Discovering Fusions Requires More Than DNA Testing in GI Cancers

E. Gabriela Chiorean, MD

As targeted therapies in colorectal, gastroesophageal, biliary tract, and other gastrointestinal (GI) cancers continue to gain traction, and as additional therapeutic targets for novel agents emerge, consistently testing for biomarkers will be key to identifying more targetable alterations for novel therapeutics and determining which patients will benefit most from these therapies, according to E. Gabriela Chiorean, MD.

With the November 16, 2023, FDA approval of pembrolizumab (Keytruda) plus fluoropyrimidine- and platinum-based chemotherapy for the first-line treatment of adult patients with locally advanced unresectable or metastatic HER2-negative gastric or gastroesophageal junction (GEJ) adenocarcinoma,¹ another immunotherapy option has joined nivolumab (Opdivo) in the treatment paradigm.²

When considering how to best incorporate recently approved agents into care, Chiorean explained that pembrolizumab plus fluoropyrimidine- and platinum-based chemotherapy adds to the immune checkpoint inhibitor data that investigators already have with nivolumab. The 2021 approval of nivolumab in combination with fluoropyrimidine- and platinum-containing chemotherapy for patients with advanced or metastatic gastric cancer, GEJ cancer, and esophageal adenocarcinoma was supported by findings from the phase 3 CheckMate 649 study (NCT02872116). Patients with a combined positive score (CPS) of at least 5 who received the combination experienced a statistically significant improvement vs chemotherapy alone in progression-free survival (HR, 0.68; 95% CI, 0.58-0.79; P < .0001) and overall survival (OS; HR 0.71; 95% CI, 0.61-0.83; P < .0001). Irrespective of CPS score, all patients receiving the combination achieved a statistically significant improvement vs chemotherapy alone in OS (HR, 0.80; 95% CI, 0.71-0.90; P = .0002).²

“Nivolumab has been approved [by the FDA] for patients with HER2-negative gastroesophageal cancer [and it’s] mostly used for patients with [a] CPS of more than 5,” Chiorean said in an interview with OncologyLive. Chiorean is a full professor of medicine at the University of Washington, clinical director of the GI Medical Oncology Program at Fred Hutchinson Cancer Center, and director of the Clinical Research GI Oncology Program at the University of Washington/Fred Hutchinson Cancer Center in Seattle.

“Pembrolizumab has been approved irrespective of CPS, but we are very aware that the benefit is mostly for patients with a CPS higher than 1 or even higher than 10,” she explained. “Immunotherapies for advanced gastroesophageal cancers do apply for those with positive PD-L1 expression, whether it’s a CPS score more than 1, more than 5, or more than 10, depending on what immune checkpoint inhibitors we use.”

Looking Beyond DNA Testing To Find Alterations

As gene alterations become more prevalent therapeutic targets, DNA and RNA testing is of the upmost importance. Findings from a diagnostic study published in JAMA Oncology examining paired DNA and RNA sequencing of 43,524 individuals who underwent germline testing for hereditary cancer revealed that RNA evidence was necessary for the classification of 17.1% of pathogenic or likely pathogenic splicing variants. Additionally, 71.1% of existing splicing variants of uncertain significance were resolved by evidence from RNA tests. Investigators concluded that concurrent RNA and DNA sequencing improves detection of novel variants and classification of existing ones.³

“It’s exciting to apply these new therapeutics based on the targeted alterations that we find—we just have to test everybody,” Chiorean said. “We also have to be very careful to include both DNA testing as well as RNA testing because we may miss certain genetic alterations if we exclusively use DNA tests. There are RNA-based tests that can be more effective in finding genetic fusions, such as NRG1 fusions and RET fusions. These fusions are important because now we have agents targeting them.”

Pralsetinib (Gavreto) and selpercatinib (Retevmo) are both targeted agents included in the National Comprehensive Cancer Network guidelines for the treatment of patients with unresectable and metastatic biliary tract cancers with RET fusions.⁴ Additionally, selpercatinib holds an indication for patients with locally advanced or metastatic solid tumors with RET fusions who have progressed on or following prior systemic treatment or who have no satisfactory alternative treatment options.⁵

“We need to make sure we test [for] everything—microsatellite instability [MSI] status, tumor mutational burden, DNA, and RNA—in order to discover all the possible targetable alterations of our patients, because there are more and more treatments available, both in clinical trials and with FDA approvals.... Every tumor needs to be sequenced and when it’s not available we need to test [for] these molecular abnormalities with liquid biopsies [and] with circulating tumor [ct]DNA,” Chiorean said.

Approximately 50% of patients with colorectal cancer (CRC) will develop colorectal liver metastases––clinically heterogeneous lesions associated with poor prognosis.^6,7 In a retrospective study conducted in China that examined the genomic alterations of CRC liver metastases in 144 patients using next-generation sequencing, investigators found that the most prevalent alterations were TP53 (83%), APC (69%), KRAS (43%), and SMAD4 (17%).⁷

“We know that certain cancers are more likely to shed ctDNA in the blood—pancreatic cancer tends to be a cancer [that is] less positive [for] ctDNA, but in CRCs, especially in those with liver metastases, liquid biopsies are very useful,” Chiorean said.

Shooting For The Stars With Biomarkers

“Moreover, we are trying to conduct more tests regarding how we can declare whether the patient is immune competent vs not. How do we determine the immune microenvironment that could be more amenable to be targeted with immunotherapies or not?” Chiorean asked. “These are very new biomarkers, which are not genetic based; they are more [representative of] a profile having to do with a tumor microenvironment and the host that the patient represents. We are doing a lot of research in this arena in terms of finding new markers for immune therapeutics [and] for stroma-targeted therapies.”

In addition to the GI biomarkers of HER2 overexpression, MSI-high status, and PD-L1 expression, emerging biomarkers include CLDN18.2, which is present in approximately 30% of gastric/GEJ cancers, and FGFR2, which is rarer and reported in approximately less than 10% of gastric cancers.⁸

In July 2023, the FDA granted priority review to the biologics license application seeking the approval of the first-in-class monoclonal antibody zolbetuximab for the first-line treatment of patients with locally advanced unresectable or metastatic HER2-negative gastric or GEJ adenocarcinoma and CLDN18.2-positive tumors.⁹

Additionally, in April 2021, the novel FGFR2 inhibitor bemarituzumab plus modified fluoropyrimidine, leucovorin, and oxaliplatin (mFOLFOX6) received breakthrough therapy designation from the FDA for the frontline treatment of patients with FGFR2b-overexpressing, HER2-negative metastatic and locally advanced gastric and GEJ adenocarcinoma following positive results from the phase 2 FIGHT study (NCT03694522).¹⁰ Bemarituzumab is currently under investigation with mFOLFOX6 in the phase 3 FORTITUDE-101 trial (NCT05052801) and with mFOLFOX6 and nivolumab in the phase 3 FORTITUDE-102 trial (NCT05111626).¹⁰

“In addition, because [we can make] adoptive immunotherapies more active and reactive against the patient’s cancer using the patient’s human leukocyte antigen [HLA] testing, HLA testing is becoming more important. Knowing the proteins that present an antigen to the immune system such that patients may become able to participate in adoptive immunotherapy trials [is important]. Biomarkers are being extended beyond next-generation sequencing,” Chiorean noted.

Tying it All Together at SOGO

Chiorean noted that upcoming presentations at the 9th Annual School of Gastrointestinal Oncology® (SOGO®), which is scheduled to take place on February 24, 2024, in Los Angeles, California, will address these novel treatment options in addition to “various aspects of multidisciplinary care, ranging from the nonoperative or operative management of stage IV CRC to using targeted [therapy] and/or immunotherapy in early-stage gastroesophageal as well as hepatobiliary cancers. [The treatment of patients with] hepatobiliary cancers is typically very multidisciplinary because it involves surgery, interventional radiology, radiation oncology, and medical oncology.”

The American Cancer Society listed 11 regimens used to treat stage IV colon cancer in August 2023, noting that these were only “some of the most commonly used regimens.” Radiation and surgery were also cited as options in certain cases.¹¹

“A lot of debate exists in terms of managing stage IV CRC that has been resected, oligometastatic disease that has been resected, [and] the role of ctDNA. These sessions will be of huge interest [at SOGO 2024] in order to understand the players that have to be engaged in making treatment decisions for our patients,” Chiorean said.

At SOGO 2024, sessions will include “The Role of ctDNA in Colon Tumor Management” presented by Sidharth R. Anand, MD, MBA, who is a medical oncologist and hematologist at UCLA Health in Los Angeles, California, and “Management of Stage IV no evidence of disease [NED] CRC” presented by Marwan G. Fakih, MD, who is a medical oncologist, professor in the Department of Medical Oncology & Therapeutics Research, associate director for Clinical Sciences, medical director of the Briskin Center for Clinical Research, division chief of GI Medical Oncology, and co-director of the Gastrointestinal Cancer Program, all at City of Hope in Duarte, California.

“[We] are looking at the RAS inhibitors, pan-RAS inhibitors, [and] KRAS G12C inhibitors, both as monotherapy as well as in combination therapies,” Chiorean noted. “Certainly, we’re also looking at cancer vaccines [and] at oncolytic viruses. These are very exciting agents that may [become a part of] combination therapeutics with immune checkpoint inhibitors or even chemotherapies. Indeed, there are several classes of agents, both targeted as well as immune-based therapies, that are very exciting and I look forward to 2024 [to see] more, hopefully positive results.”

References

1. FDA approves pembrolizumab with chemotherapy for HER2-negative gastric or gastroesophageal junction adenocarcinoma. FDA. November 16, 2023. Accessed November 30, 2023. bit.ly/46FhSpl
2. FDA approves nivolumab in combination with chemotherapy for metastatic gastric cancer and esophageal adenocarcinoma. FDA. April 16, 2021. Accessed November 30, 2023. bit.ly/482TDSQ
3. Horton C, Hoang L, Zimmermann H, et al. Diagnostic outcomes of concurrent DNA and RNA sequencing in individuals undergoing hereditary cancer testing. JAMA Oncol. Published online November 4, 2023. doi:10.1001/jamaoncol.2023.5586
4. NCCN. Clinical Practice Guidelines in Oncology. Biliary tract cancers, version 3.2023. Accessed November 30, 2019. bit.ly/3RjK2Sa
5. NCCN. Clinical Practice Guidelines in Oncology. Colon cancer, version 4.2023. Accessed November 30, 2019. bit.ly/3N5l4Ud
6. Tsilimigras DI, Ntanasis-Stathopoulos I, Pawlik TM. Liquid biopsies in colorectal liver metastases: towards the era of precision oncologic surgery. Cancers (Basel). 2022;14(17):4237. doi:10.3390/cancers14174237
7. Bao X, Wang K, Liu M, et al. Characterization of genomic alterations in colorectal liver metastasis and their prognostic value. Front Cell Dev Biol. 2022;9:760618. doi:10.3389/fcell.2021.760618
8. Sato Y, Okamoto K, Kawano Y, et al. Novel biomarkers of gastric cancer: current research and future perspectives. J Clin Med. 2023;12(14):4646. doi:10.3390/jcm12144646
9. Astellas announces US FDA grants priority review for zolbetuximab biologics license application. News release. Astellas Pharma Inc. July 6, 2023. Accessed November 30, 2023. bit.ly/3Rmo7d2
10. Amgen’s investigational targeted treatment bemarituzumab granted breakthrough therapy designation. News release. Amgen. April 19, 2021. Accessed December 6, 2023. bit.ly/3nbaEnW
11. Treatment of colon cancer, by stage. American Cancer Society. Updated August 8, 2023. Accessed November 30, 2023. bit.ly/48f6yl5