• After decades of frustrated research efforts, enthusiasm is rising for early-stage clinical work to develop drugs that target a genetic mutation known as KRAS, an oncogene known to be behind many lung, pancreatic and colorectal cancers.
• Initial findings from an Amgen study, revealed at this year’s American Society of Clinical Oncology meeting, were the first clinical proof of therapeutic activity for a KRAS inhibitor. Now, Swiss pharma Novartis is partnering on a combination study in KRAS-positive tumors with Mirati Therapeutics, a San Diego biotech developing a potential rival to Amgen’s experimental drug. 
• The collaboration between Novartis and Mirati is non-exclusive, and no investment was disclosed. Still, Wall Street analysts viewed the partnership as a positive sign for Mirati’s clinical development. 

Amgen’s ASCO data, presented in June, were from just 10 patients. Given the track record in KRAS clinical development, however, the five responses observed were enough to boost shares in both Amgen and Mirati.

Both companies have continued to benefit from raised investor expectations around their respective efforts, with Amgen up 9% and Mirati up 54% since the former’s presentation. For Mirati, that stock gain has added $1.6 billion to its market worth, making the biotech’s expected data readout in the second half of this year a major biotech event. 

Mirati will now also be working with Novartis on a combination study that will pair Mirati’s KRAS G12C inhibitor with Novartis’ experimental SHP2 inhibitor, called TNO155. A protein, SHP2 is thought to play a role in cell growth signaling via the RAS pathway. 

Mirati will sponsor the study, which Cantor Fitzgerald analyst Varun Kumar wrote in a Wednesday note to clients will likely begin in the fourth quarter of this year or early next. Costs will be split between the two companies and Novartis will provide TNO155 at no cost. 

Combination treatment will likely be an increasing focus of KRAS clinical development, provided drugs like Amgen’s and Mirati’s show continued proof of single-agent efficacy. 

While targeted therapy can be effective in shrinking tumors, resistance often emerges over time, allowing tumors to grow again. 

“I wouldn’t be so naive to think that after everything we’ve learned about targeted therapy in oncology that resistance will not emerge at least in some tumors,” said David Reese, Amgen’s head of R&D, at a recent conference hosted by Goldman Sachs.

“It’s one reason I actually like very much the combination of checkpoint inhibitors to really bring an orthogonal immunologic approach to bear on the tumor at the same time and try to prevent that sort of escape,” Reese added, referring to the process by which tumors grow resistance and evade treatment. 

In past presentations, Mirati has noted interest in exploring combinations of its KRAS G12C inhibitor with PD-1, SHP2, EGFR and CDK 4/6 blockers. 

Another company exploring both KRAS and SHP2 inhibition is Revolution Medicine, which this week raised $100 million in Series C financing. A late 2018 deal to buy Warp Drive Bio handed Revolution a preclinical KRAS G12C program, while its own SHP2 inhibitor is now in a Phase 1/2 clinical study. 

That SHP2 blocker is at the center of a partnership deal with Sanofi, which paid Revolution $50 million upfront to license the smaller company’s work targeting the protein.