Esophageal Cancer Awareness Month: Paradigm Shifts in Targetable Disease

Arturo Loaiza-Bonilla, MD, MSEd

A new array of biomarker-based targeted therapies are on the horizon for patients with esophageal and gastroesophageal junction (GEJ) cancers, and it is important for healthcare providers to be aware of the recent changes in this evolving field.

In the setting of advanced disease, standard-of-care treatment has incorporated immune checkpoint inhibitors and other types of agents beyond chemotherapy. Patients with HER2-positive adenocarcinoma who received trastuzumab (Herceptin) and progressed can now receive the antibody-drug conjugate fam-trastuzumab deruxtecan-nxki (Enhertu) in the second line.¹

Drugs targeting other molecular biomarkers such as Claudin18.2 and NRG1/NRG2 have shown efficacy in recent clinical trials. Broader use of biomarker testing is now crucial to identifying less common targets such as KRAS to provide another avenue of treatment for eligible patients.

“Everyone should be tested with broad panels, looking for all those biomarkers, because you [wouldn't] want to miss that for yourself,” said Arturo Loaiza-Bonilla, MD, MSEd, in an interview with Targeted Oncology^TM for Esophageal Cancer Awareness Month.

With these developments, there are new challenges to adopting and sequencing new therapies as well as ensuring patients have access to clinical trials when the standard of care does not offer the best possible outcomes.

Loaiza-Bonilla, a medical oncologist and director of research at Capitol Health Cancer Center, discussed the pressing need to keep up with the developments in targeted therapies for esophageal and GEJ cancers.

Targeted Oncology^TM: How has the field changed compared with a few years ago for esophageal cancer?

LOAIZA-BONILLA: This is an evolving field because for many years we were used to only using chemotherapy for the first line and we didn't have a lot of biomarkers to guide our treatment, particularly in the metastatic setting. With the advent of the most recent clinical trials, we have seen a proliferation of biomarkers, incorporation of immune checkpoint inhibitors to our treatment paradigm, and going beyond [targeting] HER2. Within HER2, investigators are looking at the sequencing of treatments and how we can make the best outcomes for patients as we move along in the treatment paradigm.

What trials have been the most practice changing recently?

Esophageal cancer has had a tremendous number of successful studies that have changed the way we treat [patients]. One of the first things that we're seeing is incorporation of checkpoint inhibitors. The first one is the incorporation of nivolumab [Opdivo] based on CheckMate 649 [NCT02872116], where fluoropyrimidine plus oxaliplatin with or without nivolumab was investigated in patients with a CPS [composite positive score] of 5 and above.² This added on to the armamentarium of how patients are treated.

[Another trial looked at] the incorporation of pembrolizumab [Keytruda], which is another checkpoint inhibitor we use now in the first-line setting, in this case with a different cutoff of CPS score of 10 and above. This was with fluoropyrimidine, [oxaliplatin], plus pembrolizumab in the KEYNOTE-590 trial [NCT03189719].³ So now we have CheckMate-649, we have KEYNOTE-590, and lastly, in the HER2-positive space, we have...KEYNOTE-811 [NCT03615326], where we incorporated not only the addition of trastuzumab to fluoropyrimidine and oxaliplatin, but also added pembrolizumab for those patients.⁴ That was also a positive study.

It's [been] a whirlwind of new things happening and a lot of controversy as well, because we have a couple of checkpoint inhibitors to use now. Which do we use first? What assay do we test? Should we do the CPS score with one specific assay versus the other? How [do we] make the best decisions for our patients with multiple biomarkers [they were tested for] from the very beginning?

Do you have preferences when it comes to sequencing these therapies for your patients?

The major…change in terms of sequencing has been based on the HER2 space. In the past, we added on trastuzumab to the first-line chemotherapy, and sometimes [investigators] added on new treatment options. Now, there are data using trastuzumab with a payload in the DESTINY-Gastric01 study [NCT03329690] of trastuzumab deruxtecan [Enhertu] in previously treated patients with HER2-positive GEJ adenocarcinoma. There was a significant improvement in overall survival and progression-free survival that now made it an option for patients in the second line.⁵

There are additional studies coming up that are trying to tell us [if] there's also room here to use tyrosine kinase inhibitors, for example, tucatinib [Tukysa] and trastuzumab. There are a number of options that we have in front of us. That is the sequencing part that is becoming much more interesting.

In the patients who were already treated with checkpoint inhibitors in the first line, is there any role for rescue with other kinds of agents, for example, CTLA-4/PD-1 combinations? The jury is still out on those. [Another question is] how to sequence therapy for patients who have gone into the second line past checkpoint inhibitors using taxanes and ramucirumab [Cyramza]. For those patients in the second line, what do we use in the third line when we also have options such as TAS-102 [trifluridine/tipiracil hydrochloride; Lonsurf]? It is becoming a vast field that has a lot of different options, and that's where the studies should be coming from as well.

What are some other targets and corresponding trials relevant in this setting?

Going back almost 6 years or so, there was this biomarker called Claudin18.2. It is something that we find by immunohistochemistry, a structural component of intracellular tight junctions that typically is not expressed in normal tissues. They express in several tumor types, including GEJ, biliary, and pancreatic cancers in different frequencies. I was very interested in the monoclonal antibody zolbetuximab, which used to be called claudiximab. The company that did the first study sold the asset and brought it to the United States, and that's when the phase 3 study came up. Recently, we had the SPOTLIGHT clinical trial [NCT03504397] that was reported in [the 2023 American Society of Clinical Oncology (ASCO) Gastrointestinal Cancers Symposium]. Patients with unresectable, metastatic GEJ adenocarcinoma who had Claudin18.2-positive disease [received] zolbetuximab plus mFOLFOX6 [modified oxaliplatin, leucovorin, and fluorouracil] versus placebo plus mFOLFOX6. Investigators followed them and their results were very positive.⁶

Claudin18.2 gave you an 18.2-month median overall survival [versus 15.5 months with placebo]. That is a very important milestone for patients who have biomarkers beyond HER2. We're going to learn more on a couple other studies as well. There is a combination of [zolbetuximab], but this time with capecitabine [Xeloda] plus oxaliplatin in the GLOW study [NCT03653507]. This is changing the paradigm dramatically for patients with GEJ and esophageal cancer who are positive for Claudin18.2, and now it becomes almost a [necessity] that we test those patients for Claudin18.2 right away.

Something else happening in the biomarker space is the incorporation of new biomarkers that we'd look for before as well, for example, NRG fusions. NRG fusions are found typically by RNA testing. It's not a common assay that we do. We do next-generation sequencing based on DNA. Now we have to go into the RNA component to find those fusions, and there are a couple of agents. The one that is seeing the most development now [is in] a study called eNRGy [NCT02912949], which is investigating zenocutuzumab [MCLA-128; Zeno], a bispecific antibody targeting HER2 and HER3. We saw some interesting data for the phase 1/2 study with a good [objective] response rate of 34%.⁷ There are a few more like seribantumab, but the jury's still out [on if it’s] going to be available for patients in clinical trials because the study [CRESTONE; NCT04383210] was closed, but [there is] a lot of promising information for NRG-positive cancers.

Lastly, we will look at the KRAS mutations; even though KRAS is not as common in esophageal and GEJ cancers, they're still present in some of those patients. Using a new agent, such as sotorasib [Lumakras] or adagrasib [Krazati] for KRAS G12C is making a difference in those patients. We're going to learn more about those used mostly in combination as well as with EGFR inhibitors, such as cetuximab [Erbitux] and panitumumab [Vectibix]. So there is more to follow in this space, and I cannot wait to see those results from those studies.

What is some advice you have for staying up-to-date on treating GEJ and esophageal cancers?

It's no longer considered one of those cancers that you treat...with the same agents. It's becoming a very dynamic space, and I encourage everyone to be involved coming to our meetings, ASCO reviews, and all the reviews that we do on the particular scenarios. Get acquainted on the latest updates in terms of things that are happening with the FDA. There is not only the NCCN [National Comprehensive Cancer Network guidelines] but many other resources. It is becoming an essential thing for us to look for information in real time that is succinct and to the point.

I'm a strong proponent of precision oncology. Anything that I do with my patients is always focused on what I would do if I was facing the situation with my family and myself. Having the opportunity to see so many new biomarkers come in is making the call for all of us to become advocates for precision oncology. Everyone should be focusing on getting more patients in clinical trials. We do send patients to clinical trials, but we do not [do enough]. This is a time for us to come together [and] test as many patients as possible because that is the appropriate value-based care approach for patients.

Everyone should be tested with broad panels, looking for all those biomarkers, because you [wouldn't] want to miss that for yourself. Having my family being affected by cancer, my brother being diagnosed with leukemia, and [with] all my patients that I see every day, it has become…a passion to get those patients into clinical trials and use biomarker testing as much as possible. That is my call to everyone.

_References:

_{1. FDA approves fam-trastuzumab deruxtecan-nxki for HER2-positive gastric adenocarcinomas. News release. FDA. January 21, 2021. Accessed April 11, 2023. https://bit.ly/3UqvLDk}

_{2. Janjigian YY, Shitara K, Moehler M, et al. First-line nivolumab plus chemotherapy versus chemotherapy alone for advanced gastric, gastro-oesophageal junction, and oesophageal adenocarcinoma (CheckMate 649): a randomised, open-label, phase 3 trial. Lancet. 2021;398(10294):27-40. doi:10.1016/S0140-6736(21)00797-2}

_{3. Sun JM, Shen L, Shah MA, et al. Pembrolizumab plus chemotherapy versus chemotherapy alone for first-line treatment of advanced oesophageal cancer (KEYNOTE-590): a randomised, placebo-controlled, phase 3 study. Lancet. 2021;398(10302):759-771. doi:10.1016/S0140-6736(21)01234-4}

_{4. Janjigian YY, Kawazoe A, Yañez P, et al. The KEYNOTE-811 trial of dual PD-1 and HER2 blockade in HER2-positive gastric cancer. Nature. 2021;600(7890):727-730. doi:10.1038/s41586-021-04161-3}

_{5. Yamaguchi K, Bang Y-J, 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). J Clin Oncol. 2022;40(suppl;242). doi:10.1200/JCO.2022.40.4_suppl.242}

_{6. Shitara K, Lordick F, Bang YJ, et al. Zolbetuximab + mFOLFOX6 as first-line (1L) treatment for patients (pts) with claudin-18.2+ (CLDN18.2+) / HER2− locally advanced (LA) unresectable or metastatic gastric or gastroesophageal junction (mG/GEJ) adenocarcinoma: Primary results from phase 3 SPOTLIGHT study. J Clin Oncol. 2023;41(suppl_4):LBA292. doi:10.1200/JCO.2023.41.4_suppl.LBA292}

_{7. Schram AM, Goto K, Kim DW, et al. Efficacy and safety of zenocutuzumab, a HER2 x HER3 bispecific antibody, across advanced NRG1 fusion (NRG1+) cancers. J Clin Oncol. 2022;40(suppl 16):105. doi:10.1200/JCO.2022.40.16_suppl.105}