ASCO 2019: The Long Game, Targeted Pills, First-Ever Buzz & More

Xconomy National — 

The American Society of Clinical Oncology meeting in Chicago has wrapped up for another year.

Last week, we featured two stories that you wouldn’t find at the ASCO frenzy: Immunotherapy’s lack of progress in treating breast cancer, and one woman’s risky bet of tens of millions of dollars from her personal fortune to speed drug development for the nastiest form of brain cancer.

This week, we’ll wrap up ASCO with highlights and context on the immunotherapy wins and losses, the continued push toward more genetically focused pills, the first glimpses of data from places cancer treatment has never been, and a step up in the race to make blood tests to find cancer in otherwise healthy people.

Immuno-Oncology Going Long

—Often during this decade’s wave of cancer immunotherapy, regulators have approved a drug based on short studies of relatively few people. Long-term efficacy has remained unknown. ASCO delivered a glimpse of durability for two so-called checkpoint inhibitors, the immunotherapy class whose discoverers won a Nobel Prize last year. Merck (NYSE: MRK) kept up momentum for pembrolizumab (Keytruda) in metastatic non-small cell lung cancer (NSCLC) with five-year survival marks of 23.2 percent in 101 patients whose first treatment was Keytruda, and 15.5 percent for those (449 patients) who had received previous treatments. The rate was higher for people whose tumors carried a high percentage of the protein PD-L1, which Keytruda is engineered to disrupt. Without immunotherapy, long-term survival for these cancer patients is otherwise is around 5 percent.

Merck’s main rival, Bristol-Myers Squibb (NYSE: BMY), had its own long-term revelation at ASCO. Its in-house checkpoint combination of ipilimumab (Yervoy) and nivolumab (Opdivo) showed five-year survival in advanced melanoma of 57 percent. After ending therapy, 56 percent of patients survived at least three years.

In a different study, a seven-year follow-up of patients who received Yervoy alone to support surgical removal of their melanoma showed favorable survival rates compared to placebo; investigators said the next step was to look for similar results in Opdivo and Keytruda, which have fewer serious side effects than Yervoy.

—There was negative checkpoint news too. Keytruda combined with chemotherapy didn’t meet its goal of besting chemo alone in gastric cancer.

Other Late-Stage Advances

—Roche’s in-house combination of venetoclax (Venclexta) and obinutuzumab (Gazyva) met its Phase 3 goals in previously untreated chronic lymphocytic leukemia (CLL). Nearly 90 percent of patients saw their cancer held at bay for two years—one of those years without treatment. The combination is only given for one year. In the comparison arm, with Gazyva and the chemotherapy chlorambucil, 64 percent were progression-free at the two-year mark. The combination arm showed a nearly two-thirds reduction in the risk of death or cancer progression.

—Headlines were laudatory for olaparib (Lynparza), co-owned by Merck and AstraZeneca (NYSE: AZN), for nearly doubling the median progression-free survival in BRCA-positive pancreatic cancer. “Roughly one in five patients responded to olaparib for a median of two years… we may be seeing a change in patients’ disease trajectory,” said the lead author of the Phase 3 POLO study in an ASCO release. But the study showed no benefit in overall survival, which is a cause for concern, writes Jacob Plieth of Vantage. The disease is such a terrible scourge, however, that the PFS success could be enough for approval.

—Checkpoint inhibitors have begun to transform some areas of cancer care, but not breast cancer, as Xconomy’s Ben Fidler detailed last week. One reason is that other drugs like targeted therapies continue to make progress. Take ribociclib (Kisqali) from Novartis (NYSE: NVS), which reported at ASCO that the pill, combined with more than one hormone therapy, has boosted survival chances of premenopausal women nearly 30 percent compared with hormone therapy alone. The study was in patients with HR-positive, HER2 negative breast cancer and no prior hormone therapy.

—Blueprint Medicines (NASDAQ: BPMC) said it would ask regulators next year to approve its BLU-667 (also a pill) to treat non-small cell lung cancer with RET mutations. It could be the first cancer treatment approved to target RET, in competition with a drug from Loxo Oncology, now owned by Eli Lilly (NYSE: LLY). Blueprint also has approval plans in medullary thyroid cancer. Fierce Biotech has more about Blueprint’s lung and thyroid cancer data at ASCO.

Earlier in the Pipeline

—Nektar Therapeutics (NASDAQ: NKTR) pulled its first-line melanoma combination NKTR-214 and Opdivo out of a year-long funk with a better complete response rate—34 percent—than it had previously shown in the same Phase 2 study. Nektar hopes to make the case that the cocktail takes a while to kick in, and deserves not just approval but consideration over checkpoint-only treatments. As Fierce Biotech explained, Nektar needs to show it can sustain the complete responses in a much larger Phase 3 trial.

—Amgen (NASDAQ: AMGN) caused a stir with Phase 1 results from the first-ever clinical trial of a KRAS inhibitor. Mutations in the RAS gene pathway, in particular one called KRAS-G12C, drive a fraction of cancers that are extremely difficult to treat. Amgen’s AMG 510 was tested in 35 patients across several cancer types with KRAS-G12C, showing no serious side effects. Nine people dropped out of the trial; in the 26 others the effects were enough to be “encouraging,” according to the study’s leader. The highlight: tumors shrank in five of 10 lung cancer patients.

Pushing deeper into cancer, not traditionally its domain, Amgen also provided updates on two experimental candidates from its “BiTE” platform, which uses an engineered antibody to draw a patient’s own cancer-killing T cells into range of a tumor. The first is AMG 420 for multiple myeloma, which Amgen hopes will present a simpler immuno-oncology alternative to CAR-T cell therapy. But simple is relative: AMG 420 requires several cycles of an infusion for five weeks straight, then one week off. The same goes for AMG 212, the first BiTE to go after a solid tumor, prostate cancer. Amgen presented AMG 212 data for the first time and, for AMG 420, updated results it presented last December, with signs pointing toward more testing of the highest dose in the Phase 1 study. In a note to investors, SVB Leerink analyst Geoffrey Porges said the BiTE updates “reconfirms the therapeutic potential of these programs, but also highlights their liabilities,” such as the continuous infusions and the risk of infection. Porges believes Amgen needs to develop more traditionally dosed versions.

—Moderna (NASDAQ: MRNA) reported interim Phase 1 data for its cancer vaccine in solid tumors. The Cambridge, MA, company said that its vaccine, mRNA-4157, given alone and in combination with Keytruda, was well tolerated at all doses and drew out T-cell responses with no serious side effects. Moderna said the data support a Phase 2 study testing a higher dose of the vaccine with pembrolizumab.


—With ambitions to screen healthy people for early signs of cancer, Grail released data from a small study showing its liquid biopsy—a blood test for fragments of cancer DNA—was accurate in one important respect: only one in 100 diagnoses of cancer turned out to be false, an excellent rate. Could it also correctly identify the type of cancer—or for this study, one of the 12 deadliest cancers? That depended on the tissue of origin and the state of advancement. The earliest cancers, stage 1, were hardest to detect, about one-third of the time, and metastatic stage 4 cancers, the easiest, more than 90 percent of the time. For earlier cancers, stages 1 through 3, head and neck cancer was most easily detectable, lung cancer the hardest.

Grail now needs to duplicate the study’s success in much larger populations, all while facing new competition. As Xconomy reported last week, the startup Thrive Earlier Detection is refining a liquid biopsy developed at the Johns Hopkins School of Medicine, with similar results as Grail’s: very low false positive rates and a range of accuracy based on cancer type and advancement. Grail’s test analyzes DNA only; Thrive’s test looks at proteins secreted by tumors as well.

—Veracyte (NASDAQ: VCYT) announced data showing that its genomic test for the rare, aggressive medullary thyroid cancer, has potential in guiding treatment decisions. The South San Francisco-based company said its test, Afirma Xpression Atlas, identified a gene variant or gene fusion in 74 percent of medullary thyroid cancer cases. Veracyte added that 99 percent of these cases had one or more of the variants or fusions targeted by experimental cancer therapies currently in clinical development.

Frank Vinluan contributed to this report.

“Chicago Skyline” courtesy of Tony Webster via Creative Commons.