Selinexor and Docetaxel Indicate Promise in KRAS-Mutant NSCLC

In this interview, Mitchell von Itzstein, MD, discusses the challenges of treating KRAS-mutant non-small cell lung cancer (NSCLC), the potential of selinexor in combination with docetaxel, and the need for further research to refine treatment strategies for this patient population.

Please introduce yourself by stating your name, title, and any relevant clinical experience.

Mitchell von Itzstein, MD: My name is Mitchell von Itzstein. I am a thoracic medical oncologist at UT Southwestern Medical Center. I completed my residency and fellowship training at UT Southwestern focused on lung cancer research and subsequently joined the faculty. I have been involved in several clinical trials, including coleading this study that we published in Clinical Cancer Research.

Can you provide an overview of the significance of KRAS-mutant non-small cell lung cancer (NSCLC) and the challenges it presents in terms of therapeutic options?

Dr von Itzstein: KRAS is one of the most common abnormalities that we see in NSCLC. It has historically been a very difficult patient population to treat. It’s known to confer a more aggressive disease phenotype in patients. For a long time, we had no way to target the KRAS abnormality in these patients in the way that we have been able to for some other abnormalities and other types of lung cancer, such as EGFR alterations. KRAS abnormalities are also relatively common. It happens in close to one-third of NSCLC cases.

Recent developments have led to the approval of targeted therapies for a specific subset of the KRAS abnormalities. With KRAS, there are many different types of specific abnormalities. One of them is called the KRAS G12C abnormality. The KRAS G12C abnormality now has some oral targeted therapies that have been approved. That has been a significant advance in the past couple of years, but there are many other types of KRAS abnormalities that still have no specific targeted treatment. Importantly in our study, we included patients with any type of oncogenic KRAS abnormality.

Even for KRAS G12C mutations, the benefits of these targeted drugs are relatively modest. They might control the cancer for 6 months or so. Overall, this specific type of lung cancer is very difficult to treat, and patients need advances in treatment options.

The study noted partial responses in 22% of patients and stable disease in 56%. How do these results compare to current treatment options for KRAS-mutant NSCLC?

Dr von Itzstein: These results compare favorably to the standard second-line treatment option that we usually provide for patients, which is a chemotherapy called docetaxel. Historically, docetaxel alone produces partial responses in approximately 5% to 10% of patients. So, we saw higher responses than what has been historically seen.

In our study, we combined that preexisting standard treatment docetaxel with our investigational treatment, selinexor. What we observed is that when we combine the selinexor treatment with the standard of care, docetaxel, it seems to confer an increased number of responses in patients.

It is important to note that the study we conducted was not a randomized controlled trial comparing the docetaxel chemo alone with our combination treatment. We don't have a direct comparison within the same randomized trial. All patients in our trial received the investigational combination of selinexor and docetaxel. While we cannot draw definite conclusions based on a comparison to docetaxel alone, we can look at previous studies where patients did just get docetaxel alone and make some less conclusive comparisons, and it appears to combination increases the response rates.

How do you see selinexor plus docetaxel fitting into the treatment landscape for KRAS-mutant NSCLC, especially for TP53 wild-type cases?

Dr von Itzstein: At this stage, our results suggest that this treatment combination is a promising approach. However, it's not quite ready for incorporation into clinical guidelines. Further research is still needed to determine which patients are most likely to benefit and whether it is really necessary for us to give selinexor with docetaxel. Could we consider administering the selinexor treatment by itself? There are still some unanswered questions. For these reasons, at this stage, we would consider our results to be promising but not ready to be incorporated into standard clinical practice just yet.

What additional studies or trials would you like to see conducted to further validate and expand upon these findings?

Dr von Itzstein: We definitely need more clinical trials. In our study, we found that patients with TP53 wild-type disease seemed to benefit the most. The logical next step would be to evaluate our selinexor and docetaxel treatment in patients with KRAS mutations and wild-type TP53 status. That's the group that seemed to derive the most benefit. If we were to conduct that study, I think it's possible that the results would be very promising, potentially leading to approval and integration into standard-of-care clinical practice.

There are some specific biological reasons why TP53 wild-type cases may benefit the most, related to the mechanism of action of selinexor. Based on our understanding of how the drug works, it makes sense that patients with TP53 wild type would benefit most.

Another study that could be conducted is to just look at selinexor alone, without combining it with docetaxel. The TP53 wild-type, KRAS-mutant population may benefit significantly from selinexor alone. The reason to think about that strategy is that if it is successful in controlling cancer by itself, we may be able to spare patients from a lot of the toxicity from the docetaxel chemotherapy, which can be difficult for many patients to tolerate. In summary, the ideal next study would assess selinexor by itself in patients with KRAS mutations and TP53 wild-type NSCLC.

What are the key takeaways from this study for oncologists and payers managing advanced KRAS-mutant NSCLC?

Dr von Itzstein: The key takeaway is that KRAS-mutant NSCLC represents a very important and difficult to treat patient population in lung cancer, and the field is rapidly changing. Two new KRAS-targeted inhibitors have recently been approved for KRAS G12C specifically, and there are many, many more trials and studies being done to develop new options for these patients. Our study shows a possible new treatment strategy that may work for all KRAS abnormalities that requires further study, but so far, we have promising results. It’s something that may eventually be translated into a standard of care for patients.