has granted priority review to a new supplemental biologics license application for pembrolizumab in combination with platinum- and fluoropyrimidine-based chemotherapy as a first-line treatment in patients with locally advanced unresectable or metastatic esophageal and gastroesophageal junction cancer.

FDA Gives Priority Review to Frontline Pembrolizumab/Chemo for Esophageal/GEJ Cancer Subset

Colorectal cancer (CRC) treatment has entered an era that is both exciting and challenging, according to Nilofer S. Azad, MD, who emphasized that as new strategies continue to be explored, treatment decisions should be informed by tumor location, the alterations present, and tolerability.

“In CRC, a number of emerging therapies are being explored in the third-line setting, which underscores the importance of referring patients to clinical trials early and often,” said Azad. “Notably, when selecting for second- and third-line treatment, we must pay close attention to whether a patient’s tumor is right- or left-sided.”

Beyond tumor sidedness, the identification of actionable alterations is also important, said Azad, as several options are now available for use. For example, patients who have KRAS wild-type disease can be given EGFR inhibitors, while those with BRAF mutations, can be given BRAF/EGFR combinations. Regorafenib (Stivarga) and TAS-102 (trifluridine/tipiracil; Lonsurf) have also entered the treatment arsenal.

 during the 2020 Institutional Perspectives in Cancer webinar on Gastrointestinal Malignancies, Azad, an associate professor of oncology at Johns Hopkins &#8203;University School of Medicine and director of the Developmental Therapeutics Clinical Trials Program at Johns Hopkins Sidney Kimmel Cancer Center, spotlighted recent advances made in CRC care, the significance of tumor sidedness in informing treatment decisions, and emerging efforts that seek to propel progress even further.

: What are some of the recent advances that have been made in CRC?

 CRC has entered a new era that is both exciting and challenging. We’re starting to make some real inroads in bringing down the incidence of the disease through excellent screening [practices] and more awareness of these efforts. A couple of new drugs have also been approved in the past few years for patients with advanced disease; these were the first few approvals that we have seen after [utilizing] the same tools for over a decade.

[Despite this progress], we’re seeing that in the vast majority of patients with advanced disease, our newer approvals are only modestly beneficial. We’re happy that there is benefit [with these agents] and that patients are living longer, but we definitely have more [work to do] before we are able to turn this into a truly chronic illness. Those are some of the challenges that we are still [faced with] but we are [developing a much better] understanding of what CRC is and how we can target it better.

How is tumor sidedness being used to inform treatment decisions?

For many years, it has been clear that right-sided CRC is more aggressive and resistant; this has been shown in many large epidemiological studies that evaluated the difference [in outcomes] between [those with] right- versus left-sided tumors.

As such, we knew that there was something biologically different about these cancers; however, it was not translating back to the way we treated patients. It was just something that we considered prognostically, but we [used] the same treatment options for both sides.

About 5 years ago, a series of important trials came out that demonstrated that these tumors are not only biologically different; they should be treated differently, as well. As such, now, when a patient has right- versus left-sided CRC, some data suggest that they may benefit from more aggressive chemotherapy.

Additionally, if a patient does not have a KRAS, BRAF or NRAS alteration and they have left-sided CRC, they may benefit more from EGFR inhibitors in the first-line setting for metastatic disease. Meanwhile, for patients with right-sided disease, that is not the case.

Speaking of using the presence of alterations to inform decisions, could you speak to the significance of germline testing in CRC?

The most common hereditary cancer syndrome is Lynch syndrome or hereditary nonpolyposis CRC. This is present in 1% to 2% of patients but is still the most common. That is the syndrome that we now know, in advanced cancers, is extremely sensitive to immunotherapy. There are other cancer types and other hereditary syndromes that are even more uncommon but, if you go to a genetics counselor, they will test broadly for all of these. Patients with strong family histories of many cancers over many generations should be tested, along with those who are younger. Although they have a low chance of having a hereditary syndrome, people who are diagnosed under the age of 50 should be assessed.

Moving to the third-line setting, what are some of the options that have emerged?

We have multiple third-line options available for patients. Patients who have KRAS wild-type disease can receive agents that target EGFR. For patients who have a BRAF mutation, there are combinations therapies that actually target these mutations comprised of a BRAF inhibitor and an EGFR inhibitor. For garden-variety CRC that does not fall into one of those subsets, we have regorafenib and TAS-102. These agents are relatively new, but we continue to gain more experience with them.

In your own practice, how do you choose between regorafenib and TAS-102 in the third- and fourth-line settings?

I have found that this [decision] is very provider dependent. If you look at both of these drugs, they have overlapping survival curves. In terms of the clinical benefits they provide, they're very similar. On the other hand, everyone has a different sense of how easy it is to dose these drugs and how well patients tolerate them. 

I find TAS-102 to be far more tolerable, so I start with this agent. We now have data from a small study [showing the benefit of] the combination of TAS-102 with bevacizumab (Avastin), which is an approach that I use in my practice. This was not a large, randomized phase 3 trial, but it was a randomized trial nonetheless.

In the initial study that was published in the New England Journal of Medicine and led to the approval of the agent, investigators looked at how long patients were able to maintain their fitness and performance status; that was not done with regorafenib. Compared with those who received placebo, patients who were given TAS-102 felt better for a longer period of time. I find these data to be very convincing.

How do the safety profiles of TAS-102 and regorafenib differ?

TAS-102 is a more traditional chemotherapy agent in both the way it works and the adverse effects (AEs) that patients experience. Common AEs include fatigue and low blood counts.

Regorafenib is a multi-kinase TKI; thus, its safety profile is much broader. Some of the common AEs include fatigue, nausea, hepatitis, diarrhea, and rash. Although there are many AEs, patients will not experience all of them.

What ongoing research efforts are you most excited about?

There is a lot of exciting research being done in CRC. For example, several immunotherapy strategies are being utilized in an attempt to make [this approach] work for the vast majority of patients [with CRC]. There are also emerging targeted agents that are hitting molecular [alterations] that are found in CRC. Finally, several new chemotherapy agents are also being explored.

Some of these research efforts are going to pan out while others will not. Even so, all of this work is equally exciting and truly emphasizes the importance of enrolling patients onto clinical trials [to continue to move the needle].

CRC Treatment Enters New Era Where Personalized Care Is King

Colorectal cancer (CRC) treatment has entered an era that is both exciting and challenging, according to Nilofer S. Azad, MD, who emphasized that as new strategies continue to be explored, treatment decisions should be informed by tumor location, the alterations present, and tolerability.
 

Personalized Treatment Is Paramount in Colorectal Cancer

As the treatment landscape for colorectal cancer (CRC) continues to change, there are key points that oncology nurses need to remember, according to Edith Brutcher, NP.

Brutcher, a nurse practitioner at the Emory Winship Cancer Institute and adjunct faculty at Emory Woodruff School of Nursing, discussed CRC updates at the 

“We’ve had such a rapid increase in what we can use now in the treatment of CRC,” Brutcher said. “Like me, you may remember when there was a time when there was just a few. And all of these advancements are really exciting.”

 mutation, while the other half is considered 

 wildtype. While mutational status could play a major role in determining a patient’s treatment, it is not the only factor to be considered, Brutcher said. The location of the cancer must be taken into account, too, especially when discussing potential outcomes with a patient.

Left-sided CRCs, which are more common, tend to have better response rates, while right-sided CRCs tend to have poor prognostic futures.  

 wildtype has the best prognosis, while right-sided 

wildtype disease has the worst prognosis.

“That’s why you may see in frontline therapy that left-sided, 

 an anti-EGFR antibody in the frontline therapy,” Brutcher said.

Another exciting development that Brutcher discussed was recent findings that showed that there was no statistically significant difference in outcomes between patients with stage II CRC who were given 3 months of adjuvant capecitabine (Xeloda) plus oxalipltin (Eloxatin) — a treatment known as CAPOX – compared to those who were given 6 months.

“So we can treat patients with 3 months of CAPOX and then have the same outcome as if you would have treated it for 6 months, which is very exciting for most toxicities,” Brutcher said.

In that same study, which was published in 

, a 3-month regimen of FOLFOX (fluorouracil, leucovorin, and oxaliplatin) did prove to be noninferior to the 6-month regimen, though the shorter treatment duration was less toxic.

“The outcomes of this trial were very interesting, and helped us to make treatment decisions,” Brutcher said.

Brutcher E. Advances in Colorectal Cancer Care: What Nurses Need to Know. Presented at: 38

 Annual CFS Virtual, Interactive Meeting. November 4-6, 2020

Petrelli F, Labianca R, Zaniboni A, et. al. Assessment of Duration and Effects of 3 vs 6 months of adjuvant chemotherapy in high-risk stage II colorectal cancer. 

2020;6(4):547-551. doi:10.1001/jamaoncol.2019.6486

A nurse practitioner discusses mutations, cancer sidedness, and treatment duration for patients with colorectal cancer.
 

NP Offers Insights on CRC Updates, Treatment Options

The FDA has accepted and granted a priority review designation to a supplemental biologics license application for the antibody-drug conjugate (ADC) trastuzumab deruxtecan (Enhertu) for use in patients with HER2-positive gastric or gastroesophageal junction (GEJ) adenocarcinoma.

The application was based on data from the phase 2 DESTINY-Gastric01 trial, which showed that the ADC elicited a higher objective response rate (ORR) compared with chemotherapy in patients with advanced, HER2-positive gastric or GEJ adenocarcinoma who had progressed following trastuzumab (Herceptin)-containing treatment.

 Specifically, the ORR was 51.3% versus 14.3% with trastuzumab deruxtecan and chemotherapy, respectively.

The ADC also led to a longer median overall survival (OS) compared with chemotherapy, at 12.5 months versus 8.4 months, respectively. Additionally, the median PFS and median duration of confirmed response (DOR) proved to be longer with trastuzumab deruxtecan.

“The results of the DESTINY-Gastric01 trial are unprecedented as they represent the first time a HER2-directed medicine has demonstrated an improvement in survival following chemotherapy and HER2 treatment in the metastatic setting,” Antoine Yver, executive vice president and global head, Oncology Research and Development at Daiichi Sankyo, stated in the press release.

“Building on the recent breakthrough therapy designation, the filing of the application and priority review by the FDA for this potential new indication for [trastuzumab deruxtecan] reflects the importance of the data and the significant unmet need for patients with previously treated HER2-positive metastatic gastric cancer,” added Yver.

In the open-label, multicenter, randomized phase 2 DESTINY-Gastric01, investigators evaluated the use of the ADC versus physician’s choice of standard chemotherapy in patients with HER-expressing advanced gastric or GEJ adenocarcinoma who had received at least 2 previous regimens, including fluoropyrimidine, a platinum-based agent, and trastuzumab or approved biosimilar.

The trial enrolled 187 patients who were randomized to receive either trastuzumab deruxtecan (n = 125) or chemotherapy (n = 62). Eighty-six percent of participants received prior treatment with a taxane, 71% had ramucirumab (Cymraza), and 31% received PD-1/PD-L1 inhibitors. At the November 8, 2019 data cutoff date, 22.4% of patients on the investigational arm were still receiving treatment compared with 4.8% of those on the control arm.

The primary end point of the trial was ORR per independent central review (ICR), while secondary end points comprised OS, DOR, PFS, confirmed ORR, and safety.

Additional data from the trial presented during the 2020 ASCO Virtual Scientific Program demonstrated that the ORR per ICR was substantially higher with the ADC versus chemotherapy, at 51.3% (n = 61; 95% CI, 41.9%-60.5%; P <.0001) and 14.3% (95% CI, 6.4%-26.2%), respectively. The complete response (CR) rate was 8.4% on the trastuzumab deruxtecan arm versus no CRs on the chemotherapy arm.

The confirmed ORR per ICR was 42.9% (n = 51; 95% CI, 33.8-91.5) with the ADC versus 12.5% (n = 7; 95% CI, 5.2-24.1) with chemotherapy. The confirmed disease control rates with trastuzumab deruxtecan and chemotherapy were 85.7% (n = 102; 95% CI, 78.1-91.5) and 62.5% (n = 35; 95% CI, 48.5-75.1), respectively. Moreover, the median confirmed DOR in the investigational and control arms was 11.3 months and 3.9 months, respectively.

The ADC also led to a significant improvement in OS compared with chemotherapy, with a median OS of 12.5 months (95% CI, 9.6-14.3) versus 8.4 months (95% CI, 6.9-10.7), respectively (HR, 0.59; 95% CI, 0.39-0.88; P =.0097). The OS rate at 1 year with the ADC was 52.1% compared with 28.9% with chemotherapy; the 6-month OS rates in the investigational and control arms were 80.3% and 66.4%, respectively.

Additionally, the median PFS with trastuzumab deruxtecan was 5.6 months (95% CI, 4.3-6.9) compared with 3.5 months (95% CI, 2.0-4.3) with chemotherapy (HR, 0.47; 95% CI, 0.31-0.71). The PFS rates at 1 year in the investigational and control arms were 29.9% and 0%, respectively; the 6-month PFS rates were 42.8% and 20.6%, respectively.

With regard to safety, the most commonly reported toxicities with trastuzumab deruxtecan that were grade 3 or higher included neutropenia, decreased appetite, anemia, thrombocytopenia, and decreased white blood cell count. Treatment-emergent adverse effects led to discontinuation in 15.2% of those who received the ADC versus 6.5% of those given chemotherapy. The rates of events associated with dose reductions were 32.0% in the ADC arm and 33.9% in the chemotherapy arm. Additionally, 62.4% of those on the ADC arm had events that led to dose interruptions versus 37.1% of those on the chemotherapy arm.

One treatment-associated death was reported in the trastuzumab deruxtecan arm, due to pneumonia; no deaths occurred on the chemotherapy arm. Twelve patients experienced interstitial lung disease/pneumonitis that was determined by an independent adjudication committee to be linked with the ADC. The median time to first onset was 84.5 days, but most cases were grade 1 or 2.

In May 2020, trastuzumab deruxtecan was granted a breakthrough therapy designation from the FDA for patients with unresectable or metastatic HER2-positive gastric or GEJ adenocarcinoma who had received 2 or more previous regimens, including trastuzumab. The ADC was also granted an orphan drug designation for patients with gastric cancer, including GEJ adenocarcinoma.

1. Enhertu granted priority review in the US for the treatment of HER2-positive metastatic gastric cancer. News release. AstraZeneca and Daiichi Sankyo Company. October 28, 2020. Accessed October 28, 2020. https://bit.ly/37PkgPy.

2. Shitara K, Bang Y-J, Iwasa S, et al. Trastuzumab deruxtecan (T-DXd; DS-8201) in patients with HER2-positive advanced gastric or gastroesophageal junction (GEJ) adenocarcinoma: a randomized, phase II, multicenter, open-label study (DESTINY-Gastric01). J Clin Oncol. 2020;38(suppl 15; abstr 4513). doi:10.1200/JCO.2020.38.15_suppl.4513

FDA Grants Priority Review to Trastuzumab Deruxtecan for HER2+ Metastatic Gastric Cancer.

Gastrointestinal Cancer