RET and KRAS Targeting in Lung Cancer

The broad paradigm in the treatment of non-small-cell lung cancer (NSCLC) involves determining whether a patient has a targetable driver mutation. A mutation affecting the RET gene, as seen in 2 to 3 percent of NSCLC, falls under this category.

Currently, there is not an approved treatment with high efficacy for treating RET fusion-positive cancers, but drugs in the pipeline continue to show promise. They may, in time, fill this small yet incredibly important niche.

A non-driver mutation requires a different approach – as seen in patients who receive targeted KRAS therapy. For this population, a regimen similar to KEYNOTE-189, which involves chemotherapy alone or in combination with pembrolizumab, is common practice.

Screening Practices May Vary

Screening for mutations at the time of a patient’s NSCLC diagnosis is critically important in identifying the optimal treatment strategy. Academic institutions on the cutting edge of medicine test for both KRAS and RET mutations in the majority of newly diagnosed patients. Advances in next-generation sequencing mean that this number sometimes surpasses 90 percent in such institutions.

The screening rate in the community is far lower but should approach the rates seen in academic centers within the next 3 to 5 years. With widespread screening, novel treatments targeting specific driver or non-driver mutations can be considered in the course of treatment.

Companion diagnostics are essential in the trials of these new drugs because they are biomarker-driven. With companion diagnostics, you can select the patients that will respond to a specific therapy. The reason we have seen high success rates with novel targeted therapies is due in part to the ability for response prediction.

For the population of RET patients, it’s common to see chemotherapy with cabozantinib, vandetanib, and other similar agents is seen in practice. For 2020, we have two competing RET-targeted therapies in Blueprint Medicines’ pralsetinib and Eli Lilly’s selpercatinib (Loxo-292).

Blueprint Medicines’ Pralsetinib

Blueprint Medicines released top-line data from the ARROW clinical trial for patients who have RET fusion-positive NSCLC. Although only the top-line data has been released, the results so far are promising. From the data, we can see response rates in pralsetinib similar to other second- and third-generation tyrosine kinase inhibitors used to treat mutation-driven cancers. The drug also has brain-penetrant activity, further improving its efficacy.

Furthermore, at least two out of four patients who had previously received the Loxo compound showed a partial response with pralsetinib. This result is significant because we know that pretreated patients tend to experience slightly lower response rates. Additionally, pralsetinib’s potential treatment-related side effects are tolerable. All of this, plus an expected duration of response of at least 11.3 months could position pralsetinib to fill the need for a commonplace kinase inhibitor for RET-altered NSCLC.

Looking forward to the release of the full data set for pralsetinib, expect that if pralsetinib’s duration of response is much lower than a competing candidate, such as Eli Lilly’s Loxo, then it may not be seen as favorable.

A high occurrence of adverse events would be a negative indicator for pralsetinib’s drug profile. It’s quite unlikely considering the data already available, so barring any new reporting, the current expectation is that pralsetinib will receive FDA approval.

Eli Lilly’s Selpercatinib (Loxo)

Data on Eli Lilly’s RET-targeted drug selpercatinib was made available from the LIBRETTO-001 study presented at IASLC. The LIBRETTO study had more patients than ARROW but when comparing the two studies, LIBRETTO’s numbers fall within Blueprint Medicines’ confidence interval. These studies also tell us that there is no substantial difference between the two drugs.

The Loxo compound shows a lower complete response rate compared to pralsetinib, but its duration of response (20 months) is high. This data is competitive with tyrosine kinase inhibitors currently on the market, and a high duration of response may outweigh a low complete response rate. In terms of adverse events, the difference between the two drugs is not significant. Upon full release of the data, it would be good to examine the updated response rates as well as a comparison of patients with brain metastasis and those without who are on the drug. With all that in mind, Eli Lilly’s selpercatinib will likely also receive FDA approval.

KRAS Targeting

The two KRAS treatments to watch in 2019 were Amgen’s AMG510 and Mirati’s MRTX849. Both candidates bind covalently to the G12C site. From the reported data, we see that the Amgen and Mirati drugs are very comparable, and both seem to be fairly active. The difference is that Mirati’s drug is thought to have a longer half-life, yet is dosed orally twice a day compared to once a day for its Amgen counterpart. The dosing could be an inconvenience for patients but shouldn’t sway their physicians significantly.

It is too soon to know the duration of response for either, but it may not exceed nine months. Because of this, patients will likely see more success from combining the drugs with other agents. Due to the very low toxicity of the drugs, it should not be difficult combining either with a variety of agents currently in clinical trials.

Most of the strategy around KRAS targeting focuses on pathways that involve the G12C site. Several agents targeting pathways that work in concert with KRAS-targeting drugs have been tried, with mixed success. One promising combination is pairing with an immunomodulator – which causes some kind of inflammatory reaction, allowing the body to attack other KRAS-driven tumors that are not G12C specific. Based on the preclinical evidence, this strategy has been broadly applicable, since it targets KRAS tumors in general rather than the tumors that are driven by the G12C mutation. There is an unmet need of targeting the other mutations.

Looking to the future, with several KRAS inhibitors coming into clinical trials, it would be worthwhile to know if the KRAS-targeting agents have brain penetrant activity. Additionally, highly personalized, PCR strategies are due for commercialization. With these, we can expect progression-free survival to be between 5 and 10 years. However, such a boutique strategy, similar to CAR-T cells, is not easily scalable at this point. As more pharmaceutical companies become commercial partners, in the execution of these boutique strategies, there’s much to look forward to in the future of RET and KRAS targeting in NSCLC.

---

About Dr. Victoria Wang

Dr. Victoria Wang is a medical oncologist specializing in lung cancer at UCSF Medical Center. After completing her residency at Massachusetts General Hospital, Dr. Wang joined UCSF as a fellow, conducting translational research to understand how lung cancer cells evade drug killing and the mechanisms by which they metastasize. She treats patients with both small cell and non-small cell lung cancer (SCLC and NSCLC). She was a Damon Runyon fellow, and her research has been supported by the American Association for Cancer Research (AACR), American Society of Clinical Oncology (ASCO) Young Investigator Award, Lung Cancer Research Foundation (LCRF), and the Gateway for Cancer.

---

This article is adapted from the GLG teleconference “RET and KRAS Targeting in Lung Cancer.” If you would like access to this teleconference or would like to speak with Dr. Wang or any of our more than 700,000 experts, contact us.