Uboha Underscores Latest Breakthroughs in Gastrointestinal Cancers

Nataliya V. Uboha, MD, PhD

The advent of novel targeted agents in the HER2positive gastric and gastroesophageal junction (GEJ) cancer paradigm and the emergence of innovative chemotherapy approaches in metastatic pancreatic cancer are representative of some of the key advances made in recent years, according to Nataliya V. Uboha, MD, PhD.

In gastric cancer, the January 2021 FDA approval of trastuzumab deruxtecan-nxki (Enhertu) for use in patients with locally advanced or metastatic HER2-positive gastric or GEJ cancer generated excitement, after data from the phase 2 DESTINY-Gastric01 trial (NCT03329690) showed that the antibody-drug conjugate (ADC) elicited an objective response rate (ORR) of 40.5% vs 11.3% with irinotecan or paclitaxel in patients who had progressed after a trastuzumab-based treatment.¹ Updated findings from the study, which were presented during the 2021 ASCO Annual Meeting, demonstrated a median overall survival (OS) of 12.5 months with trastuzumab deruxtecan vs 8.9 months with chemotherapy; the updated ORR was 51.3% vs 14.3%, respectively.² Now the phase 3 DESTINY-Gastric04 trial (NCT04704934) seeks to confirm the benefit reported with the agent in a larger, global population.

Another agent that has since emerged is the bispecific HER2targeted antibody zanidatamab, which has shown early clinical efficacy in the form of an ORR ranging from 33%, when used as a single agent, up to 57%, when paired with chemotherapy.³ Moreover, margetuximab-cmkb (Margenza), a HER2-directed antibody, has been shown to have an ORR of 10% when used as a monotherapy,⁴ and a potential survival benefit when paired with immunotherapy.⁵

In metastatic pancreatic cancer, investigators are building off the success seen in the NAPOLI-1 trial (NCT01494506) by examining liposomal irinotecan (Onivyde) in combination with 5-fluorouracil (5-FU)/leucovorin and oxaliplatin vs nab-paclitaxel (Abraxane) and gemcitabine in the phase 3 NAPOLI-3 trial (NCT04083235). If the data prove to be positive, investigators will have a new chemotherapy backbone to add novel agents to, according to Uboha, an assistant professor in the Department of Medicine at the University of Wisconsin School of Medicine and Public Health.

“[These] studies have [demonstrated] how much progress is being [made] in the field of gastrointestinal oncology,” Uboha said. “Several different drugs are in development that are now becoming available to our patients. The more treatment options we have, the better our patients will do.”

The Institutional Perspectives in Cancer webinar on gastrointestinal malignancies focused on updates in metastatic pancreatic cancer, gastric cancer, hepatocellular carcinoma, and younger patients with colorectal cancer. In an interview with OncLive^®, Uboha zeroed in on the developments with ADCs and monoclonal antibodies in gastric cancer and recent changes in pancreatic cancer as key takeaways from the event.

OncLive®: Trastuzumab deruxtecan is an important agent that has joined the gastric cancer arsenal. Could you speak to the significance of this agent in the paradigm?

Uboha: This was a big breakthrough in the treatment of [patients with] HER2-positive gastric and GEJ adenocarcinoma. The phase 3 ToGA trial [NCT01041404] established trastuzumab [Herceptin] in combination with chemotherapy as a first-line treatment for HER2-positive disease. Since then, a slew of trials have been trying to improve on that signal and introduce anti-HER2 agents in the second-line setting; however, the trials were negative for several reasons.

With this approval, a targeted therapeutic option [is added to the] HER2-positive gastric and GEJ adenocarcinoma [arsenal]. DESTINY-Gastric01 enrolled patients with HER2-positive gastric and GEJ adenocarcinoma who [had received at least 2 prior regimens]. Investigators compared the activity of this ADC with chemotherapy. The study met its primary end point of ORR, but also showed improved OS. Now, we can offer an additional line of therapy to patients, [for whom] there is such a huge need to improve outcomes.

What are the next steps for the ADC?

The trial on which the FDA approval [was based] was conducted exclusively in Asia. We know that molecular differences exist in the cancers [with regard to] the patient population and risk factors. As such, it is important to confirm the results of this trial in a Western population. Moreover, this was a phase 2 trial. We would like to see phase 3 data that could confirm the results [we have seen thus far]. To this end, a phase 3 trial is planned to launch later this year and [it will be conducted] in many different countries. It will be a second-line trial that will compare this ADC with standard-of-care ramucirumab [Cyramza] and paclitaxel.

Zanidatamab and margetuximab have also demonstrated early promise in this HER2-positive population. What is the hope for these agents?

The data [from] these agents are still very preliminary, but it is exciting to see a signal that could hopefully lead to positive data in larger studies. Zanidatamab is a bispecific anti-HER2 antibody that binds to 2 different epitopes; the first epitope is the same one that trastuzumab binds to, while the other is the same one that pertuzumab [Perjeta] binds to. This antibody demonstrated activity as a single agent and in combination with chemotherapy in patients who have received prior anti-HER2 therapy. The study was quite small [in terms of the] number of patients, but the signal was seen with both ORR as well as progression-free survival [PFS]. I believe this [agent] warrants study in larger trials to see whether this will also become an available option for our patients.

Margetuximab is another novel anti-HER2 antibody that binds to the same epitope as trastuzumab; however, it is engineered to allow for engagement of the immune system in a much more efficacious way. Margetuximab was studied both as a single agent and in combination with immunotherapy already. As a single agent, it demonstrated some activity with an ORR of 10% in patients with gastric and esophageal cancer. Interestingly, when examined in combination with immunotherapy, there was quite a significant ORR of over 40% in patients who are both HER2 and PD-L1 positive. Currently, an ongoing trial [MAHOGANY; NCT04082364] is looking at the combination of this antibody with [retifanlimab] in a biomarker-selected patient population, specifically PD-L1 positive and HER2 positive, in the first-line setting. The hope is that [with these efforts], we will be able to provide a chemotherapy-free option to some of our patients.

Switching over to metastatic pancreatic cancer, what have been the key lessons learned thus far with liposomal irinotecan, and what is the hope for the NAPOLI-3 trial?

NAPOLI-3, a phase 3, international study that is being done in patients with metastatic pancreatic cancer, [is comparing] standard-of-care gemcitabine and nab-paclitaxel with the combination of liposomal irinotecan, 5-FU, and oxaliplatin. The reason this trial was launched is because [the combination had been shown to have] early evidence of activity in a phase 1/2 trial [NCT02551991] performed in [patients with] metastatic pancreatic cancer. In the trial, the median OS was over 12 months and the median PFS was over 9 months, which suggests that this is an active regimen that compares favorably with other standard options for this disease.

We have also seen evidence to indicate that this regimen is well tolerated. We can’t make cross-trial comparisons, but grade 3 or higher diarrhea has been seen in about 9% of patients [who have received NALIRIFOX] compared with 19% [who received modified] leucovorin, 5-FU, irinotecan, and oxaliplatin. Neutropenia was also seen at very comparable levels [between the regimens], potentially even less frequently, and that is without the use of growth factor support. It will be nice to see the results of the phase 3 trial; if positive, and the regimen proves to be well tolerated, we will potentially have a different chemotherapy backbone to which we can add novel agents [like] immunotherapy.

Is there anything you would like to add about developments in gastrointestinal cancers?

Translational research is so important. At our university, a lot of preclinical work is being done to examine why these drugs work and how to make them better. [We also need to learn more about the] mechanisms of resistance; this is so critical when we think about [what] the next lines of therapies [will be] for our patients who are now getting exposed to these novel agents.

References

1. FDA approves fam-trastuzumab deruxtecan-nxki for HER2-positive gastric adenocarcinomas. News release. FDA. January 15, 2021. Accessed May 5, 2021. http://bit.ly/35KBZ8T
2. Meric-Bernstam F, Hamilton EP, Beeram M, et al. Zanidatamab (ZW25) in HER2-expressing gastroesophageal adenocarcinoma (GEA): results from a phase I study. J Clin Oncol. 2021;39(suppl 3):164. doi:10.1200/JCO.2021.39.3_suppl.164
3. Catenacci DVT, Rosales M, Chung HC, et al. MAHOGANY: margetuximab combination with HER2+ unresectable/metastatic gastric/gastroesophageal junction adenocarcinoma. Future Oncol. 2021;17(10):1155-1164. doi:10.2217/fon-2020-1007
4. Catenacci DVT, Kang Y-K, Park H, et al. Margetuximab plus pembrolizumab in patients with previously treated, HER2-positive gastro-oesophageal adenocarcinoma (CP-MGAH22-05): a single-arm, phase 1b-2 trial. Lancet Oncol. 2020;21(8):1066-1076. doi:10.1016/S1470-2045(20)30326-0