Expanding Molecular Testing Leads to Personalized Care in GI Cancer

John L. Marshall, MD

A key advance in treating patients with gastrointestinal (GI) cancer is molecular profiling of the tumor that results in specific targets being identified. The standard of care for GI cancer has consisted of surgery, radiotherapy, and chemotherapy, but these standards have had limited efficacy and considerable toxicity that impact patients’ quality of life.

With the advent of molecular testing in this setting, and across a range of cancers, clinicians now have a way to identify and characterize genetic mutations, amplifications, or fusions; develop epigenetic profiles; and determine protein expression or other molecular features.¹

“Molecular profiling continues to be the story,” John L. Marshall, MD, cochair of the 6th Annual School of Gastrointestinal Oncology® (SOGO®), hosted by Physicians’ Education Resource®, LLC (PER®), said during an interview with Targeted Therapies in Oncology prior to the meeting. Emphasis on molecular profiling will be a common thread running throughout the virtual, 1-day, multidisciplinary educational conference on March 20. Attendees can expect to see presentations about emerging therapies, evolving standards of care, and case histories in colorectal, gastroesophageal, and pancreatic cancer and gastrointestinal stromal tumors.

Immunotherapies in GI Cancer

Complementary to the expansion of molecular testing is the ongoing and emerging role immunotherapy plays in GI malignancies. Immunotherapy was initially met with skepticism a decade ago. It wasn’t until the breakthrough of immune checkpoint inhibitors that the idea of using the immune system to fight cancer became a reality, Marshall said. Marshall is a professor of medicine and oncology at Lombardi Comprehensive Cancer Center at Georgetown University and director of the Otto J. Ruesch Center for the Cure of Gastrointestinal Cancers in Washington, DC.

A major challenge for wider adoption of immunotherapy is that “unlike lung cancer, melanoma, or kidney cancer, where major breakthroughs were observed, GI cancers took a little bit longer,” Marshall noted.

But in June 2020, the FDA approved pembrolizumab (Keytruda) for the first-line treatment of patients with unresectable or metastatic microsatellite instability–high (MSI-H) or mismatch repair–deficient colorectal cancer.² The approval was based on findings from the KEYNOTE-177 trial (NCT02563002), which showed that after a median follow-up of 32.4 months (range, 24.0-48.3), pembrolizumab was superior to chemotherapy with respect to progression-free survival (PFS; median, 16.5 vs 8.2 months; HR, 0.60; 95% CI, 0.45-0.80; P = .0002).³

With the identification of MSI-H as a biomarker in GI cancers, the search has expanded to discover more biomarkers, especially in microsatellite-stable colon cancers and pancreatic cancers, “both of which are [difficult to treat] with regard to immunotherapy,” Marshall said.

Turning to hepatocellular carcinoma (HCC), Marshall said immunotherapy has had a significant impact on outcomes in this setting. “I never thought I would say as a GI cancer specialist that the disease that shows the most progress is liver cancer, because [historically,] it has been one of our most difficult cancers to treat,” Marshall said.

In HCC, nivolumab (Opdivo) and pembrolizumab (Keytruda), as well as the combination of nivolumab plus ipilimumab (Yervoy) have been granted accelerated approval for sorafenib (Nexavar)-experienced patients in the United States, based on encouraging response data from phase 1 and 2 studies.^4-6 However, subsequent phase 3 trials testing nivolumab versus sorafenib in first line and pembrolizumabversus placebo in second line both failed to meet their primary survival end points.^7,8

HER2-Positive Gastric Cancer

Promising news came out in January with the FDA approval of fam-trastuzumab deruxtecannxki (Enhertu) for the treatment of adult patients with HER2-positive locally advanced or metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma who have received a prior trastuzumab (Herceptin)-based regimen.⁹ The approval was based on findings from the phase 2 DESTINY-Gastric01 trial (NCT03329690).¹⁰

“We think with this recent approval in gastric cancer, colorectal cancer may quickly follow,” Marshall said.

The open-label randomized study explored the use of trastuzumab deruxtecan versus chemotherapy in patients with HER2-positive advanced gastric cancer or GEJ adenocarcinomathat had progressed on at least 2 prior therapies, including trastuzumab.

Overall survival (OS) was significantly longer for patients who received the trastuzumab deruxtecan, with a median of 12.5 months (95% CI, 9.6-14.3) versus 8.4 months (95% CI, 6.9-10.7) with chemotherapy (HR, 0.59; 95% CI, 0.39-0.88; P = .01). At 6 months, the OS rate was 80% with trastuzumab deruxtecan versus 66% with chemotherapy; the 1-year rates were 52% and 29%, respectively.

Median PFS was 5.6 months (95% CI, 4.3-6.9) with trastuzumab deruxtecan and 3.5 months (95% CI, 2.0-4.3) with chemotherapy (HR, 0.47; 95% CI, 0.31-0.71). The 6-month PFS rate was 43% in the investigational arm and 21% in the control arm, and the PFS rates at 1 year were 30% versus 0%, respectively.

Sequencing of Therapies

Perhaps one of the more daunting challengesthat clinicians face is the order in which treatments are sequenced, which is true in GI cancers but in other cancers as well. Should immune checkpoint inhibitors be given in the adjuvant or neoadjuvant setting?

In resectable, locally advanced esophageal cancer, for example, giving nivolumab after chemotherapy, radiation, and surgery has demonstrated promising results in CheckMate 577 ( NC T 0274 3 494).¹¹ Currently, the trimodal therapy of chemoradiotherapy followed by surgery is standard of care, yet the risk of recurrence is high.

In CheckMate 577, investigators reported that nivolumab provided superior disease-free survival (DFS), with a 31% reduction in the risk of recurrence or death. Median DFS in the nivolumab group (22.4 months) was double that in the placebo group (11.0 months; HR, 0.69; 96.4% CI, 0.56-0.86; P = .0003). DFS results also favored nivolumab across multiple patient subgroups.

Marshall said he expects change is on the horizon in this setting because in January, the FDA accepted a supplemental biologics license application for this indication and granted nivolumab priority review status based on the results of CheckMate 577.¹²

Staying current with emerging therapies remains of utmost importance. As oncology care as a whole shifts away from a one-size-fits-all approach to individualized and personalized care, a greater understanding about cancer and its variable expression emerges.

“I think it’s all about precision medicine, application, and biomarker-driven therapies,” Marshall concluded.

_REFERENCES

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_{6. Zhu AX, Finn RS, Edeline J, et al. Pembrolizumab in patients with ad-vanced hepatocellular carcinoma previously treated with sorafenib (KEY-NOTE-224): a non-randomised, open-label phase 2 trial [published cor-rection appears in Lancet Oncol. 2018 Sep;19(9):e440]. Lancet Oncol. 2018;19(7):940-952. doi:10.1016/S1470-2045(18)30351-6}

_{7. Finn RS, Ryoo BY, Merle P, et al. Pembrolizumab As Second-Line Thera-py in Patients With Advanced Hepatocellular Carcinoma in KEYNOTE-240: A Randomized, Double-Blind, Phase III Trial. J Clin Oncol. 2020;38(3):193-202. doi:10.1200/JCO.19.01307}

_{8. Yau T , Park JW , Finn RS , et al . CheckMate 459: a randomized, multi-center phase III study of nivolumab (NIVO) vs sorafenib (SOR) as first-line (1L) treatment in patients (PTS) with advanced hepatocellular carcinoma (aHCC). Ann Oncol. 2019;30:v874–5.doi:10.1093/annonc/mdz394.029}

_{9. FDA approves fam-trastuzumab deruxtecan-nxki for HER2-positive gastric adenocarcinomas. FDA. January 15, 2021. Accessed February 17, 2021. https://bit.ly/3sxawRJ}

_{10. Shitara K, Bang YJ, Iwasa S, et al; DESTINY-Gastric01 Investigators. Trastuzumab deruxtecan in previously treated HER2-positive gastric cancer. N Engl J Med. 2020;382(25):2419-2430. doi:10.1056/NEJMoa2004413}

_{11. Kelly RJ, Ajani JA, Kuzdzal J, et al. Adjuvant nivolumab in resected esophageal or gastroesophageal junction cancer (EC/GEJC) following neoadjuvant chemoradiation therapy (CRT): first results of the CheckMate 577 study. Ann Oncol. 2020;31(suppl 4): S1193-S1194. doi:10.1016/j.annonc.2020.08.2299}

_{12. US Food and Drug Administration accepts for priority review applica-tion for Opdivo (nivolumab) as adjuvant therapy for patients with resected esophageal or gastroesophageal junction cancer. News release. Bristol Myers Squibb. January 20, 2021. Accessed February 17, 2021. https://bit.ly/2M9etf0}