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Mirati Therapeutics’ Adagrasin nabs Breakthrough Therapy Designation from the FDA for KRAS+NSCLC
On 24^th June, Mirati announced that its KRAS^G12C inhibitor, adagrasib (MRTX849) has been granted the Breakthrough Therapy Designation from the US FDA for treatment of KRAS^G12C mutation-positive NSCLC following prior systemic treatment. The designation is based on initial data from the Phase 1/2 KRYSTAL-1 trial.
Background: KRAS has remained a difficult therapeutic target for many decades and tumors harbouring KRAS mutations are associated with poor prognosis. Apart from efficacy, targeting KRAS also involves considerable safety issues. KRAS^G12C mutations are present in ~14% of NSCLC adenocarcinoma, 3-4% of CRC, and in subsets of various other tumors.
Details: Adagrasib is being evaluated in a Phase 1/2 KRYSTAL-1 study in 391 patients with advanced solid tumors harbouring KRAS^G12Cmutation including NSCLC following progression on prior immunotherapy and/or chemotherapy.
Data presented during the 2021 European Lung Cancer Conference demonstrated an ORR and DCR of 45% and 96%, respectively in 51 efficacy-evaluable (Phase 1/1b – 14, Phase 2 – 37) patients with 600 mg BID dosing. At a mFU of 3.6 months, mTTR was 1.5 months. Patients with active brain mets experienced 63% reduction in primary lung tumor accompanied by disappearance of active brain mets.
However, 32% had Grade ≥3 TRAEs with 4.5% TRAEs leading to treatment discontinuation.
Implications: Mirati Therapeutics plans to submit an NDA for accelerated approval of adagrasib in H2 2021. Earlier this month, Mirati entered into a collaborative agreement with Zai Lab giving the latter exclusive commercialization rights in mainland China, Hong Kong, Macau and Taiwan. The deal will accelerate enrolment in pivotal studies of adagrasib.
The company is also evaluating adagrasib in a randomized Ph 3 KRYSTAL-12 confirmatory trial versus docetaxel in previously treated KRAS^G12Cmutated NSCLC, Ph 2 KRYSTAL-7 trial in combination with pembroliumab as frontline therapy in KRAS^G12C mutated NSCLC, Ph 1/2 KRYSTAL 2 trial in combination with TNO 155 (SHP2i) in KRAS^G12C mutated NSCLC and CRC, and Ph 3 KRYSTAL-10 trial in combination with cetuximab in KRAS^G12C mutated CRC.
Additionally, it plans to submit an IND for its KRAS^G12D inhibitor, MRTX1133, in 2022.
In May 2021, Amgen’s Lumakras became the first drug to receive approval in KRAS^G12C+ NSCLC. The confirmatory Phase III CodeBreak 200 study is ongoing. Although Lumakras is the frontrunner, some analysts believe that adagrasib could “emerge as the winner in the monotherapy setting”.

Orpathys approved in China for patients with lung cancer and MET gene alterations
Dave Fredrickson, Executive Vice President, Oncology Business Unit, said: “This approval makes Orpathys the only targeted medicine approved for these biomarker-selected patients in China, and it adds another novel medicine to our already diverse lung cancer portfolio. We are proud that this first-ever regulatory approval of Orpathys is in China, where we have a long-standing commitment to improving patient outcomes and working with the right partners to achieve that goal. Alongside HUTCHMED, we look forward to the continued development of this medicine across a range of cancers where MET alterations and amplification are drivers of tumour growth and treatment resistance.”

Regulatory Applications for Oncology Treatment Investigational Combination of Aliqopa® (copanlisib) and rituximab Submitted in the U.S. and EU
“The U.S. and EU submissions of the novel combination of Aliqopa and rituximab bring us forward in advancing new treatment approaches and addressing unmet needs of patients with different types of relapsed iNHL,” said Scott Z. Fields, M.D., Senior Vice President and Head of Oncology Development at Bayer. “We are excited about the potential of this investigational combination therapy based on the findings from CHRONOS-3 and we look forward to working with global regulatory authorities.”

First participant dosed in pivotal Ph 3 talapro-3 combination study of talazoparib and enzalutamide in mCSPC
“The prognosis for men with advanced prostate cancer has significantly improved since the introduction of novel hormone therapies, but additional therapeutic options are needed for the approximately 25 percent of men with tumors harboring DNA damage response (DDR) gene mutations, who may have poorer outcomes,” said Chris Boshoff, M.D., Ph.D., Chief Development Officer, Oncology, Pfizer Global Product Development. “By combining enzalutamide, which has a proven clinical benefit in men with metastatic castration-sensitive prostate cancer, with talazoparib, our PARP inhibitor that is active in DDR-mutated cancer, we may be able to offer a new treatment option that targets the underlying genetic mechanisms associated with DDR-mutated mCSPC.”