ASCO 2022: There is still more to do

Mirati is striving to bring cutting edge science to the forefront. At this year’s meeting, among other research, we are proud to present our first clinical data set on central nervous system (or CNS) activity in patients with NSCLC harboring a KRASG12C mutation. This is important because CNS metastases can occur in up to 42% of patients with non-small cell lung cancer harboring the KRASG12C mutation, and often contribute or lead to death, posing a serious clinical challenge. I’m energized by what our team is doing to address this significant unmet medical need.

Most importantly, we want to thank the patients and physicians who make the research possible. I’m grateful to the dedicated Mirati Team who remain relentless in their pursuit of helping people living with cancer, who are counting on us to make a difference in their lives.

Follow Mirati’s LinkedIn company page for updates and perspective on our science during the 2022 ASCO Annual Meeting.

 

 

 

 

 

 

What sets KRAS biomarkers apart from other more common biomarkers?

We sat down with medical oncologist John Heymach, MD, to discuss his perspective on several ways KRAS biomarkers are unique.

Q. How does the composition of KRAS biomarkers differ from other driver oncogenes such as EGFR?

A. EGFR-mutant tumors tend to behave and present in a similar way when you look at them on an X-ray, whereas KRAS-mutant tumors have a lot more variability, or heterogeneity among them. This causes KRAS-mutant tumors to present a different appearance under the microscope. It has never been clear why the KRAS mutation has so much variability while other oncogene driver subgroups like EGFR seem to be more homogeneous.

Q. Do all mutations like KRAS or EGFR mutations respond similarly to targeted therapies and present similar response rates?

A. No, the majority of EGFR-mutant tumors have a great response to effective EGFR inhibitors. In fact, the newest drugs targeting the standard EGFR mutation average a 70% – 80% response rate. Alternatively, KRAS inhibitors have not seen response rates close to that and KRAS-mutant tumors respond differently to immunotherapies and combination therapeutic approaches.

Q. Most people are familiar with the phrase “biomarker,” but can you explain the term “co-mutation”?

A. In recent years, we’ve learned that one of the key differences between KRAS and other biomarkers are the presence and impact of co-mutations that present alongside the KRAS mutation. A co-mutation is another mutation in a separate gene that presents in addition to the original biomarker. Research into the KRAS mutation has uncovered a few frequent co-mutations, such as STK11 and P53.

Q. Do the presence of co-mutations alongside the KRAS mutation affect disease prognosis?

A. Recent research has shown that the presence of co-mutation is also a predictor of the response rate to targeted therapies. KRAS-mutant tumors that have STK11 mutations behave very differently than those that have P53 mutations. We see that those with P53 mutations appear to respond much better to immunotherapy than those with STK11 mutations.

Therefore, treating KRAS-mutant cancers is more complicated than treating other biomarkers with fewer co-mutations because it seems like we have to take into account not only the mutation but also the co-mutation and its value in predicting a patient’s response to various therapies. There is still much to learn about treating KRAS-mutant cancers, but recent research point to a future where treatment approaches will require drugs to address not only to the KRAS allele but the presence of other co-mutations as well.

References

  1. National Cancer Institute
  2. National Cancer Institute

In exploration of the next generation of precision oncology

The groundbreaking research enabling the targeting of oncogenic drivers, including targets like KRAS which have been challenging for decades, have driven the development of the next generation of cancer medicines but also captured the interest of oncology researchers around the world, including Mirati Therapeutics and many biotech companies within the local San Diego area. Last week, I was fortunate to speak to these advancements and emerging opportunities in personalized cancer treatments at the 17th UC San Diego Moores Cancer Center Industry/Academia Next Generation Precision Oncology Symposium.

During the one-day symposium, researchers gathered to share the latest advancements in precision oncology to further progress this area of research and provide hope for those with cancer and their loved ones. This forum was designed to foster an open discussion of scientific and medical advances while placing an emphasis on the utility of using unpublished research to accelerate data dissemination.

San Diego has become a hub for cutting-edge science within the biopharma industry

Hosted by UC San Diego Moores Cancer Center, this valuable knowledge exchange is another example of why San Diego has become a hub for cutting-edge science within the biopharma industry and for those who seek to push the boundaries of health care investigation. I was inspired by the progress in precision oncology treatments and the collaboration from the symposium’s participants who shared new insights on targeted treatments, immuno-oncology, biomarker testing and emerging therapeutic strategies.

At the symposium, I provided an update on Mirati’s KRAS oncology pipeline contributing to the latest cancer research showcased at the event. The complex role of KRAS mutations in the pathogenesis of colon cancer and the potential of targeting the KRAS signaling pathway through therapeutic intervention was central to the theme of the symposium. KRAS mutations have been the focus of scientific research for more than 30 years, culminating in the discovery of a KRAS binding pocket enabling the development of KRAS targeted therapies.1 This discovery has driven Mirati’s drug development program for KRAS targeted therapies, inhibiting KRASG12C as well as opportunities to target other KRAS mutant variants and other challenging drug targets.

We have always believed in innovation through collaboration to provide meaningful breakthroughs for patients with hard-to-treat cancers

At Mirati, we have always believed in innovation through collaboration to provide meaningful breakthroughs for patients with hard-to-treat cancers. It was an honor to discuss Mirati’s advancements in KRAS targeted therapies and the latest research occurring within the local San Diego community at this year’s symposium. I look forward to further exploring the future of targeted oncology as we seek to improve the lives of those with cancer.

References

  1. Ostrem JM, Shokat KM. Direct small-molecule inhibitors of KRAS: from structural insights to mechanism-based design. Nat Rev Drug Discov. 2016;15(11):771-785.

Learn more about KRAS mutations

Dr. Spira, a director at the Virginia Cancer Specialists Research Institute, Co-Chair of the US Oncology Thoracic Oncology Committee, and a faculty member at Johns Hopkins School of Medicine discusses why KRASG12C is a prolific problem in this Mirati-sponsored episode of the “Cure Talks Cancer” Podcast. Dr. Spira explains the science of the KRAS gene and introduces KRASRegeneration.com, a website for HCPs that builds awareness of the KRASG12C mutation. The conversation focuses on the importance of educating oncologists around the KRAS mutation in lung cancer. Listen here.

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Exploiting cancer’s weakness, precisely

Sometimes however, a mutation can occur in one of these “genomic guardian” genes that partially degrades the cell’s ability to repair mutational damage. Such genes are sometimes called “tumor suppressor” genes because when they function normally, they prevent the development of tumors. Often, a mutation that inactivates one of these tumor suppressor genes is on the road to becoming a cancer cell, allowing the cell to accumulate more mutations in other genes, leading to the unrestrained growth and division that characterizes cancer. Cancer, then, can be thought of as a disease of genetic instability.

Cancer can be thought of as a disease of genetic instability.

In recent years, with greater understanding of the many molecular events that result in the transformation of normal cells into cancer cells, therapies have been developed that target specific “driver” mutations. A good example is the G12C mutation in the KRAS gene – a key “on/off” switch that controls the circuitry of cell growth and division in response to cellular signals. While the normal KRAS protein can switch the circuit on and off depending on the signals it receives, mutations like G12C cause the protein to become stuck in the “on” position, constantly signaling the cell to replicate and grow. Cancers that are driven by the G12C mutation are a key focus for Mirati’s research. KRASG12C inhibitors can be thought of as the contrast to chemotherapy, and an example of personalized or precision medicine – a therapy designed to work only in the subset of cancers that have the KRASG12C mutation.

Mutations like G12C cause the protein to become stuck in the “on” position, constantly signaling the cell to replicate and grow.

Many cancer driver mutations have been identified with most of them, which can be targeted, having newer generations of “precision” cancer medicines. However, there is another approach to precision or personalized medicine that also exploits the cancer cell’s genetic instability, while more efficiently sparing normal cells. Organisms often evolve redundancies in the metabolic pathways involved in critical functions (such as DNA damage repair) that if the function of one gene is lost, another can compensate and maintain cell viability.  In contrast, cancer cells develop inactivating mutations (or outright deletions) in one or more of these functionally redundant genes, rendering the tumor cell entirely dependent on the remaining “active” gene. By targeting the product of that last remaining gene, a drug can potentially be lethal to a cancer cell while sparing normal cells in which the “back-up” is still functional. This is the concept behind “synthetic lethality.”

The quintessential example of therapies designed to exploit synthetic lethality are the PARP inhibitors. PARP is an enzyme involved in the repair of single strand breaks in DNA. When PARP is inhibited, these single strand breaks accumulate and eventually become double-stranded breaks, affecting the DNA double helix. Cells with double-stranded breaks become dependent on other DNA damage repair pathways such as the homologous recombination pathway mediated by the tumor suppressor genes BRCA1 or BRCA2. Hence, breast, ovarian or prostate tumors with mutated BRCA genes are uniquely susceptible to PARP inhibitors as the combined inhibition of PARP with loss of BRCA activity eventually leading to catastrophic damage to the tumor DNA.

Another example of this synthetic lethality approach to cancer therapy is Mirati’s PRMT5 program. PRMT5 is a critical enzyme known as a “methyltransferase” that is involved in a host of essential cellular functions. Another enzyme called methylthioadenosine phosphorylase (MTAP) plays a critical role in methionine metabolism and is often missing in cancer cells because of its chromosomal location close to a commonly deleted tumor suppressor gene (CDKN2A).

Loss of MTAP in a cancer cell causes the accumulation of an intermediate called methythioadenosine, or ‘MTA.’ MTA is a partial inhibitor of PRMT5, therefore MTAP-deleted cells are profoundly sensitive to further inhibition of PRMT5 thereby setting up the context of vulnerability to synthetic lethality. This enhanced sensitivity to PRMT5 inhibition creates a large “therapeutic window,” in which doses of an inhibitor that are harmless to normal, MTAP positive cells, are lethal to MTAP-deleted cancer cells. Mirati’s PRMT5 inhibitor is designed to selectively bind PRMT5 in MTAP-deleted cancer cells in a novel way, and positioned to potentially have an improved therapeutic index based on the concept of synthetic lethality.

The promise of delivering on personalized medicine relies on suitable diagnostic tests to identify patients who may benefit from targeted therapy.

As is the case for inhibitors of G12C mutant KRAS tumors or PARP inhibitors in BRCA mutated cancers, a PRMT5 inhibitor drug is effective only in tumors with a homozygous MTAP deletion – which occurs in about 10 percent of all human cancers. This is another example of a ‘personalized’ or ‘precision’ approach to therapy that will only be active in an identifiable subset of cancer patients.

The promise of delivering on personalized medicine relies on suitable diagnostic tests (i.e. companion diagnostics) to identify patients who may benefit from targeted therapy. This is an important area of focus at Mirati and of the Translational Medicine team.

KRAS Conversations: Providing patients with options

Cancer expert, Melissa Johnson, MD, discusses the elusive KRAS target and the importance of providing patients choices that can offer sustained targeted inhibition. Watch more of her discussion below.

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