HER2 Expression Drives Treatment Decisions in Gastric/Esophageal Cancers

Manish A. Shah, MD

The validity of HER2 expression as a prognostic marker for patients with gastrointestinal (GI) and gastroesophageal junction (GEJ) cancers has gained traction as results from several trials that point toward success with anti-HER2 therapies. HER2 positivity presents in approximately 20% of gastric cancers, and testing for HER2 amplification has been integrated into treatment guidelines to direct therapeutic decisions, with immunohistochemistry (IHC), defined as IHC3+, and fluorescence in situ hybridization (FISH) as the standard.^1,2

Results of the DESTINY-Gastric01 (NCT03329690) study demonstrated the efficacy of fam-trastuzumab deruxtecan (Enhertu) in patients with HER2-expressing, locally advanced or metastatic gastric or GEJ cancer who had received at least 2 previous regimens.³ Patients who received trastuzumab deruxtecan (n = 125) had an objective response rate of 51% vs 14% among those who received physician’s choice chemotherapy (n = 62). The median overall survival (OS) was 12.5 months (95% CI, 9.6-14.3) vs 8.4 months (6.9-10.7), respectively (HR, 0.59; 95% CI, 0.39-0.88; P = .01). Further the progression-free survival (PFS) was 5.6 months (95% CI, 4.3-6.9) vs 3.5 months (95% CI, 2.0-4.3), respectively (HR, 0.47; 95% CI, 0.31-0.71).³

Despite this, investigators noted that the patient population in DESTINY-Gastic01 does not reflect the patients they see in their practices. “The first DESTINY-Gastric study, which was published in the New England Journal of Medicine, [had] an exclusively Asian population…. The response rate originally was 50% and then it went down in central review to approximately 42%,” Manish A. Shah, MD, said in a recent episode of OncLive The Talk^™: Gastrointestinal Cancers. “We’re all aware that for different reasons the survival in Korea and Japan is better for gastric cancer than in the West.”

Experts in the field of upper GI cancers joined Shah to discuss recent data from the European Society for Medical Oncology (ESMO) Annual Congress 2021 that may bolster the uptake of HER2 as a guide for treatment decisions in the second line. Specifically, the panel paid close attention to the DESTINY-Gastric02 trial (NCT04014075), which evaluated trastuzumab deruxtecan vs chemotherapy in a Western population. They also discussed findings from INTEGA (NCT03409848), and how data regarding pembrolizumab (Keytruda) in the KEYNOTE-811 (NCT03615326) may fuel advances for patients to extend survival outcomes for patients to proceed to third or later line therapies (Tables 1-3^4-7).

Table 1. Data Snapshot: Outcomes of DESTINY-Gastric02⁴

Table 2. Data Snapshot: Outcomes of INTEGA⁵

Table 3. Data Snapshot: Outcomes of KEYNOTE-811^6,7

The panel highlighted the challenges of integrating HER2-targeted therapy into clinical practice and walked through scenarios to provide insight on their use of testing and retesting for HER2 expression over the course of treatment.

Klempner: Action on alterations, including HER2, was highlighted in data for patients with gastric and esophageal cancer presented at [2021] ESMO. Dr Ahn, take us through the data we saw from the INTEGA trial and then the hotly awaited [data from] DESTINY-Gastric02.

Ahn: In INTEGA, investigators specifically looked at patients with advanced unresectable esophagogastric adenocarcinoma [and evaluated the] combination of ipilimumab [Yervoy] plus nivolumab [Opdivo] and trastuzumab [Herceptin] vs FOLFOX [folinic acid, fluorouracil, and oxaliplatin] as the backbone. Patients were randomized to receive ipilimumab or FOLFOX plus nivolumab plus trastuzumab.

The primary objective was to look at the OS rate at 12 months. Unfortunately, the study failed to meet its primary end point where [results] favored chemotherapy rather than the combination with nivolumab plus ipilimumab. The difference is approximately 5 months.

When they looked at the subgroup analysis…[data were] pretty consistent with chemotherapy being favored over the immuno-oncology doublet. They also looked at some ctDNA clearance that suggested it was predictive of prognosis, meaning if a patient was able to clear their ctDNA after 1 cycle of treatment, they were likely going to have a better clinical outcome. Despite our hopes that the study may be positive, it looks like chemotherapy is still going to be a standard even for patients with HER2 positivity.

DESTINY-Gastric02 was a study conducted in a Western patient population, mainly to confirm the results from the DESTINY-Gastric01 study, which is now published. The primary end point of the study was objective response rate. When you look at the patient demographics, 86% of [evaluable] patients [n = 79] were found to be HER2-positive IHC3+, these patients were likely going to respond to therapy best and the objective response was slightly under 40%. The median duration of response was 8 months with a median PFS of approximately 5 months.

Treatment-emergent adverse effects associated with treatment discontinuation were less than 4% for patient with pneumonitis and less than 3% with patients having [interstitial lung disease (ILD)]. Otherwise, the treatment was well tolerated, and this is something that’s going to be interesting because of the data that we have now with KEYNOTE-811 in the front line with pembrolizumab with trastuzumab in combination in the refractory setting.

DESTINY-Gastric03 [NCT04379596] is a phase 1b/2 looking at various combinations in HER2 with immunotherapy plus chemotherapy. Even though results have not been presented, I think these data may potentially change how we use [trastuzumab deruxtecan] once there are data for it as monotherapy and in combination potentially with chemotherapy and immunotherapy.

Klempner: I have a practical question for you. In DESTINY-Gastric02, [participants] had to be confirmed HER2-positive after progression on their trastuzumab-containing regimen, unlike DESTINY-Gastric01, which allowed archival [samples]. Are you testing or retesting patients who received trastuzumab and then ultimately progressed for HER2? Do you think that that’s important in selecting patients for second-line trastuzumab deruxtecan?

Ahn: Yes, great question. For the first question, you asked me [if we are] routinely testing patients at the time of progression. Patients can develop secondary treatment resistance due to the emergence of other coactivating mutations.... Either we can see a loss of HER2 expression or we can see the emergence of other potential targets, including MET overexpression or MET activation. I think it is very important for these patients to be tested routinely at the time of progression.

In terms of using trastuzumab deruxtecan, I think that question is unanswered. These patients have a chance to respond based off the mechanism of action with that drug being an antibody-drug conjugate and its bystander effect. What we’ve seen from DESTINYGastric01 is that the patients who are low expressors are unlikely to respond as well as the high expressors. It would not be my preference to use [trastuzumab deruxtecan] in a patient who was a low expressor, but they may still potentially [receive] some clinical benefit if they have no other treatment options.

Klempner: We’re retesting, as well, whenever possible. Do we need to see [results from] DESTINY-Gastric04 [NCT04704934], which is a randomized phase 3 trial of trastuzumab deruxtecan against paclitaxel/ramucirumab [Cyramza] in the second line, before you would really feel comfortable saying that this is better than paclitaxel/ramucirumab or on par with the treatment?

Shah: We were all very happy to see the efficacy maintained in the [DESTINY-Gastric03] study. The response was perhaps not as high, with a response rate of 38%, but was still pretty good. The duration of response was not 12 months but 8 months. I think for those reasons the randomized study vs paclitaxel/ramucirumab is going [to have] important data for me.

The other thing we didn’t talk about is the rare but serious complication of interstitial pneumonitis in these patients. There were some grade 5 events that happened. If you identify this problem early you can really avoid a lot of the serious complications. But in the United States, most gastric cancer is treated by [a clinician who] may see it once a year, so I am worried that individuals may have a lot of toxicity.

A similar thing happened with irinotecan using a bolus weekly regimen. Patients died from uncontrolled diarrhea. There is real potential [to improve safety outcomes] here. Paclitaxel/ramucirumab is really well tolerated and has modest activity.... The efficacy of trastuzumab deruxtecan was similar in the third-line setting or later as well.

I’m not sure you’ll lose efficacy if you use it in the third-line setting. For those reasons, I tend to use them more in the third-line setting, barring the results of the phase 3 trial that you mentioned.

Klempner: I agree. We have not widely adopted trastuzumab deruxtecan as our default second-line pathway. Dr Uboha, are you repeat testing or are you comfortable going forward based on the current label?

Uboha: I retest all my patients for progression on trastuzumab to ensure that they are HER2 resistant or HER2 amplified. I have used trastuzumab deruxtecan in the second-line setting. It will be nice to see randomized data, but our patients don’t always get to receive third-line treatments. That’s the difference between the population that we see here [in DESTINY-Gastric02] as opposed to the studies that were done with populations enrolled in studies in Asia. We don’t [routinely] see patients [receiving treatment in the] third or fourth line being eligible for these treatments.

I’m hoping with the use of pembrolizumab in first line [following] the impressive overall response data raised from KEYNOTE-811 that soon we will be able to get more patients to later lines of therapies, but this is to be determined.

[Although] INTEGA was a negative study because it didn’t meet the primary end point, I do want to point out that this study showed that trastuzumab, nivolumab, and ipilimumab had an OS of 16 months even without chemotherapy.

It does provide a chemotherapy-free option for some patients with HER2-positive disease. I think it will be interesting to see results from the MAHOGANY study [NCT04082364] that will look at margetuximab-cmkb [Margenza] in the same setting. But I thought [the KEYNOTE-811] results were intriguing even though they’re not as good as for patients who received chemotherapy.

Klempner: MAHOGANY [investigators] did the smart thing in selecting patients with HER2 and PD-L1 dual-positive disease, which seems to be a lot of these patients based on the KEYNOTE-811 data that we have seen.

Practical question: a patient is HER2 IHC2+, you drew ctDNA, and you found high-level HER2 amplification. Are you going forward with the HER2-based therapy for that patient even though the IHC is 2+, FISH negative, but the ctDNA is positive?

Uboha: Gosh, difficult question. I’ve not encountered this, to be honest, because I usually don’t have all that information available at the time of treatment initiation. If there was a high level of amplification, I probably would be tempted to use HER2-directed therapy. The toxicities are low. I would hate to miss giving somebody life-prolonging therapy because our tests are not perfect.

Ahn: I agree with Dr Uboha. I think the data are not clear, but I would still opt to give HER2-directed treatment if we were able to get it for the patient. And I think just to go back to Dr Shah’s point about the toxicity with ILD/ pneumonitis...[in terms of incidence], the median duration of onset was approximately 80 days.

It’s [an AE] that may not show up initially when you start treatment so it’s important for the practitioner to look out for that toxicity. And it can last for a while; I think the average duration was approximately 38 days. It’s a good point [to draw attention to] especially for those in the community.

Shah: HER2 expression in gastric cancer is so heterogeneous, and that is part of the reason why it’s worthwhile to rebiopsy patients with HER2-negative disease because even those with IHC1+ or 2+ could become positive.

The problem with ctDNA is not the false positive—if it’s there, it’s there; the data show that. I think if the amplification is there it’s probably true and it just represents a portion of the disease that wasn’t biopsied.

I would feel perfectly fine vehemently arguing with insurance to provide the trastuzumab.

Klempner: Me, too. I think that’s a positive patient who warrants HER2-directed therapy.

References

1. Van Cutsem E, Bang YJ, Feng-Yi F, et al. HER2 screening data from ToGA: targeting HER2 in gastric and gastroesophageal junction cancer. Gastric Cancer. 2015;18(3):476-484. doi:10.1007/ s10120-014-0402-y
2. NCCN. Clinical Practice Guidelines in Oncology. Gastric cancer, version 2.2022. Accessed February 16, 2022. https://www. nccn.org/professionals/physician_gls/pdf/gastric.pdf
3. 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
4. Van Cutsem E, Di Bartolomeo M, Smyth E, et al. Primary analysis of a phase II single-arm trial of trastuzumab deruxtecan (T-DXd) in western patients (Pts) with HER2-positive (HER2+) unresectable or metastatic gastric or gastroesophageal junction (GEJ) cancer who progressed on or after a trastuzumab-containing regimen. Ann Oncol. 2021;32(suppl 5):S1332. doi:10.1016/j. annonc.2021.08.2135
5. Stein A, Paschold L, Tintelnot J, et al. Ipilimumab or FOLFOX in combination with nivolumab and trastuzumab in previously untreated HER2 positive locally advanced or metastatic esophagogastric adenocarcinoma (EGA): results of the randomized phase II INTEGA trial (AIO STO 0217). Ann Oncol. 2021;32(suppl 5):S1331. doi:10.1016/j.annonc.2021.08.2134
6. Janjigian Y, Kawazoe A, Weber P, et al. Initial data from the phase 3 KEYNOTE-811 study of trastuzumab and chemotherapy with or without pembrolizumab for HER2-positive metastatic gastric or gastroesophageal junction (G/GEJ) cancer. Ann Oncol. 2021;32(suppl 3):S227. doi:10.1016/j.annonc.2021.06.011
7. FDA grants accelerated approval to pembrolizumab for HER2-positive gastric cancer. FDA. May 5, 2021. Accessed February 16, 2022.bit.ly/3sOjWt2