As we previously wrote, ASCO’s focus this year was on driving the benefits of precision medicine approaches in oncology to more patients. This was reflected in several ways in the news coming out of the conference, including:
Progress Against Important, Difficult-to-Target Biomarkers
The ASCO news was particularly good this year for patients with hard-to-treat KRAS and RET mutations, especially in non-small cell lung cancer (NSCLC).
KRAS mutations are among the best known cancer drivers and occur in up to 25% of cancers. Despite this high frequency, there are no approved KRAS-targeted therapeutics due to the difficulty of designing drugs against this protein, which has no obvious binding sites. Amgen has overcome this problem by exploiting a hidden groove on the KRAS protein; the company’s AMG 510 – a KRAS G12C inhibitor – binds to cysteine 12 when the protein carries the G12C mutation, and locks it into an inactive state. KRAS G12C mutations typically occur in about 13% of NSCLC patients.
At ASCO, Amgen reported data from a small Phase 1 dose-ranging study in heavily pre-treated patients with KRAS mutations, with a particular focus on NSCLC and colorectal cancer patients. The news was especially encouraging for the 14 metastatic NSCLC patients in the study: treatment with AMG 510 shrank the tumors in half of the evaluable patients and stopped tumor growth in another four. Current treatment for NSCLC patients with KRAS mutations consists of chemotherapy, and sometimes checkpoint inhibitors, and is associated with an estimated 20% response rate. In the 18 evaluable colorectal patients in the study, 75% saw their tumors stop growing. However, Amgen only reported data on the lowest dose group of colorectal cancer patients treated with AMG 510, and hopes to see more promising activity in this cancer type at higher doses. Mirati Therapeutics also has a KRAS G12C inhibitor, now in clinical testing, with data expected later this year.
Blueprint Medicines reported data from their Phase 2 study of BLU-667 in difficult-to-treat NSCLC patients with RET mutations. Standard therapy in patients with RET-mutated solid tumors has been platinum-based chemotherapy along with a variety of other drugs, and typical response rates have been in the range of 10-15%. For the 35 evaluable NSCLC patients in this trial, 60% had a large enough size reduction in their tumors to be called responders. Treatment with BLU-667 eliminated one patient’s cancer, and stopped tumor growth in all patients. The FDA has granted breakthrough status for BLU-667 for RET fusion-positive NSCLC that has progressed on platinum-based chemotherapy, and Blueprint is planning to file for approval in this indication in Q1 2020.
Between 1-2% of lung cancer cases and about 5% of all thyroid cancers harbor alterations in the RET gene. Moreover, in papillary and medullary thyroid cancers — where Blueprint is also testing BLU-667 — the rates of RET mutations are much higher (10-20% for papillary and up to 50% in medullary thyroid cancers) than the general prevalence in thyroid cancer.
Blueprint has serious competition to be the first to market a RET-targeted drug, however. Loxo-292 — acquired early this year by Eli Lilly — was among 2018 ASCO’s “best-in-show.” LOXO-292 also has breakthrough status in NCSLC and medullary thyroid cancers with RET mutations, and Lilly is expected to file for its approval before the end of this year.
We noted in our ASCO preview that we were anticipating interesting data from Novartis on their CDK4/6 inhibitor Kisqali (ribociclib) in first-line breast cancer, and that presentation did not disappoint. In the reported Phase 3 trial in premenopausal women with HR-positive, HER-2 negative breast cancer and no prior endocrine therapy, the combination of Kisqali, the hormone suppressant goserelin, and either tamoxifen or an aromatase inhibitor cut the risk of death by 29% compared with endocrine therapy alone. Most notably, at 42 months, 70.2% of the Kisqali patients were alive compared with 46% of those in the placebo group. This is the first time that a CDK4/6 inhibitor (a group that also includes Pfizer’s Ibrance and Eli Lilly’s Verzenio) has shown an overall survival benefit when combined with endocrine therapy.
… and in Tumor Types Not Historically Associated with Markers
Pancreatic cancer has historically been an extremely difficult cancer to treat, in part due to the lack of effective targeted treatment strategies. That situation has now changed, at least for some patients. At ASCO, AstraZeneca/Merck presented data from a Phase 3 trial showing that their PARP inhibitor Lynparza (olaparib) was able to reduce the risk of disease progression or death by 47% in patients with germline BRCA-mutated pancreatic cancer that had not progressed after an initial round of chemotherapy. Disease progression was halted for the Lynparza-treated patients for a median of 7.4 months versus 3.8 months for placebo-treated patients. Moreover, at one year, disease progression remained halted for 34% of those treated with Lynparza versus 15% of the placebo group, and at two years, respective progression-free survival was 22% versus 10%. Until now BRCA has been associated primarily with women’s cancers, and so an approval in this pancreatic cancer indication will likely change current testing practices for BRCA mutations, to be tested in both men and women.
Our next post will discuss ASCO news in the areas of personalized cancer vaccines, and new technology aimed at facilitating precision medicine approaches.