Roundtable Discussion: Cho and Participants Examine Options for Second-Line Therapy in HER2+ Gastric Cancer

May Cho, MD (Moderator)

Associate Clinical Professor, Medicine

School of Medicine

UC Irvine Health

Irvine, CA

CHOUDHARY: I generally [wouldn’t] rebiopsy, but I would do an interim CT scan or restaging within 6 weeks. If the patient is not responding, then, generally, I would rebiopsy to see whether they’re losing [HER2] expression. Otherwise, I keep going.

CHO: [Would] anyone just do a liquid biopsy because they don’t want the patient to go through another biopsy? [Do you do a liquid biopsy because] you want a quick result?

BAGHIAN: Yes, a liquid biopsy would be nice. It’s convenient, and it would probably reflect the clone that had the highest [number of] circulating cells. The problem is that the insurance companies don’t always want to approve liquid biopsy. That has been my challenge, at least.

CHO: I order the liquid biopsy, and I get a quick and easy answer. My experience has been that, with next-generation sequencing [NGS], you never know whether the patient is going to get an [expensive] bill. So I usually tell [the patient] to bring the bill, and [when they get it] to the representative, they figure things out. I generally tell the patient not to pay all [that] money.

BAGHIAN: Yes, [the insurance companies] make me jump through [hoops]. I have to submit an authorization and the insurance [company] has to deny it, and then they’ll work with the patient. They have different sets of rules, and it sometimes becomes difficult to keep track of where they are in the process, and sometimes I just want to start the next treatment, especially if the patient is symptomatic. I use Guardant360 [CDx]. If I could have [testing] done onsite on the day of the visit and know that I’m going to get the results in 7 to 10 days, of course I would do it for everyone.

CHAND: [My answer is] a little bit of all [the choices]. However, quality of life is important, because [with] gastric cancer you rarely have patients who get 5 lines of treatment. Most of the patients who progress quickly on the first line usually do not have a good prognosis.

CHARU: I agree. I think achieving response and some disease control and maintaining quality of life are important.

CHOUDHARY: I had a patient with a lot of bleeding issues after they [did not respond to] first-line [therapy].

CHO: For them, controlling the bleeding [was important]. I think that the immediate response rate is a lot more important in gastric cancer than it is in colon cancer, [for example]. The patients will have bad dysphagia, and sometimes I have to temporarily [use total parenteral nutrition] because [the patient] can’t have a [gastrostomy] tube and they can’t eat anymore. And [being able to eat] improves the quality of life [so much]. [Here] in southern California, some of my patients will say, “Oh my gosh, I can eat tacos again!” Because tacos [have a hard] shell, and it’s hard for patients to swallow. So [we] all want [to improve] overall survival [and] progression-free survival, but in gastric cancer, the response rate and disease control [are] important.

CHO: I [think we] are excited to finally have the second-line HER2-targeted therapy, trastuzumab deruxtecan [Enhertu]. [But] what is it about this drug that [makes it so] compelling?

STEPHEN: It’s the leading option for targeted therapy in the second line, right? So you want to keep your targeted options going as long as possible, and the response rates are good, so [there’s] no reason not to try it.

CHO: I agree. This is targeted therapy [with a good] response rate.

JANG: Somebody [might ask] why [we need] pembrolizumab on the front line. [According to the results of] KEYNOTE-811 [NCT03615326], PD-L1 expression doesn’t matter; HER2 is still the driver.¹ As we know, HER2-low [cancer] is [responsive to trastuzumab deruxtecan], so I think that [choice] makes a whole lot of sense. The reason why pembrolizumab works to enhance the response rate in HER2+ gastric cancer is because it enhances antibody-dependent cellular cytotoxicity [From the Data¹].

With any gastric cancer, if [it is] HER2+, I don’t think you need to even bother checking the PD-L1 expression, because 82% or 85% of [those patients] are going to have a tumor proportion score greater than 1 anyway. That’s why it makes sense to use [trastuzumab deruxtecan] in this setting.

CHOUDHARY: And the toxicity is so minimal. [My patients] have had mild thrombocytopenia. [This drug is] so well tolerated.

CHO: One of the [differences] between HER2+ breast cancer and HER2+ [gastrointestinal] cancer is the dosing [of trastuzumab deruxtecan]. In breast cancer, the dosing is a little lower (5.4 mg/kg), and it seems that [gastric] and colon cancer [require] a higher dose (6.4 mg/kg).² Do you give 6.4 mg/kg for gastric [cancer]? Do you have to reduce it [because of] thrombocytopenia?

CHOUDHARY: Not really. [My patients’ platelet counts] have been always above 100,000/μL, so I don’t have to [reduce dose]; I just [have to] watch them.

CHO: Besides the lab results, [are there] any other adverse events that patients complain of, in terms of symptoms?

CHOUDHARY: I think fatigue.

CHO: Have you seen any irinotecan-like toxicity? [Do any of your patients] complain about abdominal cramping or diarrhea?

CHOUDHARY: Nothing drastic.

CHO: When do you see the response? After [the first] cycle or the second cycle?

CHOUDHARY: You see [the response] early. I’ve not used it on a lot of patients, but in my experience, the response was quick.

CHO: [Does] anyone else have experience with the 6.4-mg [dose] in gastric cancer?

DEKKER: I have not experienced anything unusual, because I often do NGS for gastric [cancer]. I often tell pathologists to [test for] polymorphisms as well, so [my patients] tend to have less irinotecan[-like] toxicity, and I do often adjust the dose if a polymorphism is identified.

JANG: [I have] used it on a patient with metastatic pancreatic cancer. The patient was initially sent to me for neoadjuvant therapy. [The patient had no] response to [their prior therapy] and [had] progressed. I [decided to] take a chance. I checked the NGS [results] and [they were positive for] HER2. [I gave the patient] trastuzumab deruxtecan, [and] 2 cycles into [treatment], [the patient had achieved] a nearly complete response.

CHO: Yes, the response rate is amazing. I’m surprised that you were able to get it, even for neoadjuvant [therapy] in pancreatic cancer. That’s great.

JANG: It was a last-ditch resort for this patient. I didn’t know what [else] to do.

YEH: Have you used this drug in HER2-low [1+] gastric cancer?

CHO: We still [don’t have] data [for that]. We’re still learning about HER2-low gastric and colorectal cancer.

CHO: In gastric cancer, the prognosis is so poor [that] I care less about ILD than [I do] if I have to manage breast cancer [in a patient] who can live 8 years or so. In a poor prognosis cancer like gastric cancer, which [requires] a highly efficacious drug, would you be OK with [the risk of ILD]?

CHAND: [Physicians] are already using it [as a] second-line [treatment] for [patients with] breast cancer, so why not [use it] for [patients with] gastric cancer? The drug is the same, with the same toxicity.

CHO: Yes, but are you concerned that 6.4 mg/kg may give a little more toxicity?

CHAND: [In comparison with] the other options, [trastuzumab deruxtecan is] still a more effective drug, and [only approximately] 8% to 10% [of patients experience] pneumonitis.¹ The key to using this drug is to [detect] the pneumonitis early. Otherwise, it seems to be a well-tolerated medication.

MOON: In the context of second- or third-line [management of] gastric cancer, [the risk of ILD] is not relevant, because [the patients] have terrible options. [The ILD] is an acceptable risk, but there are 2 issues with the ILD that have not been stated here.

First, my understanding is that the risk calculation came [from] a study of breast cancer. [I wonder whether] chest wall radiation or any [other] provocative factor [might have contributed to the ILD risk]. We looked at this drug for an adjuvant trial, and the thought is [that] 10% is a little too much [risk for] a woman who may be cured.

Second, because this is a drug [investigated almost exclusively in an] Asian population, [I wonder whether] they somehow handle this drug differently. We know so little about [this drug]. Is it like [bleomycin]? If we [treat] someone with high-flow oxygen, would it trigger something? Those are the things that affect the development [of this drug].

In the context of this scenario, a [patient with] second- [or] third-line gastric [cancer] [and] no options, I don’t think [the risk of ILD] matters at all.

CHO: What if you have given [the] CROSS [NCT01216527] regimen [of neoadjuvant chemoradiation]? Would you be concerned?

MOON: It is something that I worry about, because it looks like [this drug is] one of our most potent HER2 blockers. It’s designed better and is more effective than [trastuzumab emtansine (Kadcyla)]. This is a very effective therapy, so it’s [not] going to stay in the second line. But some of the pneumonitis was fatal, and to this day we’re not 100% sure that we can see it coming, [and in some cases it was] just catastrophic. That’s the concern.

CHO: When the drug was started, there was not a good [usage] guideline in place. [In] the subsequent study, the [ILD] rate was smaller.

MOON: Yes, smaller. And there’s concern about the Asian population. Are they [frequent] smokers? Is there something fundamentally different about [that population] that can [produce] different [results]? There’s a lot we don’t know.

CHO: Would any of you be comfortable rechallenging [after the patient has grade 1 ILD]?

CHOUDHARY: I worry about medical legal things, so I would not.

DEKKER: I would stop at grade 1, and I wouldn’t rechallenge.

JANG: I would probably not identify patients as [grade] 1. There is a very narrow line [between grade 1 and grade 2]. I [would] probably give a break, treat, and if there [was] improvement, try to rechallenge. But if there is no obvious response, I am unlikely to rechallenge.

MOON: My threshold to rechallenge is [quite] high. With [immuno-oncology] therapies, if [the patient has] colitis or dermatitis, I’ll rechallenge with no [hesitation]. But if [the patient has] pancreatitis, [hepatitis], or something [like that], I am probably not going to rechallenge. With this drug, until we know more, I would not [be comfortable rechallenging].

_References

_{1. Janjigian Y, Kawazoe A, Yanez PE, et al; KEYNOTE-811 Investigators. Pembrolizumab plus trastuzumab and chemotherapy for HER2+ metastatic gastric or gastroesophageal junction (G/GEJ) cancer: initial findings of the global phase 3 KEYNOTE-811 study. J Clin Oncol. 2021;39(suppl 15):4013. doi:10.1200/JCO.2021.39.15_suppl.4013}

_{2. Enhertu. Prescribing information. Daiichi Sanko; 2022. Accessed October 5, 2022. https://bit.ly/3Vywmmv}