Ongoing Studies May Clarify Role of ADCs in Gastric Cancer and CRC

Jeremy Kortmansky, MD

The approval of fam-trastuzumab deruxtecan-nxki (Enhertu) in HER2-positive breast cancer is generating hopes that similar strategies also may be effective against HER2-expressing gastric and colorectal cancers (CRCs), according to a panel of experts in gastrointestinal (GI) malignancies.

The antibody-drug conjugate (ADC) gained the FDA’s approval in December 2019 for patients with unresectable or metastatic HER2-positive breast cancer who received ≥2 prior targeted regimens.¹ The drug is among several ADCs that may translate into efficacy in GI cancers, the panelists said during a recent OncLive^® Scientific Interchange & Workshop in San Francisco, California.

“We need the data,” said panelist Jeremy Kortmansky, MD. “This next generation of drugs [ADCs] is very promising but still very much in clinical trials.”

Those studies may yield important findings, he said, but attempts to develop another HER2-targeting ADC, trastuzumab emtansine (T-DM1; Kadcyla), have not succeeded so far in gastric cancer, added Kortmansky, an associate professor of clinical medicine at the Yale School of Medicine and medical director of the Smilow Cancer Hospital Care Center in New Haven, Connecticut.

T-DM1 was initially indicated for patients with metastatic HER2-positive breast cancer in 2013.² In gastric cancer, findings from the phase II/III GATSBY trial (NCT01641939) of T-DM1 versus standard taxane treatment in 345 patients with HER2-positive advanced gastric cancer showed that T-DM1 did not improve survival compared with standard-of-care (SOC) chemotherapy.³

The expert panel agreed that trial results with T-DM1 suggest that there is currently no role for the ADC in gastric cancer. “I think it had its chance and unfortunately failed for any number of reasons,” said Geoffrey Y. Ku, MD, a medical oncologist at Memorial Sloan Kettering Cancer Center in New York, New York.

ADCs are the subject of “renewed interest” in gastric cancer, particularly as new data on trastuzumab deruxtecan emerge, according to panelist Ryan B. Corcoran, MD, PhD, an expert in BRAF- and KRAS-mutant GI and an associate professor at Harvard Medical School and the Dana—Farber/Harvard Cancer Center at Massachusetts General Hospital in Boston, Massachusetts. Preliminary data with trastuzumab deruxtecan are “extremely promising,” said Ku, who cited findings from the first-in-human phase I study (NCT02564900; JapicCTI-152978). Results showed that trastuzumab deruxtecan had preliminary activity and a manageable safety profile, supporting further investigation.⁴

The dose-escalation/expansion trial enrolled 274 patients with HER2-positive gastric or gastric-esophageal junction (GEJ) cancer who had previously been treated with trastuzumab (Herceptin). Investigators said all 44 patients in the HER2-positive gastric or GEJ group were evaluable for confirmed response and, after a median follow-up of 5.5 months, 43.2% (19 patients; 95% CI; 28.3-59.0) had achieved an objective response by investigator assessment.⁴

The median time to response and duration of response was 1.4 months (95% CI, 1.3-1.6) and 7.0 months (95% CI, 4.4-16.6), respectively. Most patients (79.5%; 35) also had disease control, and the median progression-free survival (PFS) was 5.6 months (3.0-8.3). At data cutoff, the median overall survival (OS) was 12.8 months.⁴

Ku said the initial data indicate that trastuzumab deruxtecan “certainly has the potential” to become an SOC in the second-line setting, where there is no established therapy.” Combination trastuzumab and chemotherapy is the first-line SOC for HER2-positive gastric cancer.

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“Interestingly, if you take patients who had prior irinotecan, the 43% response rate really does not change, suggesting that prior irinotecan does not necessarily dampen the effect of the ADC payload, including the nature of how it’s delivered,” Corcoran said.

ADCs aid the selective delivery of cytotoxic agents to cancer cells and include a tumor antigen—specific monoclonal antibody that is combined with a cytotoxic payload using a linker.⁵ Investigators said the lack of cross-resistance between irinotecan and trastuzumab deruxtecan could potentially be credited to the ADC’s efficient delivery of the cytotoxin. They theorized that this might result in a higher concentration of irinotecan in the tumor environment than with irinotecan alone. However, further investigation is needed to definitively identify the mechanism behind the “apparent lack of cross-resistance,” investigators wrote.⁴

Trastuzumab deruxtecan contains a humanized HER2-targeted antibody that has the same amino structure as trastuzumab. This antibody is attached to a potent topoisomerase I inhibitor payload by a cleavable peptide-based linker.⁶

Additionally, the agent’s drug-to-antibody ratio (DAR) is 7 to 8, about twice that of T-DM1’s, which has a DAR of 3 to 4. The higher DAR potentially enables trastuzumab deruxtecan to deliver more cytotoxic molecules to each cancer cell than T-DM1, which may lead to more intensive anticancer activity than an ADC with a lower DAR.⁶

Further, trastuzumab deruxtecan’s payload is membrane permeable, which enables payload molecules to not only induce cell death in the cytoplasm of the cancer cells that they target but also potentially spread out and kill neighboring malignant cells, including those with lower or heterogenous HER2 expression in what is recognized in the field as a “bystander effect.” This “bystander effect” means that the agent may be able to eradicate HER2-expressing cancer cells, whereas an ADC without this mechanism of action would not.⁶

The OncLive^® expert panel agreed that trastuzumab deruxtecan’s unique makeup contributes to the drug’s potential to demonstrate better efficacy than T-DM1 in gastric cancer and unanimously expressed their interest in seeing the ADC evaluated in additional studies. The agent is currently being explored in the phase II DESTINY-Gastric01 trial (NCT03329690) evaluating trastuzumab deruxtecan versus physician’s choice of therapy in approximately 220 patients with HER2-overexpressing advanced gastric or GEJ adenocarcinoma who have experienced disease progression on 2 prior regimens, including a fluoropyrimidine, a platinum-based agent, and trastuzumab.⁷

Beyond trastuzumab deruxtecan, ADCs in development for treating HER2-positive gastric cancer include MEDI4276, SYD985, and ARX-788.8,9 Another drug, XMT-1522, was also under investigation in this setting until its manufacturer, Mersana Therapeutics, Inc, announced that it was discontinuing the drug’s development to prioritize another agent in its portfolio in January 2019.¹⁰

Prior to the company’s self-imposed developmental halt, the FDA had placed a partial hold on a phase I study of XMT-1522 (NCT02952729) after treatment with the experimental ADC led to the death of 1 participant.¹¹ The trial enrolled patients with advanced HER2-expressing breast cancer, gastric cancer, and non—small cell lung cancer who progressed on standard therapy. The hold was eventually lifted on the trial and Mersana has resumed the trial.¹²

In gastric cancer, approved antibody-based therapies include trastuzumab, ramucirumab (Cyramza), and pembrolizumab (Keytruda).^13-15 Trastuzumab-dkst (Ogivri), trastuzumab-pkrb (Herzuma), and trastuzumab-anns (Kanjinti) are trastuzumab biosimilars that are also cleared for use in this setting.^16-18

Margetuximab and pertuzumab (Perjeta) are 2 HER2-targeting monoclonal antibodies currently in development in this setting, according to panelists, who added that tucatinib, an experimental tyrosine kinase inhibitor, and ZW25, an investigational bispecific antibody, are also being explored in gastric cancer.

Gastric cancer represents 1.6% of all new cancer cases in the United States, and there were an estimated 27,510 new cases in 2019. Between 2009 and 2015, the 5-year OS was 31.5%.¹⁹ Approximately 22% of gastric cancers are HER2-positive.²⁰ An immunohistochemical (IHC) score of 3+ denotes an HER2-positive result, according to the National Comprehensive Cancer Network guideline for gastric cancer. Biopsies that return this result have a cluster of 5 or more cancer cells with a strong, complete, basolateral, or lateral membranous reactivity that occurs independently of the percentage of positive cancer cells. IHC surgical specimens classified as IHC3+ will show strong complete, basolateral, or lateral membranous reactivity in ≥1% of cancer cells.²¹

CRC

Efficacy data for trastuzumab deruxtecan in CRC are also limited, and the promise that the investigational therapy could offer to patients with CRC is of similar interest. “The thought is maybe this drug is more potent than what we see with T-DM1, so I think it’s an important drug to study,” Kortmansky said.

Findings from the ongoing phase II DESTINY-CRC01 study (NCT03384940) of trastuzumab deruxtecan will expand the limited data currently available on the agent’s applicability in this setting, Corcoran said. DESTINY-CRC01 aims to enroll no more than 90 patients with HER2-expressing advanced CRC.²²

When reported, data from the trial will specifically shed light on the efficacy of trastuzumab deruxtecan versus T-DM1. DESTINY-CRC01 findings will build on existent evidence on T-DM1 in CRC, such as the results from the phase II HERACLES trial (NCT03225937), which comprised 2 cohorts.

Cohort A enrolled 27 patients with KRAS exon 2 (codons 12 and 13) wild-type and HER2-positive metastatic CRC that was refractory to SOC treatment including cetuximab or panitumumab. This group received trastuzumab in combination with lapatinib (Tykerb), a small molecule HER2-inhibitor.^23,24

Cohort B included 30 patients with RAS/BRAF wild-type HER2-positive metastatic CRC, who received pertuzumab in combination with T-DM1. This cohort was opened after Sartore-Bianchi et al showed that dual HER2 blockade is advantageous in patients with metastatic HER2-amplified disease in cohort A.²⁴

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“Without the drug conjugate, we saw response rates of 30%. With it, you see a response rate of 10%. It’s discouraging,” Kortmansky said.

Investigators said that although most patients in cohort B did not realize an ORR benefit with the doublet regimen, many did have prolonged PFS and stable disease. Among those in cohort B, all of whom were evaluable, the median PFS was 4.8 months (95% CI, 3.6-5.8) and 70% (95% CI, 50-85) achieved stable disease.²⁴

As data on the efficacy of trastuzumab deruxtecan in CRC develop, the hope is that the ADC, unlike T-DM1, will demonstrate its capacity to confer a benefit and improve patient outcomes, panelists said.

In 2020, an estimated 104,610 and 43,340 new cases of colon cancer and rectal cancer will be diagnosed, respectively.²⁵ HER2 expression is observed in about 3% of CRCs. HER2 amplification is typically assessed in CRC via fluorescence in situ hybridization and is considered positive when the HER2 to centromere enumeration probe 17 ratio is ≥2 in >50% of the cells.²⁶

Whereas treatment for HER2-amplified gastric cancer traditionally begins with a HER2-directed therapy, for colon cancer, it starts with standard chemotherapy, Corcoran said.

Akin to HER2-positive gastric cancer, various experimental agents are being investigated as potential therapies for HER2-expressing CRC, including pertuzumab, trastuzumab, ZW25, and lapatinib, panelists said.  

References

1. Enhertu [prescribing information]. Tokyo, Japan: Daiichi Sankyo; 2020. accessdata.fda.gov/drugsatfda_docs/label/2019/761139s000lbl.pdf. Accessed February 13, 2020.
2. Kadcyla [prescribing information]. San Francisco, CA: Genentech, Inc; 2013. accessdata.fda.gov/drugsatfda_docs/label/2019/125427s105lbl.pdf. Accessed February 13, 2020.
3. Thuss-Patience PC, Shah MA, Ohtsu A, et al. Trastuzumab emtansine versus taxane use for previously treated HER2-positive locally advanced or metastatic gastric or gastro-oesophageal junction adenocarcinoma (GATSBY): an international, randomised, open-label, adaptive, phase II/III study. Lancet Oncol. 2017;18(5)640-653. doi: 10.1016/S1470-2045(17)30111-0.
4. Shitara K, Iwata H, Takahashi S, et al. Trastuzumab deruxtecan (DS-8201a) in patients with advanced HER2-positive gastric cancer: a dose-expansion, phase I study. Lancet Oncol. 2019;20(6):827-836. doi: 10.1016/S1470-2045(19)30088-9.
5. Wu X, Kilpatrick T, Chau I. Antibody drug conjugate development in gastrointestinal cancers: hopes and hurdles from clinical trials. Cancer Drug Resist. 2018;1:204-218. doi: 10.20517/cdr.2018.16.
6. Tamura K, Tsurutani J, Takahashi S, et al. Trastuzumab deruxtecan (DS-8201a) in patients with advanced HER2-positive breast cancer previously treated with trastuzumab emtansine: a dose-expansion, phase I study. Lancet Oncol. 2019;20(6):816-826. doi: 10.1016/S1470-2045(19)30097-X.
7. Shitara K, Bang Y-J, Cheol Chung H, et al. A phase II, multicenter, open-label study of [fam-] trastuzumab deruxtecan (DS-8201a) in subjects of HER2-expressing gastric cancer. J Clin Oncol. 2019;37 (Suppl 4). doi: 10.1200/JCO.2019.37.4_suppl.TPS180.
8. Rinnerthaler G, Gampenrieder SP, Griel R. HER2 directed antibody-drug-conjugates beyond T-DM1 in breast cancer. Int J Mol Sci. 2019;20(5). doi: 10.3390/ijms20051115.
9. Zhao D, Klempner SJ, Chao J. Progress and challenges in HER2-positive gastroesophageal adenocarcinoma. J Hematol Oncol. 2019;12(1):50. doi: 10.1186/s13045-019-0737-2.
10. Mersana Therapeutics announces strategic priorities and goals for 2019 and beyond [news release]. Cambridge, MA: Mersana Therapeutics, Inc; January 4, 2019. https://ir.mersana.com/news-releases/news-release-details/mersana-therapeutics-announces-strategic-priorities-and-goals. Accessed February 13, 2020.
11. Mersana Therapeutics announces partial clinical hold for XMT-1522 clinical trial [news release]. Cambridge, MA: Mersana Therapeutics, Inc; July 19, 2018. https://ir.mersana.com/news-releases/news-release-details/mersana-therapeutics-announces-partial-clinical-hold-xmt-1522. Accessed February 13, 2020.
12. Mersana announces FDA lifts partial clinical hold for XMT-1522 [news release]. Cambridge, MA: Mersana Therapeutics, Inc; September 17, 2018. https://ir.mersana.com/news-releases/news-release-details/mersana-announces-fda-lifts-partial-clinical-hold-xmt-1522. Accessed February 13, 2020.
13. Herceptin [prescribing information]. San Francisco, CA: Genentech, Inc; 2018.https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/103792s5345lbl.pdf. Accessed February 14, 2020.
14. Cyramza [prescribing information]. Indianapolis, IN: Eli Lilly and Company; 2019.https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/125477s033lbl.pdf. Accessed February 14, 2020.
15. Keytruda [prescribing information]. Kenilworth, NJ: Merck & Co; 2020. https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/125514s067lbl.pdf. Accessed February 14, 2020.
16. Ogivri [prescribing information]. Canonsburg, PA: Mylan; Bengaluru, IN: Biocon Limited; 2017. https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/761074s000lbl.pdf. Accessed February 14, 2020.
17. Herzuma [prescribing information]. Incheon, KR: Celltrion Inc; 2019. https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/761091s001s002lbl.pdf. Accessed February 14, 2020.
18. Kanjinti [prescribing information]. Thousand Oaks, CA: Amgen; 2019. https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/761073Orig1s000lbl.pdf. Accessed February 14, 2020.
19. Cancer Stat Facts: Stomach Cancer. National Cancer Institute website. https://www.seer.cancer.gov/statfacts/html/stomach.html. Accessed February 13, 2020.
20. Bang Y-J, Cutsem EV, Feyereislova A, et al. Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): a phase 3, open-label, randomised controlled trial. Lancet. 2010;376(9742):697-97. doi: 10.1016/S0140-6736(10)61121-X.
21. National Comprehensive Cancer Network. Clinical Practice Guidelines in Oncology. Gastric cancer (version 4.2019). nccn.org/professionals/physician_gls/pdf/gastric.pdf. Accessed February 13, 2020.
22. Daiichi Sankyo, Inc, AstraZeneca. DS-8201a in human epidermal growth factor receptor2 (HER2)-expressing colorectal cancer (DESTINY-CRC01). NCT identifier: NCT03384940. Clinicaltrials.gov website. clinicaltrials.gov/ct2/show/NCT03384940. Accessed February 13, 2020.
23. Sartore-Bianchi A, Trusolino L, Martino C, et al. Dual-targeted therapy with trastuzumab and lapatinib in treatment-refractory, KRAS codon 12/13 wild-type, HER-2 positive metastatic colorectal cancer (HERACLES): a proof-of-concept, multicentre, open-label, phase 2 trial. Lancet Oncol. 2016;17(6):738-746. doi: 10.1016/S1470-2045(16)00150-9.
24. Sartore-Bianchi A, Martino C, Lonardi S, et al. Phase II study of pertuzumab and trastuzumab-emtansine in patients with HER2-positive metastatic colorectal cancer: the HERACLES-B (HER2 amplification for colorectal cancer enhanced stratification, cohort B trial). Ann Oncol. 2019;30(5):v869-v870. https://www.annalsofoncology.org/article/S0923-7534(19)60384-4/pdf.
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Unlike cohort A, which reported positive results, cohort B study failed to meet its primary end point, overall response rate (ORR). At the data cutoff, the ORR with pertuzumab and T-DM1 (10%; 95% CI, 0-28%) was significantly lower than it was with trastuzumab and lapatinib in cohort A (30%; 8 of 27 patients; 95% CI, 14-50; Table 2).^23,24

Results from the phase I study also indicated that the benefit seen with trastuzumab deruxtecan extended to patients previously treated with irinotecan (Table 1).⁴