Article and Video CATEGORIES

Cancer Journey

Search By

Should Patients with KRAS Mutations Be Treated with Epidermal Growth Factor Receptor Inhibitors (i.e. Iressa or Tarceva)?
Please Note: While this is Still Excellent Background Info, New Treatments Have Emerged Since this Original Post
Author
Dr Pennell

Hi again! You can think of this as a companion piece to my last post, examining some recent (but admittedly preliminary) evidence suggesting that Iressa (gefitinib) and Tarceva (erlotinib) may not be equivalent for patients with differing types of EGFR mutations. This is a slightly different topic, but one that has been quite contentious for several years: do KRAS mutations, found in 20% or more of patients with NSCLC, identify a group of patients who are resistant to EGFR inhibitors? KRAS is an oncogene that is mutated in a large percentage of pancreatic, colorectal, and non-small cell lung cancers. The significance of this gene has been known for a while, and anecdotal evidence has suggested that patients with tumors harboring KRAS mutations have a poor prognosis and tend not to respond to treatment (chemo or EGFR inhibitors) as well as KRAS non-mutated (wild type) tumors. Retrospective studies looking at KRAS mutant patients who are treated with EGFR inhibitors like Iressa and Tarceva have very consistently shown that the chance of significant tumor response (shrinkage) of tumors in this group is almost zero. However, we now know that there are 2 clear groups of patients who benefit from EGFR inhibitors: those who get a tumor “response”, and those who get tumor “stabilization”, in which the tumors simply do not grow for some period of time. Even disease stabilization can be associated with a prolongation of survival, and this phenomenon is commonly seen in patients with EGFR wild type tumors. EGFR wild type tumors also have a negligible rate of tumor shrinkage with EGFR inhibitors, much like the KRAS mutant tumors, but still seem to derive benefit. What has never been convincingly shown by the proponents of the “KRAS is bad” hypothesis is that patients with KRAS mutations (which are mutually exclusive of EGFR mutation) do not get the same level of disease stabilization and survival benefit from EGFR inhibitors as do all other EGFR wild type patients. Well, at the 2009 World Conference on Lung Cancer meeting we did get some indications that KRAS might not be so very bad after all. In the first example, let us return to the Jackman database that I described in my last post. Not all of the patients in the database had EGFR mutations, and many had KRAS mutations. Dr. Jackman showed that the time to progression and overall survival of patients with KRAS mutations, treated with EGFR inhibitors, had the exact some outcome as patients without KRAS mutations but also without EGFR mutations. Both groups did fairly poorly, but there was certainly no indication that KRAS mutation conferred a worse outcome that anyone else who did not have an EGFR mutation.

Secondly, there was Dr. Wolfram Brugger’s presentation of biomarker data from the SATURN trial. This has been discussed before, but briefly: the phase III SATURN trial randomized advanced NSCLC patients who had not progressed after 4 cycles of platinum-doublet chemotherapy to either maintenance Tarceva or the placebo. This trial showed an improvement in progression-free and overall survival for the maintenance arm (a topic for a post of its own), but Dr. Brugger’s presentation was focused on analyzing outcomes based on different biomarker subgroups (i.e. patients with EGFR mutations, KRAS mutations, etc.). Intriguingly, every single analyzed subgroup had a similar level of benefit from maintenance Tarceva, including smokers, non-smokers, squamous cell and adenocarcinoma histology, and (given the topic of this post) KRAS mutant versus wild type. Although Dr. Pasi Janne from the Dana Farber in Boston (an ardent proponent of KRAS resistance in EGFR therapy) correctly pointed out that the statistical analysis did not show a significant benefit to maintenance Tarceva in the KRAS mutation group, it was clear that the survival curves looked exactly the same in the KRAS mutant and wild type groups, and that the hazard ratio for benefit (a statistical measure of risk of death or progression in one group over the other) was identical in the two groups. The lack of statistical significance was probably (although of course not definitively) due to the very small number of KRAS mutant patients in the study. So what are we to conclude from this? I’m certain that this will not change the mind of the groups who truly believe that one should not ever ever give an EGFR inhibitor to a patient with a KRAS mutation, but I also think that the growing group of skeptics have new ammunition to say that perhaps Tarceva is about as (modestly) useful in treating patients with KRAS mutations as it is in any patient with EGFR wild type NSCLC, and I would certainly never withhold this medication from such a patient in the right situation.

Next Previous link

Previous PostNext Post

Related Content

Image
Trial data ASCO 2024
Video
In this video series from ASCO 2024, Drs. Aakash Desai and Fauwzi Abu Rous discuss trial dates and clinical data as presented at the 2024 ASCO. To watch the complete playlist, click here.         
Image
Bladder Cancer Video Library 2024
Video
Dr. Petros Grivas discusses intravesical treatment for patients with nonmuscle invasive, or early-stage, bladder cancer, the importance of participating in clinical trials for bladder cancer, combination therapy options for patients with metastatic or incurable bladder cancer, and the importance of family history of cancer and discussing that history with your doctor.
Image
Case Based Panel
Video
The panel discusses treatment options for a patient diagnosed with EGFR Exon 19 Deletion NSCLC and examines data from the Laura Trial, a patient with a smoking history and diagnosis of small cell lung cancer, and how the Adriatic Study factors into decisions, and a patient with NSCLC adenocarcinoma, and a EGFR Exon 21 L858R Alteration, and how data from the Flaura 2 Trial can impact treatment decisions.

Forum Discussions

Hi elysianfields and welcome to Grace.  I'm sorry to hear about your father's progression. 

 

Unfortunately, lepto remains a difficult area to treat.  Recently FDA approved the combo Lazertinib and Amivantamab...

Hello Janine, thank you for your reply.

Do you happen to know whether it's common practice or if it's worth taking lazertinib without amivantamab? From all the articles I've come across...

Hi elysianfields,

 

That's not a question we can answer. It depends on the individual's health. I've linked the study comparing intravenous vs. IV infusions of the doublet lazertinib and amivantamab...

Recent Comments

JOIN THE CONVERSATION
I could not find any info on…
By JanineT GRACE … on
Hi elysianfields,

 

That's…
By JanineT GRACE … on
Hello Janine, thank you for…
By elysianfields on
EGFR
By happybluesun on