For the treatment of breast cancer, the biggest newsmaker at the 2018 American Society of Clinical Oncology (ASCO) annual meeting in Chicago had nothing to do with drug development. Instead, the findings came from a National Cancer Institute (NCI)-sponsored study directing physicians to use less treatment, not more, in most women with a common form of early stage disease.

The largest breast cancer adjuvant study ever performed, Trial Assigning IndividuaLized Options for Treatment (Rx), or TAILORx, showed conclusively that the Oncotype DX Breast Recurrence Score (RS) test identified 70 percent of individuals with hormone receptor (HR)-positive, HER2-negative, node-negative breast cancer – the group of women with a mid-range 21-gene RS – who receive no benefit from chemotherapy and can be treated effectively with endocrine therapy (ET) alone. Data also showed that chemotherapy may provide life-saving benefit to the other 30 percent of such patients.

The trial was led by the ECOG-ACRIN Cancer Research Group. Findings, reported during the plenary session at the ASCO annual meeting and published simultaneously in The New England Journal of Medicine, were hailed for their immediate impact on clinical practice. (See BioWorld, June 5, 2018.)

"We'll be giving a lot less chemotherapy to that group, and that's always a good thing when you can spare chemotherapy," said Charles Shapiro, professor of medicine and director of translational breast cancer research and cancer survivorship in the Tisch Cancer Institute at the Icahn School of Medicine at Mount Sinai. The findings "are far-reaching, affecting thousands to tens of thousands of women," he acknowledged, lamenting the fact that NCI sponsors far fewer trials the size of TAILORx than a decade ago.

"These trials are very large and cost hundreds of millions of dollars, but the answer you get at the end of the day gives you greater confidence" in making treatment decisions, Shapiro told BioWorld Insight.

'More confusion' about anti-osteoporosis drugs in breast cancer

Shapiro pointed to PERSEPHONE as another study that showed less treatment in some breast cancer patients is more. Reported during an oral abstract session at ASCO, the randomized phase III noninferiority study measured six months vs. 12 months of adjuvant Herceptin (trastuzumab, Roche Holding AG) in patients with HER2-positive early breast cancer, meeting the primary endpoint of disease-free survival (DFS) over four years.

Halving the use of trastuzumab in those patients with no difference in efficacy not only reduces corresponding cardiac and other toxicities, investigators reported at ASCO but also, Shapiro said, saves money for patients and for the system as a whole, making the findings a triple win.

However, ASCO did not resolve the controversy over using anti-osteoporosis drugs in women with early stage breast cancer. The randomized phase III Optimize-2 study, reported at the 2014 ASCO annual meeting, suggested that treatment with Reclast (zoledronic acid, Novartis AG) improved DFS and bone metastasis-free survival (BMFS) in premenopausal women along with its protective effects against skeletal events. Although some researchers cautioned that the relatively modest size of the trial mitigated the findings, the study nevertheless "set the world on fire" about prospects to use such drugs to treat cancer, Shapiro recalled. (See BioWorld Today, June 2, 2014.)

Subsequent trials trying to replicate the results met with mixed results, and large dedicated trials reported this year at ASCO did the same. Findings from an analysis of 3,425 postmenopausal women in the ABCSG-18 trial of adjuvant Prolia (denosumab, Amgen Inc.) suggested the regimen improved DFS in HR-positive postmenopausal breast cancer patients receiving adjuvant aromatase inhibitors (AIs). However, that finding was not replicated in the international, multicenter, randomized, placebo-controlled phase III D-CARE study of adjuvant denosumab in more than 4,500 women with early breast cancer that was sponsored by Amgen. D-CARE showed no benefit for the addition of denosumab at a time-driven analysis performed after a median follow-up of 67 months that allowed for the full five years of treatment in all patients. Overall survival, or OS (412 events), was similar in both groups (HR=1.03, 95 percent confidence interval, 0.85-1.25). Denosumab did not improve BMFS, DFS or OS even in the postmenopausal subset (n=2,149).

"If D-CARE had been a positive trial, we would have been using denosumab routinely not only for its bone preserving properties and fracture reduction but for an anticancer effect," Shapiro said. Instead, "there's just more confusion about the anticancer effects" of drugs designed to treat osteoporosis.

Another disappointment came from Roche unit Genentech Inc., which reported that taselisib (GDC-0032, RG-7604), a beta-isoform sparing phosphoinositide 3-kinase, or PI3K, inhibitor, showed only modest benefit in the phase III SANDPIPER study in individuals with estrogen receptor (ER)-positive, PIK3CA-mutant locally advanced or metastatic breast cancer (MBC).

Although SANDPIPER met its primary endpoint – adding taselisib to Faslodex (fulvestrant, Astrazeneca plc) showed a statistically significant improvement in investigator-assessed progression-free survival (PFS) – serious side effects occurred in 32 percent of individuals in the treatment arm compared to 8.9 percent in those on placebo plus fulvestrant, and the side effect-driven discontinuation rate was 16.8 percent in the taselisib arm vs. 2.3 percent in the placebo arm. In light of the data presented at ASCO, Basel, Switzerland-based Roche pulled the plug on a planned regulatory filing. (See BioWorld, June 5, 2018.)

Roche didn't skip a beat, however. Presenting days later at the Jefferies 2018 Healthcare Conference, company officials noted that treatment outcomes in HER2-positive breast cancer have improved over those is achieved by Herceptin monotherapy in every line of treatment with the addition of Perjeta (pertuzumab), which has become substantial product in its own right, with a five-year consensus forecast of $5.17 billion, according to Cortellis Competitive Intelligence.

'We're going to be hearing a lot more about this drug'

Despite a plethora of treatment options, breast cancer continues to attract interest across the industry and the treatment landscape, as hundreds of presentations at ASCO made clear. Shapiro was intrigued by several small studies, including findings from Immunomedics Inc. on bispecific antibody IMMU-132 (sacituzumab govitecan). Jefferies LLC analyst Matthew Andrews also found a lot to like about the ASCO data, writing in a flash note that the efficacy profile was "not too shabby in a sixth-line HR+/HER2-negative setting." Patients were advanced with a median of five prior lines and 67 percent treated with a prior CDK4/6. Ten of 54 remained on study drug at the time of data cutoff, including seven with partial response (PR) and three with stable disease (SD).

"We're going to be hearing a lot more about this drug," Shapiro said.

Odonate Therapeutics Inc. presented findings in HER2-negative, HR-positive MBC from the phase II trial of its orally administered taxane, tesetaxel. The multicenter trial enrolled 38 patients, who received tesetaxel as a single agent once every three weeks at a starting dose of 27 mg/m2. The median age of those enrolled was 58 (36 to 80 years), and 87 percent had visceral disease, 74 percent previously received at least one ET, 68 percent previously received neoadjuvant or adjuvant chemotherapy and 53 percent previously received a taxane-containing regimen.

Across the enrolled population, the confirmed response rate was 45 percent, and findings were consistent across subgroups. Forty-four percent of patients who did not previously receive a taxane-containing regimen achieved a confirmed response compared to 45 percent of patients who previously received a taxane-containing regimen. Median duration of response was 10.9 months, and median PFS was 5.4 months.

Neutropenia, the most common grade 3 or higher AE, occurred in 25 percent of the 24 patients who were not dose-escalated beyond the 27 mg/m2 starting dose, which was selected as the dose for the company's phase III CONTESSA study, now recruiting.

"Updated data at ASCO last week was positive and further reinforces our belief in the activity of the drug," Jefferies analyst Michael Yee wrote in a flash note.

San Diego-based Odonate completed its IPO late last year, raising $150 million to fund CONTESSA. (See BioWorld, Dec. 8, 2017.)

In data presented by Daiichi Sankyo Co. Ltd., the Erbb2 tyrosine kinase receptor inhibitor DS-8201 (trastuzumab deruxtecan) showed a 50 percent confirmed objective response rate (ORR) and an 85.3 percent disease control rate in 34 heavily pretreated patients with HER2-low-expressing MBC. A 54.5 percent confirmed ORR and 93.9 percent disease control rate were demonstrated with the antibody-drug conjugate in an updated subgroup analysis of patients with HER2-positive MBC pretreated with ado-trastuzumab emtansine (T-DM1) and, in most cases, with trastuzumab and pertuzumab, as well.

In a phase I/II study of the ADC U3-1402, preliminary efficacy data showed a 47 percent confirmed ORR and a 94 percent disease control rate in patients with heavily pretreated HER3-positive MBC.

'You can still have endocrine resistance'

In the PARP inhibitor category, several datasets highlighted "the overall attractiveness of this increasingly underappreciated class," observed Evercore ISI analyst Steven Breazzano. Although ovarian cancer got most of the attention, he cited Tesaro Inc.'s TOPACIO data in triple negative breast cancer, calling the ASCO update "incrementally positive" with additional patients and follow up, with ORRs "firming up."

Tesaro presented incremental data evaluating the combination its PARP, Zejula (niraparib), approved last year to treat ovarian cancer, and Keytruda (pembrolizumab, Merck and Co. Inc.) in 46 evaluable patients with triple-negative breast cancer. (See BioWorld Today, March 28, 2017.)

"The results are unsurprisingly strongest in the tBRCA patients and the slightly broader tBRCA + HRRmut population, as well as the PD-L1+ patients – all factors which enrich the responses for PARP and PD-1, respectively," Breazzano wrote. "Importantly, the responses appear long-lasting, with median duration of response not reached at [nine] months."

The findings are "certainly in the ballpark of Lynparza (olaparib, Astrazeneca plc/Merck & Co. Inc.), which is now approved in mBRCA breast cancer patients as monotherapy (ORR 52 percent vs. 23 percent for chemotherapy, PFS of 7 vs. 4.2 months)," he added. "The emerging TOPACIO data suggest that combination of PARP + PD-1 potentially may add incremental, and deeper responses, though we'll be looking for additional data."

However, Piper Jaffray analyst Christopher Raymond remained Neutral on Tesaro following the data presentations and an investor update at ASCO.

"While we find the TOPACIO triple-negative breast cancer PD-1/Zejula combo data interesting, results are little changed from the abstract, and TSRO still needs to run a larger pivotal trial, which we see as a long way off," Raymond wrote.

In general, the outlook for most women with breast cancer has never been better, Shapiro said, but certain subgroups still face limited treatment options. In triple-negative breast cancer, 70 percent of those with stage 1 disease are cured, he pointed out, but the 30 percent who relapse face a grim prognosis, with average survival of one year, "and that 30 percent is higher than any other subgroup," he said.

Shapiro also hopes to see more research into ET, which "pound for pound, is more easily tolerated" than most breast cancer regimens, he said. "But you can still have endocrine resistance, and the mechanism is not understood."

Finally, he looks for future ASCO meetings to produce more data on dormancy, noting that half of ER-positive breast cancer patients who are destined to relapse do so "five, 10, 15 or 20 years after that primary breast cancer," he said. Researchers suspect the cells lay in a state of dormancy during that time, expressing a gene signature and very slowly dividing while resisting chemotherapy and radiation – behaving "like stem cells, in a sense," Shapiro observed. But no one has identified the trigger that reactivates the cells or the therapeutic approach that might prolong their dormancy.

"Relapses in women with ER-positive breast cancer are a very big problem," he said, "and we need answers."

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