New ADC Shrinks HER2-Positive Tumors

Published OnlineFirst August 2, 2019; DOI: 10.1158/2159-8290.CD-NB2019-089

NEWS IN BRIEF

he says, “I can’t cancer, and 17 had HER2-low HR- fathom that cost.” negative breast cancer. The remaining Cytoplasm –Elie Dolgin n 47 patients had gastric, urothelial, or endometrial tumors. Eye-related side effects were again New ADC prevalent: 71% of patients were Shrinks affected by problems such as conjunctivitis, keratitis, and dry eye. These Nuclear pore HER2- adverse effects have been seen with complex Positive other ADCs—although they haven’t Tumors been described with T-DM1—but the mechanism remains unclear, says A novel co-author Philippe Aftimos, MD, of Nucleus antibody–drug the Jules Bordet Institute and the Free conjugate (ADC) University of Brussels in Belgium. Tumor suppressor protein Selective inhibitor of triggers responses nuclear export inhibitor The ADC produced partial + eiF4E-bound mRNA in patients with Regulatory factor XPO1 responses in 33% of the patients with HER2-expressing HER2-positive metastatic breast breast cancer Selinexor is a selective inhibitor of nuclear export. By blocking XPO1, it cancer; 28% with HER2-low, HR- prevents molecular cargo from moving through the nuclear pore complex, and other solid positive metastatic breast cancer; and causing cell-cycle arrest, apoptosis, and other antitumor activity. (Courtesy tumors, a phase I 40% with HER2-low, HR-negative of Karyopharm Therapeutics; modified with permission.) clinical trial metastatic breast cancer. The median indicates (Lancet progression-free survival for these Oncol 2019;20:1124–35). The drug commonly experienced side effects three groups was 7.6 months, such as thrombocytopenia, hypona- could become a new treatment for 4.1 months, and 4.9 months, respec- tremia, anemia, and nausea. patients with breast cancer who are tively. The researchers also saw signs Those safety issues prompted an resistant to the ADC trastuzumab of drug activity in the patients with FDA advisory committee of outside emtansine (Kadcyla, T-DM1; Genen- other cancer types: Partial responses experts to vote 8–5 against recommend- tech) or who have low HER2 expression. occurred in 25% of patients with ing approval until additional data are T-DM1, a second-line treatment for urothelial cancer and 39% of those available. Onlookers like David Iberri, patients with HER2-positive breast with endometrial cancer. MD, of Stanford Cancer Center in Cali- cancer, kills cells by inhibiting micro- The results suggest that patients fornia, and Al-Ola Abdallah, MD, of the tubule polymerization. However, with HER2-positive breast cancer University of Kansas Medical Center in patients usually develop resistance, resistant to T-DM1 “can still respond Westwood, support that decision. prompting researchers to develop new STORM provides “really insufficient ADCs. The ADC tested in the current to other ADCs with different payloads,” data upon which to base a recom- trial, trastuzumab duocarmazine, also says co-author Udai Banerji, MD, PhD, mendation for this drug,” Iberri says. targets HER2-expressing cells, but its of the Institute of Cancer Research and “I know a lot about its toxicity now, payload triggers DNA damage. The Royal Marsden NHS Foundation but I really don’t know if it’s going to The dose-escalation portion of Trust in London, UK. Because trastu- improve outcomes in anyone because the trial included 39 patients with zumab duocarmazine works through we don’t have randomized data.” advanced or metastatic solid tumors, a different mechanism, it may kill cells Abdallah adds, “We need more each of whom received 0.3 to 2.4 mg/kg that are resistant to T-DM1, he says. mature studies.” of trastuzumab duocarmazine. One Patients with breast cancer and low But citing the need for new medi- third of the patients reported grade 3 HER2 expression, for whom there are cines, the agency granted accelerated or 4 side effects, including fatigue and no approved anti-HER2 therapies, approval contingent on verification of neutropenia. Many also experienced could also benefit from trastuzumab clinical benefit. The phase III BOSTON eye problems, with 31% developing duocarmazine, says Aftimos. “We study is evaluating progression-free conjunctivitis, for example. Four cases have proof that targeting HER2 in survival among patients taking selinexor of pneumonitis—one fatal—occurred, HER2-low breast cancer is an effective with bortezomib (Velcade; Millennium all in patients who received doses of strategy.” Although trastuzumab alone Pharmaceuticals) and dexamethasone or 1.5 mg/kg or higher, so researchers set does not benefit these patients, the bortezomib and dexamethasone alone. the dose at 1.2 mg/kg in the dose- ADC may work through a bystander Results are expected later this year or in expansion stage of the trial. effect, allowing it to kill adjacent early 2020. For that portion of the study, the tumor cells even if they don’t overex- Until then, Iberri will not prescribe researchers enrolled 146 patients with press HER2, he says. selinexor. In addition to wanting more metastatic HER2-expressing tumors. The trial was too small to confirm data, he cites the drug’s price—$22,000 Fifty patients had HER2-positive that “this drug works at a substantial per month—as another major strike breast cancer, 32 had HER2-low hor- level in patients who have progressed against it. “Without randomized data,” mone receptor (HR)–positive breast on T-DM1,” cautions Ian Krop, MD, PhD,

SEPTEMBER 2019 CANCER DISCOVERY | 1151

NEWS IN BRIEF of Dana-Farber Cancer Institute in which were pieces of the compounds NOTED Boston, MA, who wasn’t connected to they had assessed previously. These the study. But if larger studies prove smaller pieces can fi t snugly into the The f irst two cancer biosimilars are now defi nitive, he says, the ADC will be pocket and don’t clash with the pro- being sold in the United States: bevaci- a useful addition to breast cancer tein as full-sized molecules do, explains zumab-awwb (Mvasi; Amgen/Allergan), treatment. “It’s not a home run, but a McConnell. Two screens on 15,600 a biosimilar of the angiogenesis inhibi- substantial number of patients seem fragments, performed with collabora- tor bevacizumab (Avastin; Genentech), to benefi t.”–Mitch Leslie n tor Stephen Fesik, PhD, of Vanderbilt and trastuzumab-anns (Kanjinti; Amgen/ University in Nashville, TN, revealed 55 Allergan), a biosimilar of the HER2- Researchers Reveal that bound weakly to the switch I/II targeted agent trastuzumab (Herceptin; pocket. Guided by X-ray crystallog- Genentech). They cost about 12% to Another KRAS Inhibitor raphy, the team progressively tweaked 13% less than their reference products. Although researchers have long the structure of their molecules to Researchers concluded that Janssen’s thought that RAS proteins were improve binding and produced one erdafitinib (Balversa) may be effective G12C undruggable, two KRAS inhibitors that attaches tightly to the inactive and for patients with locally advanced or are now in phase I clinical trials. A active forms of the protein. metastatic urothelial carcinoma who recent study presents a third molecule, Switching on KRAS leads to phos- have an FGFR3 or FGFR2 mutation and Boehringer Ingelheim’s BI-2852, which phorylation of ERK, a change the have not responded to platinum-contain- targets a different pocket on KRAS researchers used as an indicator of KRAS ing chemotherapy (N Engl J Med 2019; and might work against all KRAS activity. They found that in culture, the 381:338–48). In the phase II BLC2001 G12C mutations, not just KRAS (Proc inhibitor almost completely blocked trial, 99 patients had an objective res- Natl Acad Sci U S A 2019;116:15823–9). ERK phosphorylation in KRAS-mutated ponse rate of 40% and a median overall Members of the RAS family are lung cancer cells and curbed their pro- survival of 13.8 months. mutated in about 20% of cancers, mak- liferation. The new molecule is not yet AbbVie announced that it acquired the ing them prime therapeutic targets. a drug, McConnell says, but it is a good biopharmaceutical company Mavupharma KRAS, for instance, is one of the most starting point for one. Its potency and for an undisclosed amount. The deal will commonly altered oncogenes, with specifi city are what need to be improved. give AbbVie access to Mavupharma’s mutations occurring in up to 96% of Both inhibitors in clinical trials pipeline of cancer therapies, which pancreatic cancers and 54% of colorec- G12C target the KRAS mutation, which target the STING immune pathway— tal cancers. However, scientists have occurs in a minority of KRAS-mutated including MAVU-104, a small-molecule only recently identifi ed pockets on cancers, notes Luke Gilbert, PhD, inhibitor of ENPP1. RAS proteins into which a drug might of the University of California, San fi t. Thus far, one inhibitor, Amgen’s Francisco, who wasn’t connected to Germline BRCA2 mutations may be AMG 510, has shown a favorable safety the study. “What this paper suggests associated with an increased risk of profi le and partial responses in patients is that there are inhibitors that could NHL in children and adolescents (JAMA with non–small cell lung cancer, target other types of RAS-mutant Oncol 2019 Jul 25 [Epub ahead of print]). Researchers analyzed whole-genome colorectal cancer, and appendix cancer proteins.” He says it’s also encourag- sequencing data from 1,380 survivors (Cancer Discov 2019;9:988–9). ing that the molecule binds to active of Hodgkin lymphoma and NHL, and Pursuing other possibilities, Darryl and inactive KRAS, which may help 59,345 healthy controls. They found McConnell, PhD, of Boehringer Ingel- prevent resistance. that the 565 survivors of NHL were sig- heim in Vienna, Austria, and colleagues The discovery “adds to the tools nificantly more likely to have BRCA2 homed in on a second pocket, known we have for understanding how to mutations than healthy controls. as switch I/II, which lies at the junction block RAS,” says John O’Bryan, PhD, of two regions that RAS uses to signal of the Medical University of South The World Health Organization added 12 and drive cell proliferation. The pocket Carolina in Charleston, who also cancer drugs to its list of essential is small, shallow, and contains slippery wasn’t connected to the research. But medicines, including the PD-1 inhibitors polar amino acids, making it extremely developing the molecule into a drug pembrolizumab (Keytruda; Merck) and challenging for chemists to fi nd mol- will require much more work, he says. nivolumab (Opdivo; Bristol-Myers Squibb) ecules that stick tightly, he says. When For instance, researchers will have to for advanced melanoma (https://www. the researchers ran a conventional assess its pharmacology in cells and who.int/medicines/en/). screen on 1.7 million compounds, they animals, test whether it works against The Biden Cancer Initiative has sus- didn’t uncover any promising hits, cells other than lung cancer cells, and pended operations indefinitely in which “shows that classical approaches show that it causes tumor regression. response to former Vice President Joe don’t work on RAS,” says McConnell. “The question is whether we can move Biden’s presidential run. Biden started the He and his colleagues turned to this compound forward to develop a nonprofit 2 years ago after the creation an alternative approach that involves potent RAS inhibitor for use in the of the federally funded Beau Biden Cancer testing molecular fragments, some of clinic,” he says. –Mitch Leslie n Moonshot. The organization facilitated collaboration among researchers, com- For more news on cancer research, visit Cancer Discovery online at http://cancerdiscovery.aacrjournals. panies, and patient groups. org/CDNews.

1152 | CANCER DISCOVERY SEPTEMBER 2019 www.aacrjournals.org

New ADC Shrinks HER2-Positive Tumors

Cancer Discov 2019;9:1151-1152. Published OnlineFirst August 2, 2019.

Updated version Access the most recent version of this article at: doi:10.1158/2159-8290.CD-NB2019-089

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