To develop safer combination therapies is still critical, and "we think that's particularly true in breast cancer," Oncothyreon Inc. CEO Robert Kirkman told BioWorld Today, even though Thursday's overwhelming torrent of abstracts seem to suggest that immunity-based approaches will steal the show again at the American Society of Clinical Oncology (ASCO) meeting later this month.

"HER2-positive breast cancer has really become in some respects a chronic disease," Kirkman said. "Patients get a sequence of therapies over a relatively prolonged period of time. They're simply not going to tolerate drugs that cause significant side effects in that setting."

Seattle-based Oncothyreon's shares of (NASDAQ:ONTY) closed 36.5 percent higher, at $2.02, up 54 cents, as Wall Street anticipated ASCO posters on ONT-380, a small-molecule selective inhibitor of HER2 being tested in a pair of phase Ib trials, one in which it's paired with Kadcyla (ado-trastuzumab emtansine, Roche AG) and another adding the compound to Herceptin (trastuzumab, Roche AG), and Xeloda (capecitabine, Roche AG), Kirkman said.

"We have presented some data from these two trials in the past," he said, but "one thing people were looking for in our data that they might not have seen before are some actual partial responses [PRs] in patients with central nervous system metastases from HER2-positive breast cancer. In the data we presented at [the San Antonio Breast Cancer Symposium in December], we were just too early. We had some patients with brain mets back then that were getting smaller, but they hadn't yet achieved a true PR." He conceded there is "a fairly small number in this abstract where we've seen that," but pointed out that the abstracts were submitted in February. "We've wanted to be clear that we'll have more data at ASCO in a couple weeks," Kirkman said.

"There are two goals" with the ONT-380 research, he said. "One is clearly to increase efficacy, and it's been demonstrated before that combinations of agents which target HER2 are in general more effective than single-agent therapy." Experiments with Herceptin and Basel, Switzerland-based Roche's Perjeta (pertuzumab) have demonstrated as much, so "that's not a novel concept," Kirkman said. But "it's proven relatively difficult so far to do that with a small molecule," he said. "There's only one on the market," which is Tykerb (lapatinib, Glaxosmithkline plc), approved in 2007. "Toxicity has been a big reason" Tykerb stands alone, he said: it also binds to EGFR, "and you get significant side effects from that."

Dodging those side effects looks like the ONT-380 advantage over another drug with a similar mechanism of action, often mentioned in the same breath as Oncothyreon's candidate: neratinib, from Los Angeles-based Puma Biotechnology Inc., also expected to take a share of the spotlight at ASCO. (See BioWorld Today, Jan. 23, 2015.)

"The primary difference between the two drugs is the additional targeting of EGFR by neratinib," Kirkman said, noting that ONT-380, licensed in 2013 from Array Biopharma Inc., of Boulder, Colo., is "designed specifically not to bind to HER1 or EGFR, with the belief that if we could get a similar level of activity against HER2 without the EGFR activity, we would have an equally effective drug" minus the side effects, "particularly the diarrhea that's been associated with neratinib." (See BioWorld Today, May 31, 2013.)

HERA-SEE HERESY?

ONT-380 has been found "equipotent in preclinical studies with neratinib," Kirkman said. "We think our early data indicate that it has efficacy in the clinic, and we think we have pretty much unequivocally proven that we don't have the diarrhea side effect. We've now treated over 100 patients at the dose we're planning to take forward without a single case of grade 3 diarrhea, [so] that part of the hypothesis is true," but more trials must establish efficacy.

Puma's shares (NASDAQ:PBYI) tumbled 18.6 percent Thursday, closing at $170.67, down $39.05, as investors combed through an ASCO abstract regarding data from the firm's phase III Extenet trial with neratinib for the extended adjuvant treatment of breast cancer, top-line results of which were reported last summer. RBC Capital Markets analyst Simos Simeonidis said Wall Street ought not to have been spooked by the abstract. "We believe that an apples-to-apples comparison of these data to prior trials points to the drug's strong efficacy and additional benefits, especially in hormone-positive patients," Simeonidis wrote in research report. "We expect the presentation of the full dataset at ASCO to reveal the real extent of neratinib's benefit in the extended adjuvant setting. Our conviction in neratinib and Puma remains unchanged, and we anticipate investor/medical community understanding of the data to be fully realized at ASCO." (See BioWorld Today, July 24, 2014.)

The Extenet trial randomized 2,821 patients 1-to-1 to receive one year of neratinib or placebo following one year of adjuvant Herceptin treatment in patients with HER2-positive disease. The primary endpoint was invasive disease-free survival (IDFS) at two years, with other important secondary endpoints, including DFS-ductal carcinoma in situ (DCIS), which is also the primary endpoint used in the adjuvant Herceptin trial, known as Hera, and distant DFS (DDFS). (See BioWorld Today, June 12, 2006.)

Simeonidis noted that, at two years follow-up from study entry (equivalent to the third year of Hera), the differences between the two arms were 2.3 percent for IDFS (93.9 percent neratinib vs. 91.6 percent placebo; HR = 0.67, p = 0.0046) and 2.9 percent for DFS-DCIS (92.9 percent neratinib vs. 91.0 percent placebo; HR = 0.63; p = 0.0009). The most common adverse event was diarrhea with 40 percent grade 3 or higher for the neratinib arm (one patient had grade 4). Other individual adverse events greater than grade 3 totaled less than 4 percent in the neratinib arm.

"At first look, efficacy seems to fall below expectations," Simeonidis conceded, "but we think the data need careful teasing out. Most investors and oncologists had approximated the minimum delta between the two arms to be about 3 percent in order to achieve meaningful clinical significance. On its face, the 2.3 percent IDFS difference falls below expectations and the 2.9 percent DFS-DCIS is right at the 3 percent benchmark." From that standpoint, Puma's stock dip makes sense.

ALPINE PIQUES

But a closer comparison to Hera turns up a fairer comparison, in Simeonidis' view. "Patients enrolling into Extenet had their HER2 status confirmed initially at local labs before being confirmed through a central review process," he wrote. "On the other hand, patients enrolled in Hera all had central review of HER2 status," a significant distinction for the analyst. When only the subset of centrally reviewed patients in Extenet are considered, "the treatment benefit was significantly more pronounced (HR = 0.52) than it is in the overall patient population (HR = 0.67)," as cited by Simeonidis. "The higher absolute levels of two-year DFS-DCIS seen with Extenet placebo arm (91 percent) vs. the comparable three-year point in Hera (86.7 percent) can be attributed to the fact that the median time from last Herceptin treatment in Extenet was around 4.5 months. Therefore, the higher Extenet DFS figures take into account the removal of the percentage of Hera patients who would have disease recurrence in those interim 4.5 months."

In any case, Leerink Partners LLC analyst Howard Liang predicted ASCO's "most impactful data" will be those from Extenet on Puma, and other pundits continued picking through ASCO abstracts, guessing at relevance and impact.

HER2-positive breast cancer is hardly the only type to make ripples at the meeting. Menlo Park, Calif.-based Corcept Therapeutics Inc., will discuss results from its phase I/II dose-escalation study of mifepristone and chemotherapy drug Halaven (eribulin, Eisai Co. Ltd.), showing the combo well tolerated and clinically active in patients with triple-negative breast cancer, one of the more aggressive and hard-to-treat varieties.

Companies galore promised details of research that suggests the CAR T approach may work not only in acute lymphoblastic leukemia but in such indications as follicular lymphoma, multiple myeloma and maybe even solid tumors such as glioblastoma. Multiple myeloma should be an area of special focus, too, with new findings due from Thousand Oaks, Calif.-based Amgen Inc. with the second-generation proteasome inhibitor Kyprolis (carfilzomib), as well as from Bristol-Myers Squibb Co., of New York, for elotuzumab. North Chicago-based Abbvie Inc., Johnson & Johnson, of New Brunswick, N.J., and Copenhagen-based Genmab A/S will have data with daratumumab.

Oncothyreon's Kirkman said immuno-oncology is strongly of interest to his firm as well, as shown by the recent buy of "a technology that we believe has the potential to be very important in the space." He was referring to last August's $27 million takeover of Alpine Biosciences Inc., of Seattle, which is developing a nanoparticle platform technology called Protocell to enable targeted delivery of multiple therapeutic agents, including nucleic acids, proteins, peptides and small molecules. The approach represents a "potential way to create a CAR T cell in vivo without any ex vivo cell processing," he said. "While we are a long way from proving we can do that, it's a big part of the reason we did the acquisition."