The KANDLELIT-001 study was a multicohort phase I study evaluating calderasib, formerly known as MK-1084 which is a novel KRAS G12C inhibitor, in KRAS G12C mutant metastatic non-small cell lung cancer. There were several cohorts in this study that enrolled non-small cell lung cancer patients, including monotherapy cohorts that evaluated calderasib in patients that had undergone at least one previous line of treatment. There were also combination cohorts evaluating calderasib with pembrolizumab, an immunotherapy, in PD-L1-positive metastatic non-small cell lung cancer that had never been treated previously. And an additional cohort evaluating calderasib with pembrolizumab and chemotherapy, irrespective of tumour PD-L1 status, again in untreated metastatic non-small cell lung cancer patients.
The key endpoints for this study were tolerability and side effects, as well as secondary endpoints such as response rate, progression free survival, overall survival and pharmacokinetics.
The key findings from our study are that calderasib as monotherapy demonstrates a clinically significant response rate as well as the potential for durable responses in metastatic non-small cell lung cancer patients with KRAS G12C mutations. More interestingly, we also presented data demonstrating that amongst a subset of metastatic non-small cell lung cancer patients that are positive for PD-L1, the combination of calderasib with pembrolizumab exhibits a very impressive response rate, as well as the potential for a very durable response with the median progression free survival approximating 29 months.
We’ve also presented data today on potential side effects of the drug but the general takeaways are that calderasib is active in metastatic non-small cell lung cancer; the combination of calderasib with pembrolizumab is very active, with the potential for durable responses; and generally the side effects of both calderasib as monotherapy as well as in combination are manageable.
The main challenge that we’ve had with drugs in this class, KRAS G12C off inhibitors, has been a peculiar side effect known as autoimmune hepatitis; we’ve seen this to a variable degree across all drugs in this class. Our study evaluating calderasib either alone or with immunotherapy found that the rates of high grade autoimmune hepatitis were relatively low and manageable, thus supporting ongoing studies looking at this combination in the frontline setting in KRAS G12C mutant metastatic non-small cell lung cancer patients. There are currently two randomised studies ongoing looking at this specific question.
What is the significance of these findings and what’s next for the study?
The findings of the KANDLELIT-001 study support the activity, both of calderasib as monotherapy as well as in combination with immunotherapy. The response rates and progression free survival that we’ve seen for that specific combination of pembrolizumab with calderasib are particularly promising and we’ve seen that the toxicity is generally manageable with that combination.
Looking forward, there are several randomised studies ongoing evaluating calderasib with immunotherapy in the frontline setting in metastatic non-small cell lung cancer with KRAS G12C mutations. These studies are going to be very important for evaluating whether this treatment can be deployed as an effective frontline treatment for our patients and I’m very much looking forward to seeing the results of those ongoing studies.
