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the results from the Keynote-048 study—which also included an arm testing pembrolizumab alone—left a raft of questions to puzzle over, as Vantage’s Jacob Plieth steps through here.
—More promise in a one-two punch came from partners Merck KGaA, of Germany, and Pfizer (NYSE: PFE), which reported that a combination of their anti-PD-L1 agent avelumab (Bavencio) and Pfizer’s axitinib (Inlyta) boosted progression-free survival in previously untreated kidney cancer. Like another immunotherapy combo from the U.S.-based Merck that just reported good results, Pfizer compared its kidney-cancer combo to the standard of care sunitinib (Sutent).
—Shares of San Diego’s Mirati Therapeutics (NASDAQ: MRTX) took a 15 percent hit Monday after it said 16 of 56 (29 percent) patients in a small study responded to a combination of its experimental sirvatinib and nivolumab. But Mirati couldn’t confirm seven of those responses. Here’s more from STAT.
A Precision Battle: Loxo Vs. Roche
Merck made history in 2017 when its immunotherapy pembrolizumab (Keytruda) was approved to treat tumors with a specific genetic alteration, no matter where those tumors formed. But it likely won’t be alone for long; multiple experimental drugs are aiming for “tissue agnostic” approvals, starting next month when the FDA reviews larotectrinib, from Loxo Oncology (NASDAQ: LOXO). ESMO provided the forum for the latest update on these drugs.
Larotrectinib is meant for cancers that share one important commonality: a genetic alteration known as a TRK fusion, which is present in 0.5 percent to 1 percent of solid tumors. It has been tested in patients with 17 different cancer types, far more than pembrolizumab had upon its landmark tissue-agnostic approval in 2017. That makes larotrectinib an important test case—will the FDA approve it for all patients with TRK fusions? Or just the patients with the strongest data? And how will payers handle Loxo’s drug?
Data released at ESMO continue to bolster Loxo’s case. The company provided updated results from 55 previous patients as well as data from 67 newer patients. Among the 55 patients, after a median follow-up of 17.6 months, 44 (80 percent) responded to treatment, meaning their tumors shrank, and 16 percent had no evidence of cancer.
In the newer group, 44 of 54 (81 percent) of patients responded, with 17 percent showing no trace of cancer after a median of 7.4 months of follow-up. Most side effects have been mild; just one patient stopped treatment because of them.
Loxo’s data set a high bar for rival entrectinib, a drug Roche acquired when it bought Ignyta in 2017.
Roche is already seeking FDA approval of entrectinib for lung cancer with a ROS-1 fusion. But it’s also testing the drug in tumors with so-called NTRK fusions, which are found in 30 solid tumor types, and thus could fight larotrectinib for market share. The two drugs’ latest results will make that battle an uphill climb for Roche, analysts said.
At ESMO, Roche reported that 57.4 percent of the 54 patients with one of 10 different NTRK fusion-positive solid tumor types have responded to treatment. Those responses lasted a median of 10.4 months, and patients survived a median of 20.9 months after treatment. The majority of side effects were mild; 3.9 percent of patients dropped out of the study.
Entrectinib “was broadly active in TRK patients, but the overall profile, including level of activity, durability, and tolerability do not appear competitive with larotrectinib,” wrote Leerink analyst Andrew Berens.
PARP inhibitors, which are meant to block tumor cells from repairing their own DNA, have been working forward in a few different cancers. The first to win approval was AstraZeneca and Merck’s olaparib (Lynparza), for certain forms of ovarian cancer in 2014. Niraparib (Zejula) from Tesaro and rucaparib (Rubraca) from Clovis Oncology (NASDAQ: CLVS) followed, all as maintenance therapies to delay ovarian cancer’s recurrence after chemotherapy.
Beyond ovarian cancer, PARPs have begun to show real benefits for patients with other tumors as well. Both olaparib and a new drug from Pfizer, talazoparib (Talzenna), have won approvals for breast cancer.
At ESMO, trials featuring olaparib and rucaparib were emblematic of the growing importance of PARPs. The first trial was SOLO-1, which tested olaparib in ovarian cancer patients whose tumors have a BRCA mutation and have responded to chemotherapy, what’s known as first-line maintenance therapy.
AstraZeneca reported that patients on placebo saw their tumors held in check (progression-free survival) for a median of 13.8 months. By comparison, after median follow-up of 41 months, AstraZeneca hasn’t reached a median progression-free survival number for olaparib patients. The tumors of 60 percent of patients on olaparib hadn’t spread after three years, compared to 27 percent for placebo patients. Taken together, Jefferies analyst Ian Hilliker wrote that the number “should cement [olaparib] as the treatment of choice” for BRCA-mutated ovarian cancer patients, which make up about 20 percent of women diagnosed with the disease. It should be noted, though, that both Clovis and Tesaro are testing their drugs in the same setting.
Next up was Clovis, which reported its PARP blocker appeared to help men with prostate cancer who have failed two treatments. The data, from a study called TRITON2, showed 44 percent of patients responded to treatment. Clovis has to accumulate more data, but could file for a speedy, “accelerated” approval next year if they hold up. That could make rucaparib the first PARP blocker approved for prostate cancer, but there are concerns. As with ovarian cancer, the competition is fierce. AstraZeneca’s drug is being tested in prostate cancer patients as well. And Leerink analyst Berens noted that Clovis’s results were less impressive in patients without BRCA mutations. Just 14 percent of them responded to rucaparib.