AACR 2022: Novartis shifting focus towards directly targeting KRASG12c after disappointment from SHP2 inhibitor, TNO155.

Post Lumakras ‘approval,  Adagrasib’s PDUFA date, Novartis now ready to enter the KRASG12C space

Novartis is now heading towards its unique KRASG12C inhibitor in patients with advanced non-small cell lung cancer (NSCLC). The company presented the promising preliminary data (Phase Ib) from the KontRASt-01 study evaluating JDQ443 in patients with advanced NSCLC. The results reported that at the median duration of 15.9 weeks, the confirmed overall response rate (ORR) at RP2D 200 mg was 57%, which somehow demonstrated the early efficacy signals and a tolerable safety profile from the dose-escalation portion of the Phase Ib/II KontRASt-01 trial. In terms of a safety point of view, the maximum tolerated dose was not reached at the time of the data cut off (January 5, 2021,). The TRAEs occurred in 71.8% of patients which included 4 grade 3 TRAEs.

The promising early data of the KontRASt-01 study demonstrated high systemic exposure at the recommended dose of 200 mg with a favorable safety profile. The results of the KontRASt-01 study may improve the outcomes of patients with KRAS G12C-driven cancers and bring a new ray of hope to patients with advanced NSCLC in terms of survival benefits.

Additionally, the competitors in KRASG12C mutation space also involves Mirati’s Adagrasib (close to getting its approval as the PDUFA date is December 14, 2022) and Amgen’s Lumakras (already in the market). Surprisingly, JDQ443 (57% confirmed ORR), on a cross-study basis seemed to be on par with both its competitors with:

• 36% ORR of Lumakras in G12C-mutant NSCLC (Codebreak-100 trial), and
•  45% ORR of the next most-advanced KRAS inhibitor, Mirati’s adagrasib (Krystal-1 trial)

Infact, on the safety front too, JDQ443 is leading, with the least number of patients suffering from severe adverse events, although in a very small sample size.

Moving on to assessing these drugs for KRASG12 C mutation in colorectal cancer patients, Adagrasib is leading with 22% ORR, Lumakras has shown lower efficacy and JDQ443 has data on a very limited sample. Focusing on NSCLC, Novartis is all set to start a Phase III trial in mid-2022 (JDQ443 vs Docetaxel) and we now await to see the challenges Novartis faces if there are no plan for a head to head comparison against Lumakras. Moreover, we also look forward to SHP-2 inhibitor as a part of combination trials in future, considering its failure as a monotherapy.

Increase response rate of Lumkaras

Amgen presented the promising long-term efficacy and safety data from the CodeBreaK 100 Phase I/II trial in patients with KRAS G12C-mutated advanced NSCLC who received Lumakras. The results demonstrated an overall survival rate of 32.5% at 2 years in patients with KRAS G12C–mutant NSCLC. The ORR achieved was 40.7% and the disease control rate (DCR) was 83.7%. Additionally, the median duration of response (DOR) was 12.3 months followed by the median progression-free survival (PFS) that was 6.3 months and the median OS was 12.5 months. Moreover, long-term treatment did not raise any new safety concerns. The Treatment-related adverse effects (TRAEs) of grade 3/4 occurred in 21% of patients, with one patient developing a new-onset grade 3 TRAE of hemolytic anemia after one year.

The impressive findings from the Lumakras study demonstrated that since the FDA approval of Lumakras, the treatment paradigm for patients with advanced non-small cell lung cancer who harbor the KRAS G12C mutation has now begin to change. We so believe that the durable efficacy and positive benefit-risk profile seen in the two-year analysis of CodeBreaK 100 highlight the important role of this innovative targeted therapy. Considering that Lumakras is the first-ever KRASG12C approved, we look forward to its market positioning post the entry of Adagrasib in late 2022 or early 2023, followed by Novartis’ DQ443.