[Ben Fidler co-authored this report.] The European Society for Medical Oncology is wrapping up its annual conference today, replete with clinical data from cancer’s front lines. We’ve sorted the headlines into a few big categories: immunotherapy combinations, breast cancer, lung cancer, the growing class of drugs called PARP inhibitors, and new drugs that treat tumors based on genetic signature.
Patients with two different types of breast cancer got promising news at ESMO from studies exploring relatively new methods of treatment.
Drugs that boost a patient’s immune system to fight back against cancer have been approved to fight several types of cancer and have even become a first-line option against some advanced lung and kidney cancers. But experimental results unveiled over the weekend are the first in immunotherapy to show a survival benefit in breast cancer, which causes the second-most cancer deaths among U.S. women.
The results were in metastatic triple negative breast cancer (TNBC), a particularly aggressive form of the disease that cannot be treated with well-known drugs like trastuzumab (Herceptin) or hormone therapy. It represents about 15 to 20 percent of breast cancer cases, according to the Susan G. Komen advocacy group.
The Phase 3, 902-patient study, IMPassion130, showed patients taking Roche’s atezolizumab (Tecentriq) and Abraxane, a version of the chemotherapy paclitaxel sold by Celgene (NASDAQ: CELG), lived longer than patients on Abraxane alone. The difference was statistically significant in patients whose tumors carried the protein PD-L1, which atezolizumab targets. PD-L1-positive patients on atezolizumab-chemotherapy survived a median of 25 months following treatment, compared with 15.5 months for the chemo-only group.
“There are limited treatment options for TNBC and we think the combination could become the new standard of care for PD-L1 positive patients,” wrote Jeffries analyst Ian Hilliker in a note to investors.
Among all patients, regardless of PD-L1 status, median survival for the atezolizumab-chemo group was 21.3 months versus 17.6 months for chemotherapy alone, but it was not statistically significant. Investigators said it was likely because the results were interim; median follow-up was just short of 13 months. Another goal of the study was to measure progression-free survival, or the length of time before a patient’s tumor starts to grow again. Again, the results were better for PD-L1-positive patients, who constituted 41 percent of the study, than for the entire group.
Merck is following behind with pembrolizumab (Keytruda), which is being studied (Keynote-355) in metastatic triple negative breast cancer in combination with different chemotherapy combinations. Keynote-355 is due to reveal data at the end of 2019, though strong results could push an earlier disclosure, as happened last week with pembrolizumab in kidney cancer.
The second study to show good results from a new approach was targeting a different breast cancer: hormone-receptor (HR) positive, but HER2 negative, which means the tumor growth is fueled by hormones. The investigators gave patients alpelisib, a drug known as a PI3K inhibitor. Unlike other PI3K drugs, alpelisib only blocks one of the four main kinds of PI3K mutation, which could make for fewer side effects and let patients stay on alpelisib longer than other anti-PI3K drugs.
The “alpha” mutation that alpelisib targets is present in about 40 percent of HR-positive breast cancers, and 341 of the 572 women in the SOLAR-1 trial had the mutation. Patients taking alpelisib plus the chemotherapy fulvestrant saw their tumors held in check for a median of 11 months. Those taking fulvestrant only had 5.7 months. They were followed for a median of 20 months.
The follow-up time was not long enough to determine a survival benefit.
It remains to be seen how alpelisib, which is owned by Novartis (NYSE: NVS), might fit into the treatment landscape. A different type of drug blocking enzymes CDK4 and CDK6, which help tumor cells divide and grow, has become the standard of care for HR-positive breast cancer. Three drugs in this class have been approved, and an ESMO summary of the SOLAR-1 results cautioned that few patients in the study had been pretreated with CDK4/6 inhibitors.
Lung cancer is the biggest killer of all cancers in the U.S., with more than 150,000 estimated deaths this year.
Multiple immunotherapies are now approved for lung cancer, including a chemotherapy-immunotherapy combination from Merck that could become the new standard for non-small cell lung cancer, the most common form of the disease. That leadership position has come at the expense of Bristol-Myers Squibb, which has suffered a few clinical setbacks and disclosed another one as ESMO got underway on Friday. The FDA has delayed review of an immunotherapy combination, nivolumab (Opdivo) and ipilimumab (Yervoy), that Bristol wants to use to treat a subset of newly diagnosed lung cancer patients. Bristol’s shares sank 6.3 percent on Monday.
ESMO didn’t provide any landscape-shifting updates in lung cancer, but one tidbit emerged from Roche, which has been testing a number of combinations in a bid to grab slices of the market from Merck. Roche detailed the results of its IMpower130 study, which tested atezolizumab with two chemotherapies, carboplatin and Abraxane. Patients on atezolizumab-chemotherapy lived a median of 18.6 months, compared to 13.9 months for those on chemo alone. Here’s more on that study and Roche’s strategy from Fierce Pharma.
It’s well documented that single-agent immunotherapies can work wonders, but only in limited numbers of patients. The next frontier: combinations that hit tumors from two or more angles. But companies have been burned by moving too quickly.
—Merck shed a little light on a target called STING, or stimulator of interferon genes, which helps trigger immune response against invaders or tumors. (The idea is to boost STING, not block it.) A Merck STING drug on its own showed no effect in a range of tumors but fared a bit better when combined with pembrolizumab.
No word yet about a rival STING-PD-1 combination from Novartis and Aduro Biotech (NASDAQ: ADRO), also in Phase 1.
—Merck fared better doubling up pembrolizumab and chemo in first-line head-and-neck cancer, but 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.