Research Clarifies Treatment Patterns and Raises New Questions Across GI Cancers

Jimmy Hwang, MD

The treatment advances made thus far for patients with gastrointestinal (GI) cancers are direct results of the work of multidisciplinary experts in the field who, despite facing a variety of unanswered questions, continue to collaborate to achieve a shared goal of improving patient care and strengthening therapeutic outcomes, according to Jimmy Hwang, MD.

“Cancer [care], perhaps more than any other disease, [requires] a team [effort],” Hwang said in an interview following an OncLive^® State of the Science Summit™ on GI cancer, which he chaired. “With that team cooperation, we have seen progress, maybe not as fast as we would like to see it, but we are making progress.”

In the interview, Hwang discussed findings supporting the use of immunotherapy in hepatocellular carcinoma (HCC) and biliary tract cancer, the potential benefits of antibody-drug conjugates in metastatic colorectal cancer (mCRC), unmet needs in esophageal squamous cell carcinoma (ESCC) and rectal cancer, and the increasingly important role of multidisciplinary approaches to address patient needs at every step of their treatment in the wake of shifting standards of care.

In patients with HER2 immunohistochemistry (IHC) 3+ or IHC2+/in situ hybridization–positive mCRC, the phase 2 DESTINY-CRC01 trial (NCT03384940) showed the efficacy of fam-trastuzumab deruxtecan-nxki (Enhertu), which, at a median follow-up of 62.4 weeks, elicited an overall response rate of 45.3% (95% CI, 31.6%-59.6%).¹ Hwang highlighted the significance of these results within the larger colorectal cancer (CRC) treatment paradigm. He also emphasized the significance of the phase 3 TOPAZ-1 trial (NCT03875235) in advanced biliary tract cancer, in which the addition of durvalumab (Imfinzi) to gemcitabine and cisplatin led to a median overall survival of 12.8 months (95% CI, 11.1-14.0) vs 11.5 months (95% CI, 10.1-12.5) with placebo plus gemcitabine and cisplatin.²

Hwang is a medical oncologist at Atrium Health’s Levine Cancer Institute in Charlotte, North Carolina.

OncLive®: Regarding the presentation given by Alaa Muslimani, MD, of Levine Cancer Institute, on updates in the treatment of HER2-positive mCRC, how do findings from the DESTINY-CRC01 trial support the use of trastuzumab deruxtecan in patients with advanced HER2-positive disease?

Hwang: To some extent, the findings were self-explanatory in the sense that certainly they and other supporting data suggest that in patients with HER2-positive CRC, trastuzumab deruxtecan does seem to have activity, and therefore, is potentially useful in those patients. The results were striking enough to reinforce data we’ve seen with other agents.

Caio Max Sao Pedro Rocha Lima, MD, MS, of Atrium Health Wake Forest Baptist Medical Center in Winston-Salem, North Carolina, discussed emerging treatment strategies in HCC. What are some of the limitations of first-line treatment options for patients in this population?

Outside the context of a clinical trial, in patients with good, preserved hepatic function, many exciting new options are available as we sit here in March of 2023, and there may be more in the offing. The advent of molecular immunotherapy, either combinations of immunotherapy [agents] with other immunotherapy [agents] or immunotherapy [agents] with VEGF inhibitors, has been beneficial in comparison with the prior standard of oral TKIs. That’s true regarding response in terms of survival, which is the most important [outcome], but also regarding total toxicity and tolerability, [which is] almost equally important.

One of the biggest challenges we have in this field is that although this is a good select group of patients, what are the best treatment options for the patients who don’t fit all those nice, neat little borders that we have on clinical trials? The reality is, we haven’t proven that immunotherapy is safe or tolerable in those patients. It’s less clear how we treat them. That will be an important next step for that group of patients, who comprise [around] 30% to 40% of the overall patient population with HCC.

Regarding the presentation given by Mohamed Salem, MD, of Levine Cancer Institute, on the role of immunotherapy in ESCC, what information with biomarkers remains to be determined in this area?

For esophageal squamous cell cancers, there are no biomarkers that definitively inform therapy. PD-L1 is 1 we think of, certainly in adenocarcinomas, in both esophageal and gastric [cancers, but] it’s less clear that it’s an important biomarker for ESCC.

Kunal Kadakia, MD, of Levine Cancer Institute, shared pancreatic cancer updates. What is the importance of germline testing for biomarkers that are predictive of response to platinum-based therapies in pancreatic cancer?

The data seem clear that germline testing may help identify patients who are more responsive to platinum-based therapies, as well as potential benefits for other subsequent therapies. The clearest biomarker-directing [approach] we have for pancreas cancer is germline testing.

Vernon Mackie, MD, of Levine Cancer Institute, discussed recent advances in advanced biliary tract cancer. What are some questions left unanswered by findings from the TOPAZ-1 trial?

TOPAZ-1 is an interesting study in terms of its results. The bottom line for me, and I think for patients, is that the addition of an immunotherapy [agent] like durvalumab to standard chemotherapy, helped patients live longer than those who got chemotherapy alone. There are still questions about what the optimal timing is for the combination, how long to combine them. However, regardless of those important, nuanced questions, adding immunotherapy clearly improves survival for patients.

Regarding the presentation by Joshua Hill, MD, MS, of Levine Cancer Institute, on surgical perspectives in rectal cancer, what are some of the most important aspects of multidisciplinary care that can improve outcomes for patients in this population?

The data have been increasingly clear that to have the best outcomes for patients with locally advanced rectal cancer, multidisciplinary therapy is necessary, both for the treatment and for the subsequent management of patients, regardless of biomarker selection. Even the patients with mismatch repair–deficient [dMMR] disease who may benefit from immunotherapy alone still need to be monitored, and that’s part of multidisciplinary care. However, for most patients, combining chemotherapy, radiation, and surgery seems to be important for getting us to the best outcomes we can, pending the outcomes of some other important ongoing studies like the [phase 2/3] PROSPECT trial [NCT01515787].

What is your main message for colleagues regarding the current state and future direction of GI cancer treatment?

The nice thing about this group of discussions is that while we haven’t seen as many of the home runs that we’ve seen in some other diseases, or in dMMR rectal cancer, [we have] a collection of data representing the efforts of thousands of [researchers] and thousands of patients that shows we’ve made progress in different diseases. Each step is an improvement in patients’ lives. That progress has required the assistance and cooperation of folks in a variety of fields.

GI oncology is a broad space, and we are making progress on broad fronts. However, [we will] require continued efforts across those fronts to continue making improvements like we have so far. We want to make sure we can spread those benefits across all patients, not just the ones who are well enough to participate in clinical trials.

What ongoing GI cancer studies at Levine Cancer Institute are you most interested in?

[We have] a couple of exciting studies ongoing here. We’d like to see more studies for the patients who don’t have diseases that are amenable to targeted therapies. Having said that, some of the exciting [trials] we’re getting ready to open are ones that involve targeted therapies, which is a smaller group of patients.

We’re part of the phase 1 expansion cohort [for the phase 1b/2 CodeBreak 101 trial (NCT04185883)] for patients with metastatic colon cancer that is KRAS G12C–mutated. [This trial is combining] sotorasib [Lumakras] with panitumumab [Vectibix], trying to see if targeting that escape mechanism can improve outcomes, as we’ve seen in some other early-stage studies.

One of the other exciting studies is [the phase 3 BREAKWATER trial (NCT04607421)] in patients with BRAF-mutated [CRC], in which we know that encorafenib [Braftovi] plus cetuximab [Erbitux] can improve outcomes in the late-line setting. [We are] trying to see whether targeting [BRAF] in the initial setting will improve outcomes, hopefully with a better toxicity profile than standard chemotherapies.

References

1. Yoshino T, Di Bartolomeo M, Raghav KPS, et al. Trastuzumab deruxtecan (T-DXd; DS-8201) in patients (pts) with HER2-expressing metastatic colorectal cancer (mCRC): final results from a phase 2, multicenter, open-label study (DESTINY-CRC01). J Clin Oncol. 2022;40(suppl 4):119. doi:10.1200/JCO.2022.40.4_suppl.119
2. Oh DY, He AR, Qin S, et al. Durvalumab plus gemcitabine and cisplatin in advanced biliary tract cancer. NEJM Evid. 2022;1(8). doi:10.1056/EVIDoa2200015