Role of HER2-Directed Therapies Rapidly Evolves in Esophageal and Gastric Cancer

Yelena Y. Janjigian, MD

Future research efforts are focused on examining anti–PD-1 combination strategies, particularly with HER2-directed therapies, according to Yelena Y. Janjigian, MD, who added that certain molecular features will affect response and inform treatment selection and timing.¹

“We’re going to examine what’s to come in 2021 and 2022 for anti–PD-1 combination strategies and review some of the molecular features that will allow us to understand how to time treatments and allow our patients to achieve maximum benefits with maximum options to maximize cures,” said Janjigian, associate attending physician and associate professor of Weill Cornell Medical College, and chief of Gastrointestinal Oncology Service at Memorial Sloan Kettering Cancer Center, in a virtual presentation during the 2020 Ruesch Center Symposium.

Immunotherapy is an approach that is utilized in later lines of treatment in gastric cancer. Checkpoint inhibitors are typically given after disease progression on standard chemotherapy, usually in the third-line setting, said Janjigian.

In Asia, the PD-1 agent nivolumab (Opdivo) was approved for use as third-line treatment in patients with adenocarcinoma, regardless of PD-L1 expression status. Additionally, pembrolizumab (Keytruda) was approved by the FDA for use in the third-line setting in patients with a PD-L1 combined positive score (CPS) of 1 or higher, tumor mutational burden (TMB) of 10 or higher, or those with microsatellite instability–high tumors.

“TMB has been approved for pembrolizumab as well, although it’s important to know that for gastric cancer, pretty much all patients who have TMB-high tumors are also MSI high; that’s really our niche,” said Janjigian. “Disappointingly, with anti–PD-1 therapy alone, CPS-low expressors benefit very little. That’s part of the frustration that [our patients] experience. When their tumors are PD-L1 negative, they feel like you’re withholding some therapy from them, but [this approach] really doesn’t benefit them. However, 2020 was a groundbreaking year.”

KEYNOTE-062 Fails to Change Practice

The randomized, controlled, partially blinded phase 3 KEYNOTE-062 trial (NCT02494583) enrolled patients with untreated, locally advanced, unresectable, or metastatic gastric/gastroesophageal junction (GEJ) cancer with a PD-L1 CPS of 1 or greater.²

A total of 763 patients were randomized 1:1:1 to receive pembrolizumab at 200 mg (n = 256); pembrolizumab plus chemotherapy which was comprised of cisplatin at 80 mg/m2 on day 1 plus fluorouracil (5-FU) at 800 mg/m2 on days 1 to 5 or capecitabine 1000 mg/m2 twice daily (n = 257); or chemotherapy plus placebo (n = 250) every 3 weeks. The primary end points of the trial were overall survival (OS) and progression-free survival (PFS) in patients with PD-L1 CPS of 1 or greater or 10 or greater.

Results showed that pembrolizumab was noninferior to chemotherapy in terms of OS in patients with a CPS of 1 or greater, at a median OS of 10.6 months versus 11.1 months, respectively (HR, 0.91; 99.2% CI, 0.69-1.18). Single-agent pembrolizumab was not superior to chemotherapy alone in patients with a CPS of 1 or greater. The PD-1 inhibitor prolonged OS versus chemotherapy in patients with a CRPS of 10 or greater, at a median of 17.4 months versus 10.8 months, respectively (HR, 0.69; 95% CI, 0.49-0.97).

Moreover, pembrolizumab plus chemotherapy was not superior to chemotherapy for OS in patients with a CPS of 1 or greater, at a median of 12.5 months versus 11.1 months, respectively (HR, 0.85; 95% CI, 0.70-1.03; P = .05) or a CPS of 10 or greater, at a median of 6.9 months versus 6.4 months, respectively (HR, 0.84; 95% CI, 0.70-1.02; P =.04).

“This was an eagerly awaited study, but relatively poorly designed with a small sample size. Statistically, it was underpowered and had too many complicated alphas and questions to answer,” said Janjigian. “Nonetheless, the study was heartbreaking to everyone because it did not change practice. There was no benefit for pembrolizumab compared with chemotherapy or pembrolizumab with chemotherapy.”

CheckMate-649 Introduces New Standard First-Line Treatment Option

The phase 3 CheckMate-649 trial (NCT02872116) was a larger study than KEYNOTE-062. Patients with previously treated, unresectable advanced, or metastatic gastric cancer, GEJ cancer, or esophageal adenocarcinoma were enrolled to the trial, irrespective of PD-L1 expression. Those with HER2 positivity were excluded from the trial.

Participants were randomized to receive nivolumab at 360 mg every 3 weeks or 240 mg every 2 weeks plus chemotherapy comprised of XELOX every 3 weeks or FOLFOX every 2 weeks, nivolumab plus ipilimumab (Yervoy), or chemotherapy. The primary end points of the trial for nivolumab plus chemotherapy versus chemotherapy were OS and PFS by blinded independent central review in patients whose tumors expressed PD-L1 with a CPS of 5 or greater.

“Importantly, patients were enrolled based on histology as opposed to tumor location. Biology and histology trump anatomic location,” said Janjigian. “Patients were randomized to receive chemotherapy that we all easily give in the clinic. As such, there weren’t any artificial barriers with the cisplatin-based therapy, which was used in KEYNOTE-062.”

A total of 1581 patients were randomized in the nivolumab/chemotherapy and chemotherapy arms, which included 955 patients with PD-L1 CPS of 5 or greater. At a minimum follow-up of 12 months, nivolumab/chemotherapy significantly improved OS (HR, 0.71; 98.4% CI, 0.59-0.86; P <.0001) and PFS (HR, 0.68; 98% CI, 0.56-0.81; P <.0001) versus chemotherapy in patients with PD-L1 CPS of 5 or greater. Notably, OS benefit was also reported in patients with PD-L1 CPS of 1 or greater as well as in the all-randomized patient population. In the nivolumab/chemotherapy arm, the median OS was 14.0 months versus 11.3 months with chemotherapy (HR, 0.77; 95% CI, 0.64-0.92; P = .0001).

“Looking across subsets, the MSI-high subset had a hazard ratio for survival of 0.30, which is amazing and really practice changing and it highlights the importance of MSI testing in routine practice in the first-line setting,” said Janjigian. “Please remember to ask for PD-L1 and MSI testing on all of your patients with gastric cancer.”

HER2 as a Target in Esophagogastric Cancer

HER2 is overexpressed in approximately 20% of patients with esophagogastric adenocarcinomas, said Janjigian. Trastuzumab (Herceptin) in combination with 5-FU and platinum serves as the standard of care for frontline treatment in patients with metastatic HER2-positive disease based on data from the ToGA trial (NCT01041404). Several negative studies examining other HER2-targeted therapies have read out subsequently.

“Since the ToGA study, which led to the approval of trastuzumab, we ran into a major roadblock and faced dry spells. Study after study has been non–practice changing,” said Janjigian. “Why? HER2 is not as straightforward as it is in breast cancer…Patients who do best are those with a very high level of HER2 amplification in their tumor.”

In an open-label, single-arm, single-center, phase 2 trial (NCT02954536), patients with HER2-positive metastatic esophagogastric cancer received an induction cycle comprised of a flat dose of 200 mg of intravenous (IV) pembrolizumab and an 8-mg/kg loading dose of IV trastuzumab.4 In subsequent cycles, patients were given 130 mg/m2 of IV oxaliplatin or 80 mg/m2 of cisplatin on day 1, 850 mg/m2 of oral capecitabine twice daily for 2 weeks followed by 1 week off, and a 200-mg flat dose of IV pembrolizumab, and 6 mg/kg of trastuzumab given on day 1 of each 3-week cycle. The primary end point was 6-month PFS.

Results showed that this approach elicited an ORR of 91% (95% CI, 78%-97%), with a 17% complete response rate, a 74% partial response rate, and a 9% stable disease rate. The disease control rate was 100%.

“Instead of the 47% ORR that you would expect with historical control, you got a 91% ORR. We biopsied all these patients and some of them went on to have surgery, which is transformative,” said Janjigian. “We found that HER2 was important, not PD-L1. Some of these pathologic CR rates were actually very low in PD-L1 expression. A phase 3 trial is now enrolling, so that will hopefully be another option for patients with HER2-positive disease.”

Antibody-Drug Conjugates: The Next Wave of Treatment

“Antibody-drug conjugates [ADCs] are the next wave; it’s not even the future, it’s the present…fam-trastuzumab deruxtecan-nxki [Enhertu] is the star of the show now,” said Janjigian.

The ADC is comprised of 3 components: a humanized HER2-targeted monoclonal antibody, a topoisomerase I inhibitor payload, and a tetrapeptide-based cleavable linker. The drug has a high drug-to-antibody ratio of about 8:1. The agent has a high potency payload that was developed to be membrane permeable, causing a bystander antitumor effect.

Trastuzumab deruxtecan was granted a priority review designation from the FDA in October 2020 for use in patients with HER2-positive gastric or GEJ adenocarcinoma based on data from the phase 2 DESTINY-Gastric01 trial (NCT03329690), which showed that the agent elicited a higher ORR versus chemotherapy in this patient population who had progressed on trastuzumab-based therapy.5 The ORR was 51.3% versus 14.3% with trastuzumab deruxtecan and chemotherapy, respectively.

The ADC also resulted in a longer OS versus chemotherapy, at 12.5 months versus 8.4 months, respectively. Moreover, the median PFS and median duration of confirmed response proved to be longer with trastuzumab deruxtecan.

“What’s the difference between trastuzumab deruxtecan and ado-trastuzumab emtansine [T-DM1; Kadcyla]? T-DM1 does not have the same amount of bystander effect as trastuzumab deruxtecan,” said Janjigian. “The effect on the heterogeneity of the tumor [is different]. Sometimes, even if 10% of the cells have a very high level of HER2 expression, the rest of the cells may be HER2 low or negative. That’s an important factor for de novo resistance in gastric cancer.”

Practice-Changing Reflections

“Chemotherapy with 5-FU and nivolumab will likely be FDA approved this year. Moreover, HER2, MSI, and PD-L1 should really be tested on all patients,” concluded Janjigian. “Watch out for dual anti–PD-1 and targeted agents. HER2 combinations are certainly coming. Trastuzumab deruxtecan is also likely to be FDA approved in this disease. This is a marathon, not a sprint. We want to give our patients as many options as possible. The longer a patient does better, the more options there will be.”

References

1. Janjigian YY. Esophageal and gastric cancer 2020: therapeutic evolution. Presented at: 2020 Ruesch Center Symposium; November 20-21, 2020; Virtual.
2. Shitara K, Van Cutsem E, Bang Y-J, et al. Efficacy and safety of pembrolizumab or pembrolizumab plus chemotherapy vs chemotherapy alone for patients with first-line, advanced gastric cancer: the KEYNOTE-062 phase 3 randomized clinical trial. JAMA Oncol. 2020;6(10):1571-1580. doi:10.1001/jamaoncol.2020.3370
3. Moehler M, Shitara K, Garrido M, et al. Nivolumab (nivo) plus chemotherapy (chemo) versus chemo as first-line (1L) treatment for advanced gastric cancer/gastroesophageal junction cancer (GC/GEJC)/esophageal adenocarcinoma (EAC): first results of the CheckMate 649 study. Ann Oncol. 2020;31(suppl 4):LBA6_PR. doi:10.1016/j.annonc.2020.08.2296
4. Janjigian YY, Maron SB, Chatila WK, et al. First-line pembrolizumab and trastuzumab in HER2-positive oesophageal, gastric, or gastro-oesophageal junction cancer: an open-label, single-arm, phase 2 trial. Lancet Oncol. 2020;21(6):821-831. doi:10.1016/S1470-2045(20)30169-8
5. Shitara 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: a randomized, phase II, multicenter, open-label study (DESTINY-Gastric01). J Clin Oncol. 2020;38(suppl 15; abstr 4513). doi:10.1200/JCO.2020.38.15_suppl.4513