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The Role of Multikinase TKIs for NSCLC

Insights From: Jessica Bauman, MD, Fox Chase Cancer Center; Robert Doebele, MD, PhD University of Colorado Hospital Cancer Center; Shirish M. Gadgeel, MD, MBBS Rogel Cancer Center
Published: Wednesday, May 13, 2020



Transcript:

Shirish M. Gadgeel, MD, MBBS: The efficacy results with multikinase tyrosine kinase inhibitors are better in patients with medullary thyroid carcinoma with RET alterations. They are not as efficacious in patients with non–small cell lung cancer who have RET alterations in their tumor.

The precise reasons are not clear, however, it is important to note the RET alterations observed in medullary thyroid carcinoma are mutations, whereas, the RET alterations in non–small cell lung cancer are fusions. It is possible that these multikinase inhibitors are much better at inhibiting RET in tumors that have mutations compared with patients whose tumors have RET translocations.

Another suggestion that this reason might be true is that in non–small cell lung cancer it has been observed, at least in some trials, that the multikinase tyrosine kinase inhibitors are more efficacious in certain RET translocations compared with others. The partner genes with RET translocations can be different, with the most common partner gene being KIF5B.

What has been observed is that these multikinase tyrosine kinase inhibitors may not be as efficacious in patients with non–small cell lung cancer whose tumors have RET alterations where the partner gene is KIF5B. Whereas, if there are other genes that are the partner genes, then in those patients the multikinase inhibitors might be more efficacious.

There could be several reasons that could account for this difference. But yes, it is important to note that multikinase tyrosine kinase inhibitors are not as efficacious in patients with non–small cell lung cancer with RET translocations in their tumor compared with patients with medullary thyroid carcinoma who have RET mutations in their tumor.

We have very limited data of use of immunotherapy [I/O] as frontline treatment for patients with targetable alterations. It’s important to note that in many of the frontline immunotherapy trials, specifically patients whose tumors are EGFR mutations or ALK translocations, were excluded from the study. And therefore we have very limited data of use of I/O as frontline therapy for patients with targetable alterations.

The only data we really have as frontline therapy is in patients with EGFR mutations. What was observed is that use of I/O, at least as a single agent in these patients, actually had very poor results, with a response rate of only about 12% and extremely limited progression-free survival.

Though we don’t have data in patients with other targetable alterations, I think the experience in patients with EGFR alterations has led to a great deal of caution in using at least single agent I/O as frontline therapy in patients with targetable alterations.

Both cabozantinib and vandetanib, as well as certain other drugs that are used primarily as VEGF inhibitors, also have activity against RET, and therefore, these drugs were evaluated in relatively small phase II studies as treatments for patients with RET translocated non–small cell lung cancer.

It is important to note that almost all of these patients enrolled in these trials were previously treated with multiple different treatments before, and so the data have to be viewed in that context. What these studies showed was that the response rate with agents such as cabozantinib and vandetanib was in the range of about 16% to 50%, and the median progression-free survival ranged from about 2.3 to 7 months.

So efficacy was observed, but the efficacy was reasonably modest and not comparable to what we observe with targeted therapy in patients with other genetic alterations, such as EGFR and ALK. These drugs are mentioned in the NCCN [National Comprehensive Cancer Network] guidelines for the management of RET translocated non–small cell lung cancer. However, in general, these agents are used in subsequent lines of therapy because the benefit is fairly limited. And an important aspect of these drugs is, because they not only inhibit RET but also inhibit other molecular targets, these drugs do have more toxicities, particularly toxicities associated with VEGF inhibition, such as fatigue, diarrhea, and other GI [gastrointestinal] symptoms, which further limits the applicability of these agents in routine practice.

I did not specifically participate in the studies of these drugs, but I have personally used this off study in patients, I would say about 3 patients. The experience was very similar to what has been reported in the clinical trials, with a very modest response rate. I believe only 1 of the 3 patients had some evidence of response, and the 2 other patients had, essentially, stable disease. And all the 3 patients progressed about 3 to 4 months after starting therapy.

Transcript Edited for Clarity
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Transcript:

Shirish M. Gadgeel, MD, MBBS: The efficacy results with multikinase tyrosine kinase inhibitors are better in patients with medullary thyroid carcinoma with RET alterations. They are not as efficacious in patients with non–small cell lung cancer who have RET alterations in their tumor.

The precise reasons are not clear, however, it is important to note the RET alterations observed in medullary thyroid carcinoma are mutations, whereas, the RET alterations in non–small cell lung cancer are fusions. It is possible that these multikinase inhibitors are much better at inhibiting RET in tumors that have mutations compared with patients whose tumors have RET translocations.

Another suggestion that this reason might be true is that in non–small cell lung cancer it has been observed, at least in some trials, that the multikinase tyrosine kinase inhibitors are more efficacious in certain RET translocations compared with others. The partner genes with RET translocations can be different, with the most common partner gene being KIF5B.

What has been observed is that these multikinase tyrosine kinase inhibitors may not be as efficacious in patients with non–small cell lung cancer whose tumors have RET alterations where the partner gene is KIF5B. Whereas, if there are other genes that are the partner genes, then in those patients the multikinase inhibitors might be more efficacious.

There could be several reasons that could account for this difference. But yes, it is important to note that multikinase tyrosine kinase inhibitors are not as efficacious in patients with non–small cell lung cancer with RET translocations in their tumor compared with patients with medullary thyroid carcinoma who have RET mutations in their tumor.

We have very limited data of use of immunotherapy [I/O] as frontline treatment for patients with targetable alterations. It’s important to note that in many of the frontline immunotherapy trials, specifically patients whose tumors are EGFR mutations or ALK translocations, were excluded from the study. And therefore we have very limited data of use of I/O as frontline therapy for patients with targetable alterations.

The only data we really have as frontline therapy is in patients with EGFR mutations. What was observed is that use of I/O, at least as a single agent in these patients, actually had very poor results, with a response rate of only about 12% and extremely limited progression-free survival.

Though we don’t have data in patients with other targetable alterations, I think the experience in patients with EGFR alterations has led to a great deal of caution in using at least single agent I/O as frontline therapy in patients with targetable alterations.

Both cabozantinib and vandetanib, as well as certain other drugs that are used primarily as VEGF inhibitors, also have activity against RET, and therefore, these drugs were evaluated in relatively small phase II studies as treatments for patients with RET translocated non–small cell lung cancer.

It is important to note that almost all of these patients enrolled in these trials were previously treated with multiple different treatments before, and so the data have to be viewed in that context. What these studies showed was that the response rate with agents such as cabozantinib and vandetanib was in the range of about 16% to 50%, and the median progression-free survival ranged from about 2.3 to 7 months.

So efficacy was observed, but the efficacy was reasonably modest and not comparable to what we observe with targeted therapy in patients with other genetic alterations, such as EGFR and ALK. These drugs are mentioned in the NCCN [National Comprehensive Cancer Network] guidelines for the management of RET translocated non–small cell lung cancer. However, in general, these agents are used in subsequent lines of therapy because the benefit is fairly limited. And an important aspect of these drugs is, because they not only inhibit RET but also inhibit other molecular targets, these drugs do have more toxicities, particularly toxicities associated with VEGF inhibition, such as fatigue, diarrhea, and other GI [gastrointestinal] symptoms, which further limits the applicability of these agents in routine practice.

I did not specifically participate in the studies of these drugs, but I have personally used this off study in patients, I would say about 3 patients. The experience was very similar to what has been reported in the clinical trials, with a very modest response rate. I believe only 1 of the 3 patients had some evidence of response, and the 2 other patients had, essentially, stable disease. And all the 3 patients progressed about 3 to 4 months after starting therapy.

Transcript Edited for Clarity
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