Exploring KRAS Mutations in Oncology: A Look at the Challenges and Opportunities - Part Two
A rich pipeline with a wide range of treatment options
The graphic below shows the numbers of KRAS inhibitors by phase of development. From this we can see that most drugs are being developed to target G12C in its active state, and since G12C is predominantly seen in NSCLC, we can expect significant attention to be focused here. Most of the other drugs are focused on other specific mutations of KRAS or are following a multiple mutation approach.
What have we learned from the approved KRAS inhibitors?
In comparing LUMAKRAS and KRAZATI, it's helpful to consider:
- The data used to obtain accelerated/condition approval in NSCLC, and
- Developments since these approvals
The table below compares LUMAKRAS with KRAZATI, based on the data used to obtain accelerated approval from FDA. In both cases, the data came from Phase 2 single arm studies, and so confirmatory Phase 3 studies were mandated by FDA. Whilst we see some differences in efficacy and safety, perhaps the main advantage sits with LUMAKRAS having been the first to market. This head start is likely to explain the difference in sales between the two drugs, with LUMAKRAS generating $52M in Q3 23 compared to $16M for KRAZATI in the same period. (4)
The race is not over ...
Whilst LUMAKRAS has benefited from its earlier approval, recent developments suggest that KRAZATI is catching up, if not poised to take the lead:
- Phase 3 NSCLC read outs: data from the Phase 3 CodeBreaK 200 NSCLC trial of LUMAKRAS vs docetaxel showed a statistically significant improvement in PFS of 5 weeks for LUMAKRAS. This disappointed many interested parties who had hoped for more. Nevertheless, safety improved significantly providing a good rationale to continue treating patients with LUMAKRAS instead of docetaxel. Meanwhile, BMS recently announced that KRAZATI had met its primary end points for its Phase 3 KRYSTAL-12 study. Data for the PFS and ORR end points were statistically and clinically meaningful, according to BMS. In the meantime we are waiting for the full results to be published. (4)
- Regulatory set back for LUMAKRAS: Amgen had their application for full approval for LUMAKRAS turned down by FDA in Dec 23. The main reason for this is that aspects of the study design had led to large potential biases making it difficult for the assessors to rely on the data. Amgen will need to complete a new confirmatory study to obtain full approval. Crucially this highlights the need for well designed studies, and may have given KRAZATI a significant advantage. (6)
- Combination studies with PD(L)1: Both drugs are being investigated for combination with PD(L)1s. However, KRAZATI is already conducting this in a Phase 3 study (NCT04613596), whereas LUMAKRAS is in Phase 2, giving an advantage to KRAZATI. Furthermore, KRAZATI may fare better in combination therapies due to its lower levels of hepatotoxicity which may be related to its longer half life. (1)
- KRAZATI ahead in Colorectal Cancer (CRC): FDA has accepted the application for Priority Review for KRAZATI in combination with cetuximab, with a target approval date set for Jun 24. Meanwhile, Amgen plans to submit their application in the first half of this year. This may give KRAZATI a first mover advantage and the opportunity to establish itself as the therapy of choice ahead of LUMAKRAS. (4)
What is coming next?
To get a sense of the next wave of KRAS inhibitors, I have selected several molecules from the pipeline either due to their late stage of development or based on their novel mechanism of action.
The three Phase 3 G12C inhibitors:
- JDQ443, Novartis: is currently in Phase 3 for NSCLC. At ASCO last year, Novartis provided an update from its KontRASt-01 (NCT04699188) Phase 1B/2 study, stating that just 7% of patients reported a TRAE of grade 3, with no grade 4 or 5 TRAEs reported (N=56, at 200MG dose). This may in part be due to differences in patient populations, however it suggests JDQ443 could be a good candidate for combination therapies. (7)
- Divarasib, Genentech/Roche: is currently being developed for 2L NSCLC. Studies suggest that it is 5 to 20 times as potent and up to 50 times as selective as compared to the currently approved KRAS G12C inhibitors. (8)
- MK-1084, Merck: began its NSCLC Phase 3 study just this month (NCT06345729). Of particular note is that in this study MK-1084 is being tested in combination with pembrolizumab. Merck believes this combination will drive improvements in PFS and OS based on ORR data from its Phase 1 study. (9)
Novel mechanisms:
- MRTX1133, BMS: Is a G12D inhibitor currently in Phase 2 and is the most advanced such inhibitor in the development pipeline. It is being investigated for NSCLC, pancreatic cancer, and CRC. The main advantage of MRTX1133 over sotorasib and adagrasib is that it targets G12D (instead of G12C) which as we saw in my previous article, occurs far more frequently in other tumors e.g., over 90% of pancreatic tumors. As such, MRTX1133 could become a first-in-class treatment in these areas.
- RMC-6326, Revolution Medicines: Is a multi-RAS inhibitor currently in Phase 1. There are two key differentiators for this drug. First, it is selective for not only KRAS, but also HRAS and NRAS (mutant and wild type). This means it could potentially offer a broader scope of action across various KRAS mutations. Second, it has a novel trimeric structure that allows it to target RAS in its active state. This is thought to lead to faster inhibition of KRAS than inhibitors of the inactive state, which could result in a therapeutic advantage to RMC-6326. However, caution will be needed as this mechanism of action may result in more on-target toxicity due to the inhibition of RAS in normal tissues. It is also possible this could affect immune responses to tumors due to the role that RAS proteins play in the immune system.
Conclusion
The development of inhibitors like sotorasib and adagrasib has resulted in significant progress. Nevertheless, drug resistance and the complexity of tumor biology continue to drive the search for more effective therapies. Drug developers are pursuing strategies that include combination therapies, new G12C inhibitors, other KRAS mutation targeting drugs, active vs inactive inhibitors, and KRAS/RAS-wide inhibitors.
Whilst there is still much to be learnt, the drivers of success will come from the sophistication and precision of the molecules under investigation, as well as carefully designed development plans and study designs. With so many different therapeutic strategies being investigated at the same time, this makes a very exciting time with much promise for patients.
References:
- Molina-Arcas et al, Exploiting the therapeutic implications of KRAS inhibition on tumor immunity, Cancer Cell, March 2024
- Clinicaltrials.gov
- Drug company websites
- After Amgen's stumble, BMS touts KRAS confirmatory trial win for newly bought Krazati, FiercePharma, Mar 24
- FDA approved labels
- Amgen provides regulatory update on status of LUMAKRAS (sotorasib), Amgen press release, Dec 23
- Cassier et al, KontRASt-01 update: Safety and efficacy of JDQ443 in KRAS G12C-mutated solid tumors including non-small cell lung cancer (NSCLC), oral abstract, ASCO, 2023
- Divarasib in Combination with Cetuximab Demonstrates a Manageable Safety Profile and Promising Activity in Patients with KRAS G12C-positive CRC, Oncology News ESMO, Dec 2023
- Conroy, Pembrolizumab/MK-1084 Combo Is the Focus of Phase 3 Trial in KRAS G12C+ Metastatic NSCLC, Cancer Network News, Apr 24
