Not only did ARO-HIF2, an investigational RNA interference (RNAi) therapy, reduce levels of hypoxia inducible factor-2 alpha (HIF2α) expression in patients with clear cell renal cell carcinoma (RCC), the agent was also found to have a manageable safety profile, according to data from the phase 1b AROHIF21001 trial (NCT04169711).

Findings from the trial, which were presented during the 2022 Genitourinary Cancers Symposium, showed that of 26 evaluable patients, 9 experienced a median reduction in HIF2α mRNA of 30% (range, -19% to -59%) by qPCR.

In the subset of patients who received ARO-HIF2 at 225 mg (n = 7) the median reduction in HIF2α mRNA was 46% (range, -22 to -47). In those who were administered 525 mg of ARO-HIF2 (n = 10), the median reduction in HIF2α mRNA was 27% (range, -19 to -39). In the subset of patients who were given 1050 mg of the agent (n = 9), the median reduction in HIF2α mRNA was 44% (range, -28 to -49).

Additionally, 14 patients achieved a median reduction in HIF2α protein of 26% (range, -1700 to -98) by immunohistochemistry (IHC). The HIF2α protein reduction rates in the 225-mg, 525-mg, and 1050-mg cohorts were 26% (range, -26 to -82), 47% (range, 0 to -90), and 0% (range, 1700 to -98), respectively.

“This ongoing phase 1 study provides initial proof of target engagement based on reductions in HIF2α expression, as well as an acceptable safety profile in response to escalating doses of ARO-HIF2,” lead study author James Brugarolas, MD, PhD, of UT Southwestern Medical Center, and colleagues, wrote in a poster on the findings.

HIF2α is usually expressed at low levels and targeted for degradation by the von Hippel-Lindau (VHL) tumor suppressor protein. However, VHL inactivation, which is a causative event of clear cell RCC, prompts tumorigenesis through uncontrolled HIF2α accumulation. The synthetic double-stranded RNAi trigger, ARO-HIF2, which includes an alpha-v beta3 targeting ligand, was developed to silence HIF2α expression.

The AROHIF21001 trial enrolled patients with advanced or metastatic clear cell RCC that progressed during or after at least 2 prior regimens which must have included a VEGF-targeted therapy and a checkpoint inhibitor therapy.

 To be eligible for participants, patients needed to be at least 18 years of age, have an ECOG performance status of 0 or 1, a life expectancy that was longer than 3 months, and organ function that was considered to be acceptable at the time of the screening.

Exclusion criteria included a history of untreated brain metastases, having received prior systematic therapy or radiation therapy within 2 weeks of the first dose of study treatment, or having previously undergone solid organ or stem cell transplantation. Moreover, patients could not be receiving current treatment with immune checkpoint inhibitors, nor could they have received prior HIF2 inhibitors within 6 months before their first dose of study treatment.

Intravenous ARO-HIF2 was administered weekly at 225 mg in cohort 1 (n = 7), 525 mg in cohort 2 (n = 10), and 1050 mg in cohort 3 (n = 9). Moreover, tumor growth was evaluated by biopsy at baseline and again at 2 weeks. Additionally, patients were evaluated for safety each week. Every 8 weeks, participants were examined for tumor response by RECIST criteria.

The primary end point of the study was to evaluate treatment-emergent adverse effects (TEAEs) associated with ARO-HIF2. Secondary end points included pharmacokinetics and preliminary efficacy per RECIST v1.1 criteria.

Exploratory end points included the assessment of post-dose tumoral expression of HIF genes in response to treatment with the agent, change in tumor integrin expression, correlation of integrin expression with changes in HIF gene expression, and the examination of serum biomarkers of agent activity. The correlation of disease-related gene expression to the activity of the agent is also under exploration. Plasma and urine metabolites will also be assessed.

Spanning cohorts, the mean age was 65.1 years (range, 44-87). Seventy-seven percent of patients were male. Regarding performance status, 42.3% of patients had an ECOG performance status of 0, and 57.7% had a status of 1. Most patients (53.8%) had intermediate-risk disease per International Metastatic RCC Database Consortium criteria; 23.1% had good-risk disease and 15.4% had poor-risk disease.

Additionally, 30.8% of patients received 2 prior lines of therapy, 30.8% received 3 prior lines, and 11.5% received 4 prior lines of therapy. Notably, 26,9% of patients received 5 or more prior lines of treatment. Prior treatment included anti-VEGF therapy (100%) and checkpoint inhibition (100%). Regarding 

 mutation status, 17.6% of patients had frame shift mutations, 29.4% had missense mutations, 5.9% had in frame deletion, 11.8% had no variant, and 35.3% did not have this information available.

Prior data from the trial showcased early signals of activity with ARO-HIF2 in the 225 mg and 525 mg cohorts.

 Specifically, 7 of 9 patients who had evaluable tumor samples and received treatment experienced reductions in HIF2α per IHC H-score. Notably, these reductions ranged from -9% to -82%, with a mean reduction of -48%.

Additional data presented during the 2022 Genitourinary Cancers Symposium showed that ARO-HIF2 elicited an objective response rate of 7.7% in all patients, with 2 patients experiencing a partial response. Furthermore, 30.8% of patients achieved stable disease and 50.0% experienced disease progression. One patient was not evaluable for response, and response data were missing for 2 patients. Overall, the disease control rate with the agent was 38.5%.

At least 1 TEAE of any grade occurred in 96.2% of patients. Specifically, 57.7% of patients experienced at least 1 grade 1 or 2 TEAE, 30.8% reported at grade 3 TEAE, 3.8% experienced a grade 4 TEAE, and 3.8% experienced a grade 5 TEAE. Serious TEAEs were reported in 34.6% of patients. Moreover, treatment-related AEs of any grade occurred in 65.4% of patients. One patient discontinued treatment due to TEAEs.

TEAEs of any grade that occurred in more than 4 patients included fatigue (50.0%), dizziness (26.9%), dyspnea (26.9%), nausea (23.1%), abdominal pain (23.1%), neuropathy (19.2%), and constipation (19.2%).

Enrollment for the phase 1 trial remains open and enrollment is ongoing.

Brugarolas J, Beckermann KE, Rini BI, et al. Initial results from the phase 1 study of ARO-HIF2 to silence HIF2-alpha in patients with advanced ccRCC (AROHIF21001). 

 2022;40(suppl 6):339. doi:10.1200/JCO.2022.40.6_suppl.339

Study of ARO-HIF2 in patients with advanced clear cell renal cell carcinoma. ClinicalTrials.gov. Updated April 19, 2021. Accessed May 3, 2022. 

https://clinicaltrials.gov/ct2/show/NCT04169711

Arrowhead announces positive interim results from phase 1b study of ARO-HIF2 for treatment of clear cell renal cell carcinoma. News release. Arrowhead Pharmaceuticals, Inc. July 6, 2021. Accessed May 3, 2022. 

This article was originally published on OncLive as “ARO-HIF2 Lowers HIF2α Expression and Demonstrates Favorable Safety Profile in Clear Cell RCC”

Articles

Patients with clear cell renal cell carcinoma experienced reduced levels of hypoxia inducible factor-2 alpha expression following treatment with ARO-HIF2. 

Investigational RNA Interference Therapy, ARO-HIF2, Yields Encouraging Phase 1 Results in Clear Cell RCC

Suppose you have a female patient who is 52 years old with a metastatic colorectal carcinoma (mCRC) diagnosis plus peritoneal carcinomatosis. This female patient has received 7 doses of FOLFIRI, followed by cytoreductive surgery with bilateral salpingo-oophorectomy, proximal colon, and omentectomy. After developing liver and lung metastases, this patient received 4 doses of FOLFIRI plus bevacizumab (Avastin).

One week following the final dose of FOLFIRI plus bevacizumab, she underwent a 13-cm small bowel resection for closed loop obstruction and lysis for adhesions.

This patient resumed chemotherapy for mCRC with 5 cycles of FOLFOX. However, on day 5 of cycle 5, she started to experience diffuse abdominal pain and arrived at the oncology urgent care. The night before, she drank a cup of tea and immediately vomited it; she found herself unable to tolerate any food or water over the prior 12 hours. Now she is still passing flatus but has not had any bowel movements since having a normal one yesterday morning.

What does ideal care for this patient look like?

In their presentation at the 47th Annual ONS Congress, “Complex Cases and Acute Management of Emergent Complications in Cancer Care,” Laura Zitella, MS, RN, ACNP-BC, AOCN, of the University of California San Francisco, discussed how best to care for a patient presenting this potential emergency.

Upon physical exam, it was revealed that this patient had mild tenderness to epigastrium, no abdominal distention nor any comorbidities, and an ECOG performance status of 1. A check of vital signs found that her temperature was 36.9o C, heart rate was 66 bpm, respirations are 18/min, and blood pressure is 124/72 mm Hg.

In addition, her white blood count was 8.8 x 109/L, hemoglobin was low at 11 g/dL, platelets count was 285,000/mm3, blood urea nitrogen (BUN) was 10 mg/dL, and creatine was 0.84 mg/dL. In addition, her potassium levels were 4.1 mEq/L, glucose was 107 mg/dL, calcium was low at 8.1 mg/dL, sodium was 137 mEq/L, chloride was 103 mEq/L, CO2 was 23 mgEq/L, albumin was 3.4 g/dL, magnesium was 2.mEq/L, and lactate was 1.1 mmol/L.

As a provider, it may seem there are many different potential diagnoses, Zitella noted. For example, the patient may be experiencing delayed chemotherapy-induced nausea and vomiting, pancreatitis, peritoneal metastases, appendicitis, bowel obstruction, gastroesophageal reflux disease, or a gastric ulcer. In this case a CT scan of the abdomen would be considered appropriate, she said.

“I find that workup of abdominal symptoms can be some of the most challenging,” she explained. “So, for this patient, we went straight to CT and got a CT of the abdomen. Often that’s what you have to do [because with] these patients there are so many different abnormalities, and it is really hard to assess [their condition] without having the proper imaging.”

The treatment algorithm for a case of malignant bowel obstruction is as follows: the provider must consider whether there is a concern for perforation, ischemia, or necrosis. If there is, then emergent surgery should be considered. If perforation, ischemia, or necrosis do not represent valid concerns, then surgery should be considered if there is evidence of closed-loop obstruction, volvulus, intussusception, or small bowel tumor.

If there is no evidence of these conditions, then a 24- to 72-hour trial of medical management should be applied. If this does not yield improvement, surgery may be considered, or, for some patients, a stent or venting gastrostomy tube may be appropriate.

The study authors noted that malignant bowel obstruction management decisions need to be highly individualized as this emergency is associated with a high rate of recurrence and morbidity.

Immediate management of malignant bowel obstruction involves the “drip and suck” approach: this comprises intravenous (IV) hydration with a normal saline solution or a lactated Ringer’s solution, a correction of fluid deficit, acid-base disorders, and electrolyte abnormalities, as well as nasogastric tube decompression if the patient is nauseated or vomiting.

Other important nursing considerations include an NPO order (nothing by mouth), monitoring urine output to assess hydration status, and serial abdominal exams. IV hydration helps prevents dehydration and correct electrolyte abnormalities, while opioids can help control pain.

Treatment with antiemetics can be useful for controlling nausea; steroids help decrease bowel edema, inflammation, and distention, while still providing antiemetic effects—dexamethasone at 4 mg/kg to 12 mg/day is recommended. Antisecretory medications can also be helpful in decreasing intestinal secretions, some treatment options include 1.5 mg of a scopolamine transdermal patch every 3 days, a histamine-2 blocker, glycopyrrolate at 0.1 mg to 0.2 mg IV 3 to 4 times daily, and octreotide at 100 mcg to 300 mcg subcutaneously 2 to 3 times per day or 10 mcg/h to 40 mcg/h continuous infusion. 

Finally, a nasogastric tube decompresses the stomach. This, in turn, can help resolve the obstruction. It can also be useful in preventing gastric content form aspirating. When placing the tube, output should be monitored and replaced with IV fluids. Additionally, when the output has become greater than 1 liter, the patient should be trialed for tube removal through clamping the tube. If there are residuals greater than 100 mL in 4 hours, the obstruction may have resolved.

A CT scan revealed that the patient was experiencing a partial small bowel obstruction with no evidence of peritoneal carcinomatosis or abdominal metastases.

“In this case, we managed her medically,” said Zitella. “This is in contrast to how she was managed earlier in the course of therapy when she did not have metastatic disease.”

Zitella added that the patient had a closed loop obstruction that was due to an adhesion.

“She was managed conservatively with bowel rest and IV fluids. NG (tube) to decompression was considered but she wasn't actively having nausea, vomiting, so we diverted as she preferred not to have it.

By her second day in the hospital, she began to feel less distended. She also had 2 bowel movements and was passing gas. She began a clear liquid diet, which she tolerated so well that she was advanced to a regular diet on the day of discharge.

Zitella noted that patients with a history of small bowel resection and adhesions may be at an increased risk for small bowel obstruction (SBO). This condition is often resolved spontaneous with medical management and there is currently no compelling evidence suggesting that surgery improved quality of life or survival in this patient population.

Patients with advanced cancer at an increased risk of recurrent SBO; surgically correctable caused may include closed-loop obstruction, volvulus, intussusception, and small bowel tumor.

Adhesions cannot be directly seen on any imaging studies, therefore adhesive SBO is diagnosed through exclusion: it is determined through a combination of known history of prior abdominal surgery with no alternative explanation for the obstruction.


Surgery should be considered carefully since it can be a transition to the terminal phase of the disease, it also carries the risk of additional adhesions.

“Surgery is really reserved for those cases where [there is] a keratitis or ischemia or a closed loop obstruction,” Zitella concluded, adding that, “the role of surgery [for] our patients has to be considered really carefully, because most patients who have a malignant bowel obstruction have a very poor survival and this would be a transition that this is sort of a crossroads in their in their face of care.”

Furthermore, small bowel obstruction is a diagnosis of exclusion, she reiterated to listeners. “It cannot be seen directly on any imaging adhesive,” she said. “It [involves] knowing that [patient’s] history and having no alternative explanation for the small bowel obstructions, and [understanding that], if there is advanced cancer, there's a very high risk of recurrence.”

1. Zitella L, Petrofsky M. Complex cases and acute management of emergent complications in cancer care. Presented at: 47th Annual Oncology Nursing Society Congress; April 27-May 1, 2022; Anaheim, CA.

2. Franke AJ, Iqbal A, Starr JS, Nair RM, George TJ Jr. Management of malignant bowel obstruction associated with GI cancers. 

. 2017;13(7):426-434. doi:10.1200/JOP.2017.022210.

Laura Zitella, MS, RN, ACNP-BC, AOCN, reviews a case study where a 52-year-old female patient with metastatic colorectal carcinoma begins experiencing diffuse abdominal pain. 

Complex Cancer Cases: Caring for a Patient With Malignant Bowel Obstruction 

Cholangiocarcinoma (CCA) and gallbladder (GB) cancers are rare types of gastrointestinal (GI) malignancies and account for 3% of all GI cancers. Each year, there are approximately 8000 new CCA and GB diagnoses in the United States.

The classification of CCA subtypes are determined by the location within the bile duct from which the tumor arises.

Intrahepatic cholangiocarcinomas (IHCCs) are tumors located within the hepatic portion of the bile ducts, whereas extrahepatic cholangiocarcinomas (EHCCs) are tumors that occur outside the liver and start at the junction of the left and right hepatic ducts, extending down to the common bile duct. EHCC can be subdivided into hilar or distal. Hilar tumors originate in the mid portion of the bile duct. GI specialists commonly refer to these as 

. In contrast, tumors that originate in the distal bile ducts are appropriately called 

Fortunately, CCAs are rare cancers, but they have a dismal prognosis. The 5-year overall survival (OS) for all stages and subtypes of CCA range between 2% and 25%.

 Because of this poor prognosis and lack of great treatment options, CCA is often fatal.



Historically, chemotherapy has been the only option for these cancers. Cisplatin (Platinol) and gemcitabine (Gemzar) represent the current standard of care to treat metastatic or unresectable disease. This has been the standard since the ABC-02 trial (NCT00262769) demonstrated that gemcitabine plus cisplatin significantly improved patient’s OS compared with gemcitabine alone in patients with biliary tract cancer (BTC).

Interestingly, one aspect of CCA that has evolved significantly over the years is our ability to identify and target proteins that are overexpressed on some CCAs. We typically target 

expression with pemigatinib (Pemazyre) or infigratinib (Truseltiq), 

 with dabrafenib (Tafinlar) and trametinib (Mekinist), 

 with entrectinib (Rozlytrek) and larotrectinib (Vitrakvi), and MSI-H with pembrolizumab (Keytruda).

Today, durvalumab (Imfinzi) represents the newest potential addition to the CCA treatment landscape. Durvalumab-related outcomes were presented at the 2022 American Society of Clinical Oncology GI Cancers Symposium as part of the TOPAZ-1 trial (NCT03875235). 

 This phase 3, randomized, double blind, placebo-controlled trial assessed the safety and efficacy of durvalumab in combination with cisplatin and gemcitabine in advanced BTCs. Eligible participants for the trial included patients with advanced IHCC, EHCC, and GB cancers, who had either not received prior therapy or had completed adjuvant therapy more than 6 months before study initiation. Patients also needed to have an ECOG status of 0 or 1.

Patients were randomized 1:1 to receive either durvalumab or placebo in addition to cisplatin and gemcitabine placebo for up to 8 cycles. Following these 8 cycles, maintenance therapy, either with durvalumab or placebo, was administered to the patients. Main study objectives included OS and progression-free survival.

Results from TOPAZ-1 showed that at a 13.7-month follow-up, the median OS was 12.8 months (95% CI, 11.1-14.0) in the durvalumab/chemotherapy arms vs 11.5 months (95% CI, 10.1-12.5) in the placebo/chemotherapy arms. Impressively, at a 24-month follow-up, OS rates were 24.9% in the study arm (95% CI, 17.9%-32.5%) and 10.4% in the control arm (95% CI, 4.7%-18.8%). Overall, the introduction of durvalumab resulted in a 20% reduction in the risk of death in this patient population (HR, 0.80; 95% CI, 0.66-0.97; 

These findings highlight a key take-home message from the trial: Although the results are modest, with no early separation of the curves, the tail of the curve is impressive. In addition, these findings suggest that by adding immunotherapy to first line chemotherapy, we can positively affect a subset of the population and impact their OS, possibly giving a small number of patients a longer disease-free interval or maybe even a cure. Identifying which patients will benefit remains a challenge.

Although CCAs are rare, they are starting to become known as one of the most targetable cancers within GI oncology, and genomic sequencing is now highly recommended for patients with unresectable or advanced BTCs. The results from the TOPAZ-1 trial will likely change clinical practice by demonstrating the potential value of immunotherapy in combination with chemotherapy for frontline treatment. We now have data showing superior outcomes for some patients, with a very acceptable safety profile.

Bile duct cancer (cholangiocarcinoma): statistics. Cancer.Net. Updated February 2022. Accessed March 1, 2022. https://bit.ly/3q9WtSC

NCCN. Clinical Practice Guidelines in Oncology. Hepitobiliary cancer, version 5.2021. guidelines: hepatobiliary cancers.Accessed March 1, 2022. https://bit.ly/36nr3Bc

Valle J, Wasan H, Palmer DH, et al. Cisplatin plus gemcitabine versus gemcitabine for biliary tract cancer. 

. 2010;362(14):1273-1281. doi:10.1056/NEJMoa0908721

Kam AE, Masood A, Shroff RT. Current and emerging therapies for advanced biliary tract cancers. 

. 2021;6(11):956-969. doi:10.1016/S2468-1253(21)00171-0

Oh DY, He AR, Qin S, et al. A phase 3 randomized, double-blind, placebo-controlled study of durvalumab in combination with gemcitabine plus cisplatin (GemCis) in patients (pts) with advanced biliary tract cancer (BTC): TOPAZ-1. 

. 2022;40(suppl 4):378. doi:10.1200/JCO.2022.40.4_suppl.378

Adding the immunotherapy to chemotherapy in the frontline setting may improve overall survival for patients with advanced biliary tract cancer.

Durvalumab Outcomes Could Change Treatment Approaches in Cholangiocarcinoma

Trastuzumab Deruxtecan Improves OS in Select Gastric/GEJ Cancer


Updated trial survival results from the phase 2 DESTINY-Gastric01 trial (NCT03329690) revealed that fam-trastuzumab deruxtecan-nxki (Enhertu) 

reduced mortality rates by 40% compared with standard chemotherapy

among patients with HER2-positive gastric cancer or gastroesophageal junction (GEJ) adenocarcinoma. The data were presented during the 2022 American Society of Clinical Oncology Gastrointestinal Cancers Symposium.

The updated median overall survival (OS) with trastuzumab deruxtecan remained at 12.5 months (95% CI, 10.3-15.2) compared with 8.9 months (95% CI, 6.4-10.4) with chemotherapy (HR, 0.60; 95% CI, 0.42-0.86).

In January 2021, the FDA approved trastu- zumab deruxtecan for the treatment of adult patients with locally advanced or metastatic HER2-positive gastric or GEJ adenocarci- noma who have received a previous trastu- zumab (Herceptin)-based regimen.

“With continued follow-up after the primary analysis, trastuzumab deruxtecan demonstrated a clinically meaningful OS benefit and clinically relevant improve- ment in [objective response rate] compared with standard chemotherapy in HER2- positive advanced gastric or GEJ cancer,” lead study author Kensei Yamaguchi, MD, of The Cancer Institute Hospital of the Japanese Foundation for Cancer Research in Tokyo, Japan, said in a presentation during the meeting.

Yamaguchi K, Bang YJ, Iwasa S, et al. Trastuzumab deruxtecan (T-DXd; DS-8201) in patients with HER2–positive advanced gastric or gastroesophageal junction (GEJ) adenocarcinoma: final overall survival (OS) results from a randomized, multicenter, open-label, phase 2 study (DESTINY-Gastric01). 

. 2022;40(suppl 4):242. doi:10.1200/JCO.2022.40.4_suppl.242

FDA approves fam-trastuzumab deruxtecan-nxki for HER2-positive gastric adenocarcinomas. News release. FDA; January 15, 2021. Accessed January 15, 2021. http://bit.ly/35KBZ8T

Ivosidenib Maintains Quality of Life in Patients With Cholangiocarcinoma 

promising preservation of health-related quality of life 

among patients with advanced chemotherapy-refractory cholangiocarci- noma and an IDH1 mutation, according to a long-term follow-up of the ClarIDHy study (NCT02989857). The data were presented at the 2022 American Society of Clinical Oncology Gastrointestinal Cancers Symposium.

Investigators specifically assessed how the oral targeted therapy impacted patients’ physical function, pain, and appetite loss compared with placebo. In terms of phys- ical function, the changes between baseline and 27 days of treatment did not reach the prespecified 12- to 13-point threshold— marking a lack of clinically meaningful decline among those treated with ivosidenib.

However, patients who received placebo demonstrated clinically meaningful dete- rioration across multiple cycles. Similarly, for pain, appetite loss, and eating, the least square means of change were reported for patients receiving ivosidenib compared with those on placebo.

“Cholangiocarcinoma is a rare and aggressive cancer, and treatment options
are primarily limited to chemotherapy. Mutations in the IDH1 protein have been found to occur in approximately 1% to 3% of intrahepatic cholangiocarcinomas and 1% of extrahepatic cholangiocarcinomas globally,” Christina X. Chamberlain, PhD, of Servier, explained in a presentation of the findings.

“Overall, patients who remain on ivosid- enib tend to maintain their health-related quality of life based on the least squares mean changes over time from baseline through cycle 27, day 1, which corresponds approximately to year 2,” she said.

Chamberlain CX, Hua Z, Gliser C, et al. Longitudinal trends in health-related quality of life (HRQoL) among patients treated with ivosidenib (IVO) for 

-mutated cholangiocarcinoma (CCA) in the ClarIDHy study. 

. 2022;40(suppl 4):388. doi:10.1200/JCO.2022.40.4_suppl.388

Adding Nivolumab to Encorafenib/ Cetuximab Yields High Response Rates in MSS, BRAF V600E+ Metastatic CRC 

Patients with refractory microsatellite stable, BRAF V600E–mutant metastatic colorectal cancer 

experienced high response rates and manageable adverse events 

after receiving nivolumab (Opdivo) in addition to encorafenib (Braftovi) plus cetuximab (Erbitux), according to data from a phase 1/2
trial (NCT04017650), presented during the 2022 American Society of Clinical Oncology Gastrointestinal Cancers Symposium.

The results highlighted an overall response rate of 50% (95% CI, 28%-72%) among those treated with the combina- tion, with all patients achieving partial responses. The disease control rate was 96% (95% CI, 77%-100%).

“Encorafenib, cetuximab, and nivolumab appears to be a safe and well-tolerated combination,” lead study author Van K. Morris, MD, an assistant professor in the Department of Gastrointestinal Medical Oncology, Division of Cancer Medicine at The University of Texas MD Anderson Cancer Center in Houston, said during a presentation of the data. “The efficacy of this combination appears promising when considering the precedent of encorafenib and cetuximab alone from the previ- ously reported BEACON [CRC] study [NCT02928224].”

The study regimen included a 300-mg dose of oral encorafenib that was administered daily, 500 mg/m2 of cetuximab intravenously every 14 days, and 480 mg of nivolumab intravenously every 28 days.

Morris VK, Parseghian CM, Escano M, et al. Phase I/II trial of encorafenib, cetuximab, and nivolumab in patients with microsatellite stable, BRAF V600E metastatic colorectal cancer. 

. 2022;40(suppl 4):12. doi:10.1200/JCO.2022.40.4_suppl.012

Ivosidenib maintains quality of life in cholangiocarcinoma, immunotherapy outperforms chemotherapy in select gastric/gastroesophageal junction adenocarcinoma, and nivolumab induces high response rates are observed among patients with BRAF V600E–mutant metastatic colorectal cancer.

2022 ASCO Gastrointestinal Cancers Symposium Highlights

Long-term data support capecitabine’s role as an adjuvant therapy for patients with curatively resected biliary tract cancer (BTC) and should continue to be considered as standard of care (SOC) for this patient population, according to an exploratory analysis of the phase 3 BILCAP study (EudraCT 2005- 003318-13) that was published in the 

At a median follow-up of 106 months (95% CI, 98-108), the median overall survival (OS) in the intention-to-treat (ITT) analysis for patients treated with capecitabine was 49.6 months (95% CI, 35.1-59.1) compared with 36.1 months (95% CI, 29.7-44.2) for those who underwent observation (adjusted HR, 0.84; 95% CI, 0.67-1.06). Moreover, in an analysis adjusted for minimization factors, nodal status, grade, and sex, the OS hazard ratio was 0.74 (95% CI, 0.59-0.94).

“These long-term data confirm the benefit of capecitabine as adjuvant therapy after surgical resection of BTC, which is now recommended by ASCO guidelines,” lead study author John Bridgewater, MD, PhD, UCL Cancer Institute and coinvestigators, wrote in the study.

Although intrahepatic cholangiocarcinoma is increasing worldwide, BTC remains a rare cancer, and is often linked with poor outcomes. For patients with operable disease, the 5-year survival rate is 25%. Five-year survival rates for those with advanced stage is less than 5%.

BILCAP is a randomized, controlled, multicenter, phase 3 study that enrolled 223 patients with BTC (histologically confirmed cholangiocarcinoma or muscle-invasive gallbladder cancer) resected with curative intent between March 15, 2006 and December 4, 2014. To be eligible for enrollment, patients needed to be at least 18 years old and have an ECOG status of 2 or higher.

Enrolled participants were randomized 1:1 to receive either oral capecitabine at 1250 mg/m2 twice daily on days 1 to 14 of a 21-day cycle for 8 cycles or observation.

OS was the trial’s primary outcome. Key secondary outcomes included a per-protocol (PP) analysis of the data and recurrence-free survival (RFS), as well as toxicity, health economics, and quality of life. Toxicity, health economics, and quality of life data are not yet mature.

The median RFS in the ITT analysis was 24.3 months (95% CI, (18.6-34.6) for patients who received capecitabine and 17.4 months (95% CI, 11.8-23.0) for patients undergoing surveillance. The median RFS in the PP analysis was 25.3 months (18.9-36.7) months with capecitabine and 16.8 months (11.8-20.7) with surveillance. After adjusting for resection, status, performance status, and site of disease, the HR was 0.77 (95% CI, 0.61-0.97). Furthermore, the adjusted HR for RFS was 0.74 (95% CI, 0.57-0.96) for the first 24 months, but data was insufficient beyond this 2-year time period.

At a 5-year analysis, the RFS rate in the ITT population was 34% (95% CI, 28-40) for patients receiving capecitabine and 31% for those undergoing observation.

These data suggest that local recurrence remains a significant issue for up to 50% of all patients after resection, whether the resection is classified as R1. However, local recurrence occurs more frequently in patients in R1, the authors stated.

“The frequency of local recurrence suggests the need to develop novel therapeutic strategies, accepting that more extensive surgery is seldom possible even in the context of expert centers. Neoadjuvant approaches or local therapies such as stereotactic radiotherapy warrant investigation,” the authors concluded.

Bridgewater J, Fletcher P, Palmer DH, et al. Long-term outcomes and exploratory analyses of the randomized phase III BILCAP study. Published online March 22, 2022. 

. 2022;JCO2102568. doi:10.1200/JCO.21.02568

A long-term analysis of the phase 3 BILCAP study highlighted modest benefit for patients with resected biliary tract cancer who received capecitabine following surgery. 

Adjuvant Capecitabine Continues as Mainstay in Biliary Tract Cancer, But More Research Is Needed in Neoadjuvant Setting

Frontline treatment with TTX-030 plus budigalimab and mFOLFOX6 was observed to be safe in patients with locally advanced or metastatic HER2-negative gastroesophageal junction (GEJ) adenocarcinoma, according to phase 1 findings recently presented at the 2022 AACR Annual Meeting. In addition, the anti-CD39 antibody yielded encouraging clinical activity across all participating populations, including patients with low PD-L1 combined positive scores (CPS).

Investigators also observed that the combined therapeutic was linked to an increase of PD-L1 and CD8 T cells.

Overall, TTX-030 as monotherapy or in combination was not associated with any reported drug-limiting toxicities, and the maximum-tolerated dose of TTX-030 alone was also undetermined. Based on these data, investigators determined that TTX-030 can be safely combined with FOLFOX and anti–PD-1 agents and administered to patients, so long as there are no excessive or synergistic toxicities.

In the total evaluable population (n = 40), the confirmed overall response rate (ORR) was 52.5%. A total of 4 patients experienced a complete response (CR; 10%) and 17 patients experienced a partial response (PR; 42.5%). Sixteen patients (40%) achieved stable disease (SD) and the disease control rate was 92.5% (n = 37), and 3 patients (7.5%) experienced disease progression.

In a subgroup of patients with a CPS score less than 1 (n = 11), the confirmed ORR was 36.4%, compared with 66.7% in those with a CPS score between 1 and 5. In patients whose CPS score as at least 5, the ORR was 64.3%.

“TTX-030 in combination with budigalimab and modified FOLFOX6 for the treatment of patients with HER2-negative metastatic gastric cancer was well tolerated without excessive toxicities,” Zev A. Wainberg, MD, professor of medicine at University of California, Los Angeles (UCLA), and co-director of the UCLA GI Oncology Program, said in a presentation of the findings. “It revealed promising antitumor activity, including in patients [with] PD-L1 tumor CPS less than 5, [and] induced intertumoral increases in PD-L1 expression and CD8 eight cells. These results support further evaluation of TTX-030 combination treatment in patients with metastatic gastric cancer.”

TTX-030 is the first fully human IgG4 antibody designed to target CD39, as well as the first CD39 agent to undergo a phase 1 trial. The non-competitive allosteric inhibitor of CD39 ectoenzyme enzymatic activity functions by binding and inhibiting CD39 at sub-nanomolar potencies in an environment with high extracellular ATP. In doing so, the agent increases extracellular ATP and consequently prevents the generation of adenosine.

“The blockade of CD39 is the first step involved in [the] process by which extracellular ATP is converted to ANP,” explained Wainberg. “The value of that is twofold because first [there is] suppression of adenosine, which is an immunosuppressive agent, along with the maintenance and increased production in essence of extracellular ATP; extracellular ATP has the advantage of activating an innate immune function. Therefore, we have this dual strategy behind blockade CD39.”

In this study, patients with a histologically or cytologically confirmed diagnosis of advanced unresectable or metastatic adenocarcinoma of the stomach or gastroesophageal junction with HER2-negative disease were enrolled to receive a 28 day-cycle of mFOLFOX6, budigalimab, and TTX-030.

To enroll, patients could not have received prior treatment for metastatic disease, nor could they have received neoadjuvant or adjuvant therapy within 6 months of trial enrollment. The study’s coprimary end points were safety and tolerability, while secondary end points included progression-free survival and ORR, per RECIST/iRECIST criteria.

In the dose-escalation and expansion phases, TTX-030 monotherapy doses ranged from 0.5 to 4.0 mg/kg every 3 weeks. The recommended phase 2 dose (RP2D) was determined to be a 40 mg/kg loading dose 7 days before day 1 of cycle 1. Once the cycle began, the RP2D was 20 mg/kg every 2 weeks.

The median age of patients was 61 years (range, 30-81), and 41% of patients were female; 57% of patients were Asian and 93% of patients were of non-Hispanic or Latino ethnicity. Most patients (61%) had an ECOG performance status of 1. Sixty-eight percent of patients had gastric adenocarcinoma, and the median number of prior therapies was 1.

Treatment is ongoing in 59.1% of patients, and the median time on study was 214 days (range, 8-464).

Overall, 11 patients (25%) experienced at least 1 grade 3 or greater adverse event (AEs) related to budigalimab, and 9 patients (20.5%) experienced at least 1 grade 3 AE related to TTX-030. Twenty-eight patients (63.6%) experienced at least 1 grade 3 AE regardless of relatedness. The most common AEs overall included increased gamma-glutamyl transferase (4.5%), hyperglycemia (4.5%), and deceased neutrophil count (34.1%), hyperglycemia (6.8%), febrile neutropenia (4.5%), and gastric perforation (4.5%).

Investigators are also evaluating the combination as a potential treatment for patients with pancreatic cancer.

Wainberg ZA, Kang YK, Lee KW, et al. Efficacy and safety of TTX-030, an anti-CD39 antibody, in combination with chemoimmunotherapy for thefirst-line treatment of locally advanced or metastatic gastric/GEJ cancer. Presented at: 2022 AACR Annual Meeting; April 8-13, 2022; New Orleans, LA. Abstract CT015.

TTX-030 is the first fully human IgG4 antibody designed to target CD39, as well as the first CD39 inhibitor to undergo a phase 1 clinical trial.

Frontline TTX-030 Plus Budigalimab/mFOLFOX6 Is Safe, Tolerable in Advanced Gastric/GEJ Cancer

Patients with microsatellite stable (MSS) and 

-silenced metastatic colorectal cancer (mCRC) experienced priming clinical benefit after receiving treatment with temozolomide priming followed by the combination of low-dose ipilimumab (Yervoy) and nivolumab (Opdivo), according to data from the phase 2 MAYA trial published in the 

The trial met its primary end point by demonstrating that the 9-month progression-free survival (PFS) rate among participants was 36% (95% CI, 23%-57%). At a median follow-up of 23.1 months (interquartile range, 14.9-24.6), 12 out of 33 patients achieved a PFS that was longer than 8 months.

In addition, trial participants achieved a median PFS of 7.0 months (95% CI, 5.5-8.3), and a median overall survival (OS) of 18.4 months (95% CI, 14.9–nonassessable). At a 12-month follow-up, the PFS rate was 24% (95% CI, 13%-44%), and at an 18-month follow-up, the PFS rate was 20% (95% CI, 10%-41%).

““The MAYA study provided evidence on the role of temozolomide as an immune-sensitizing agent for MSS and immune-cold mCRCs selected by the presence of 

 silencing and disease control on temozolomide priming,” lead study author Federica Morano, MD, of the Department of Medical Oncology at the Fondazione IRCCS Istituto Naziionale dei Tumori, and colleagues, wrote in the paper. “Further investigation is warranted to optimize the molecular and clinical selection of patients eligible for this therapeutic approach with the aim of maximizing its success rate.”

The oral alkylating agent temozolomide is approved for the treatment of patients with glioblastoma, and its efficacy is associated with the predictive biomarker, 

 promoter methylation. Because MGMT plays a role in the repair of DNA damage that is caused by alkylating agents, it is known that epigenetic 

silencing represents a mechanism of synthetic lethality following temozolomide exposure.

Although tumor responses to temozolomide are restricted to those with concomitant lack of MGMT protein expression, complete MGMT silencing at both the gene and protein level as well as proficient mismatch repair/MSS status, are needed but are not sufficient to adequately predict for response or benefit that will be derived with the agent.

Investigators hypothesize that acquired resistance to the drug could be linked with the onset of hypermutation with a certain genomic scar that is defined by C>T transitions and the frequent emergence of secondary mutations in MSH6 and other MMR genes. Evidence of this effect has been described in hypermutated relapses of glioblastoma, and in both models of CRC and patients with mCRC. MAYA was launched to provide clinical validation of this hypothesis.

The trial enrolled those with histologically confirmed metastatic and inoperable adenocarcinoma of the colon or rectum who were 18 years of age or older, had an ECOG performance status of 0 or 1, and measurable disease per RECIST v1.1 criteria. Patients also needed to have progressive disease, or a contraindication to irinotecan, fluoropyrimidines, irinotecan, and anti-EGFR drugs.

Moreover, patients needed to also have centrally confirmed MSS status per multiplex polymerase chain reaction, 

 promoter methylation per pyrosequencing, and MGMT absent expression per immunohistochemistry.

In the first treatment portion of the trial, 135 study participants were given oral temozolomide monotherapy at a once-daily dose of 150 mg/m2 on days 1 through 5, once every 4 weeks, for 2 cycles. By week 7 plus or minus 5 days, patients then underwent radiologic assessment per RECIST v1.1 criteria and blinded independent central review (BICR). Patients who were found to achieve a complete response (CR), a partial response (PR), or stable disease, then went onto the second treatment portion of the trial.

In this portion of the research, 33 participants received temozolomide at the same dose and schedule paired with a flat intravenous (IV) dose of nivolumab, given at 480 mg once every 4 weeks, and low-dose ipilimumab at an IV dose of 1 mg/kg once every 8 weeks. Here, patients received treatment until disease progression per RECIST v1.1 criteria, intolerable toxicity, withdrawn consent, death, or immune-related RECIST (ir-RECIST) progressive disease.

The primary end point of the trial was the 8-month PFS rate per investigator assessment in those who started the second treatment portion of the trial. Key secondary end points included PFS, OS, objective response rate (ORR) per RECIST v1.1 and ir-RECIST criteria, duration of response (DOR), safety, and quality of life. Other end points included BICR-assessed PFS, ORR, and DOR.

At a data cutoff date for the research was December 17, 2021, the median number of immunotherapy cycles received was 7 (range, 1-26). Moreover, a total of 26 RECIST v1.1 PFS events were reported, as well as 23 ir-RECIST PFS events. Seventeen deaths had occurred.

Regarding baseline characteristics, 72% of patients had 

-mutated tumors, which proved to be consistent with the profile of 

 hypermethylation. Fifty-five percent of patients had received 3 or more prior lines of treatment.

“When comparing patients with or without clinical benefit after temozolomide priming, no statistically significant differences were observed, except for lower median age and higher frequency of right-sidedness in patients who started the second treatment,” the study authors wrote.

Additional findings showed that the approach elicited an ORR of 45% (95% CI, 29%-62%) according to RECIST v1.1 criteria; this included 15 PRs and no CRs. Seventy-nine percent of patients experienced tumor shrinkage. When looking specifically at those included in the second treatment portion of the research, the ORR was found to be 18% (95% CI, 9%-34%). Moreover, the median DOR per RECIST v1.1 criteria was 4.8 months (95% CI, 3.8–nonassessable).

Regarding safety in the first treatment portion of the research, 53% of the 135 patients experienced any-grade adverse effects (AEs) associated with temozolomide; 3% of these effects were grade 3 or higher in severity. The most frequently experienced toxicities were noted to be hematologic and gastrointestinal effects. In the second portion of the research, 91% of patients experienced any-grade AEs and 21% experienced effects that were grade 3 or higher.

Immune-related effects included skin rash (any grade, 18%; grade 3 or higher, 6%), colitis (18%; 3%), hypothyroidism (21%; 0%), hyperthyroidism (9%; 0%), hypophysitis (6%; 3%), and adrenal insufficiency (3%; 0%).

“Our results represent the clinical transition of seminal efforts carried out in CRC models and patients and in other temozolomide-sensitive cancers,” the study authors concluded.

Morano F, Raimondi A, Pagani F, et al. Temozolomide followed by combination with low-dose ipilimumab and nivolumab in patients with microsatellite-stable, O6-methylguanine-DNA methyltransferase-silenced metastatic colorectal cancer: the MAYA trial. 

. Published online March 8, 2022. doi:10.1200/JCO.21.02583

This article was originally published on OncLive as “Temozolomide Followed by Low-Dose Ipilimumab/Nivolumab Shows Potential in MSS and MGMT-Silenced mCRC”

The addition of temozolomide to a low-dose treatment plan of ipilimumab and nivolumab extended progression-free survival among patients with metastatic colorectal cancer.

 Pretreatment With Temozolomide, Immunotherapy Combo Elicits Encouraging Responses in MSS and MGMT-Silenced mCRC

There are currently a variety of treatment options for patients with renal cell carcinoma—spanning from active surveillance for low-volume or indolent disease, to cytoreductive nephrectomy for diseases that have more favorable outcomes, as well as with immune-oncology (IO) agents or tyrosine kinase inhibitors (TKI) alone or in combination in advanced stages. However, determining the best treatment option for a newly diagnosed patient involves determining their risk stratification, according to Primo Nery Lara Jr, MD.

 Interdisciplinary Prostate Cancer Congress® and Other Genitourinary Malignancies, Lara, who is director of the University of California Davis (UC Davis) Comprehensive Cancer Center as well as Codman-Radke Endowed Chair in Cancer Research and executive associate dean for Cancer Programs at UC Davis Health in Sacramento, provided an overview of the treatment landscape for patients with metastatic RCC.

A key feature to developing treatment pathways that involve risk stratification according to International Metastatic RCC Database Consortium (IMDC) criteria is to leverage a multidisciplinary tumor board. “The [first] question that the tumor board tackles is whether an individual with metastatic RCC is a candidate for active surveillance.” Lara said.

From that point, several options are available including cytoreduction and combination immunotherapy-based therapy which is the standard of care for most patients.

IO Eligibility: Choosing the Right Treatment Path

With numerous approved combination regimens, including dual IO therapies and IO/TKI combinations, Lara noted that strategies for choosing between regimens goes beyond eligibility and relies on risk stratification. “The standard of care in 2022 for metastatic kidney cancer is immunotherapy-based combination therapy,” Lara said. “Most of these patients should be considered for combination therapies, and there are several combinations that we would offer depending on their risk group.”

If a patient is deemed eligible for an IO-based combination, patients with favorable-risk, intermediate-risk, and poor-risk disease have several options available including pembrolizumab (Keytruda) in combination with either axitinib (Inlyta) or lanvantanib (Lenvima), nivolumab (Opdivo) plus cabozantinib (Cabometyx), or avelumab (Bavencio) plus axitinib.

For those with intermediate- or poor-risk disease, Lara noted that the immunotherapy doublet of nivolumab plus ipilimumab (Yervoy) is the preferred treatment option, noting that the combination does not improve outcomes over sunitinib (Sutent) alone for those with favorable-risk disease.

Four-year follow-up data from the phase 3 CheckMate 214 trial (NCT02231749), which led to the approval of nivolumab (Opdivo) plus ipilimumab (Yervoy) in patients with frontline metastatic RCC, show advantage of the combination vs sunitinib in terms of OS for the intention-to-treat population (HR, 0.69; 95% CI, 0.59-0.81) and the intermediate/poor-risk subgroup (HR, 0.65; 95% CI, 0.54-0.78).

 Patients with favorable-risk disease failed to derive an OS benefit (HR, 0.93; 0.62-1.40).

“[This combination] would be great for intermediate- and poor-risk disease, not so much for favorable risk where it was no better than sunitinib,” Lara said

Despite being recommended for all-risk groups, Lara noted that, most of the benefit with pembrolizumab/axitinib in the phase 3 KEYNOTE-426 trial (NCT02853331) was isolated to patients with intermediate/poor-risk disease. Updated data at the 42-month follow-up showed sustained OS benefit of the combination (HR, 0.73; 95% CI, 0.60-0.88; 

< .001) vs sunitinib in the intention-to-treat population.

 The benefit was more prominent in the progression-free survival (PFS) analysis with a median PFS of 15.7 months (95% CI, 13.6-20.2) with the combination vs 11.1 months (95% CI, 8.9-12.5) with sunitinib (HR, 0.68; 95% CI, 0.58-0.80; 

In terms of the other recommended therapies, Lara highlighted the advantage of the IO combinations vs single-agent TKI for patients with all-risk disease who are eligible for this treatment pathway. In data from the phase 3 CheckMate 9ER trial (NCT03141177), which supported the approval of cabozantinib and nivolumab in this setting, Lara spotlighted OS results which showed a 40% reduction in the risk of death with the combination vs sunitnib (HR, 0.60; 98.89% CI, 0.40-0.89; 

Finally, the phase 3 CLEAR trial (NCT02811861) showed an advantage of lenvatinib plus pembrolizumab vs sunitinib in terms of PFS (HR, 0.39; 95% CI, 0.32-0.49; 

 < .001) and OS (HR, 0.66; 95% CI, 0.49-0.88; 

Comparing results of CLEAR with the previously reviewed trials, Lara said “results superficially seem to be better if you look at the complete response rate, the median PFS, and [OS]. But you must note that this trial had the lowest percentage of poor-risk patients [vs other pivotal trials reviewed], which will drive a lot of the of the results of these trials.”

Patients with metastatic renal cell carcinoma have multiple effective frontline treatment options. 

Gastrointestinal Cancer