Molecular therapy for lung cancer has not evolved quickly enough

Neal E. Ready, MD, PhD
Neal E. Ready

Molecular therapy for the treatment of lung cancer has not evolved enough to adequately extend survival of patients, according to a presenter at HemOnc Today New York.

Understanding primary and secondary resistance in the EGFR, ALK and ROSI genes, turning immune “cold” tumors to “hot” tumors, overcoming secondary immune resistance, improving quality of life and reducing financial toxicity are specific areas where improvement is still needed, Neal E. Ready, MD, PhD, professor of medicine at Duke University, said during a presentation.

“We’ve made a lot of progress, but we’re not where we need to be,” Ready said.

There are 36,000 cases of KRAS-mutated non-small cell lung cancer, 18,000 cases of EGFR-mutated NSCLC, and 9,000 cases of EML4-ALK NSCLC every year in the United States.

One area of improvement against the resistance of EGFR mutations was demonstrated in a trial that tested the efficacy of osimertinib (Tagrisso, AstraZeneca) for patients with NSCLC.

Osimertinib-treated patients had significantly longer median PFS (18.9 months vs. 10.2 months; HR= 0.46; 95% CI, 0.37-0.57) than patients treated with the previous standard of care. Researchers observed the PFS benefit across all subgroups, including patients who had central nervous system metastases at study entry (15.2 months vs. 9.6 months; HR = 0.47; 95% CI, 0.3-0.74) and those who did not have CNS metastases at study entry (19.1 months vs. 10.9 months; HR = 0.46; 95% CI, 0.36-0.59).

Results also showed longer median duration of response (17.2 months vs. 8.5 months) and higher overall response rate (80% vs. 76%) in the osimertinib group.

“This was kind of like a beer commercial advertising that it’s better tasting and less filling, but in this case, the osimertinib was more effective and less toxic,” Ready said. “It should be the standard of care because it is the most effective and least toxic therapy that has been tested to date.”

But unlike EGFR, there are numerous resistance mutations that can occur after ALK-positive lung cancer is treated with crizotinib (Xalkori, Pfizer).

A trial that tested the efficacy of alectinib (Alecensa, Genentech) vs. crizotinib for treatment-naive advanced ALK-positive NSCLC showed significantly longer PFS in the alectinib group (HR = 0.47; 95% CI, 0.34-0.65).

The results persisted among patients with CNS metastases at baseline (HR = 0.4; 95% CI, 0.25-0.64) and patients without CNS metastases at baseline (HR = 0.51; 95% CI, 0.33-0.8).

“There was a dramatic improvement in PFS, and we now know that the PFS lasted about 30 months. ... There is also some difference in OS,” Ready said. “The main thing about alectinib is it has very good penetration to the brain, whereas crizotinib has modest penetration to the brain. So not only do you get better systemic control of the disease, you get better CNS control over the disease.”

Ready said the challenge moving forward will be helping patients after tyrosine-kinase inhibitors fail.

“Many of the patients are younger,” Ready said. “When you take a step back and realize that the [patient] is a 40-year-old woman who is a schoolteacher with young children at home, a survival of 3, 4 or 5 years is not enough.” – by John DeRosier

 

Reference:

Ready NE. Molecular therapy: Non-small cell lung cancer. Presented at: HemOnc Today New York; March 21-23, 2019; New York.

Ramalingam S, et al. Abstract LBA2_PR. Presented at: European Society for Medical Oncology Congress; Sept. 8-12, 2017; Madrid.

Katayama R, et al. Clin Cancer Res. 2015;doi:10.1158/1078-0432.CCR-14-2791.

 

Disclosure s : Ready reports advisory roles with, as well as honoraria or research funding from, AbbVie, AstraZeneca, Bristol-Myers Squibb, Celgene, G1 Therapeutics, Merck and Novartis.

Neal E. Ready, MD, PhD
Neal E. Ready

Molecular therapy for the treatment of lung cancer has not evolved enough to adequately extend survival of patients, according to a presenter at HemOnc Today New York.

Understanding primary and secondary resistance in the EGFR, ALK and ROSI genes, turning immune “cold” tumors to “hot” tumors, overcoming secondary immune resistance, improving quality of life and reducing financial toxicity are specific areas where improvement is still needed, Neal E. Ready, MD, PhD, professor of medicine at Duke University, said during a presentation.

“We’ve made a lot of progress, but we’re not where we need to be,” Ready said.

There are 36,000 cases of KRAS-mutated non-small cell lung cancer, 18,000 cases of EGFR-mutated NSCLC, and 9,000 cases of EML4-ALK NSCLC every year in the United States.

One area of improvement against the resistance of EGFR mutations was demonstrated in a trial that tested the efficacy of osimertinib (Tagrisso, AstraZeneca) for patients with NSCLC.

Osimertinib-treated patients had significantly longer median PFS (18.9 months vs. 10.2 months; HR= 0.46; 95% CI, 0.37-0.57) than patients treated with the previous standard of care. Researchers observed the PFS benefit across all subgroups, including patients who had central nervous system metastases at study entry (15.2 months vs. 9.6 months; HR = 0.47; 95% CI, 0.3-0.74) and those who did not have CNS metastases at study entry (19.1 months vs. 10.9 months; HR = 0.46; 95% CI, 0.36-0.59).

Results also showed longer median duration of response (17.2 months vs. 8.5 months) and higher overall response rate (80% vs. 76%) in the osimertinib group.

“This was kind of like a beer commercial advertising that it’s better tasting and less filling, but in this case, the osimertinib was more effective and less toxic,” Ready said. “It should be the standard of care because it is the most effective and least toxic therapy that has been tested to date.”

But unlike EGFR, there are numerous resistance mutations that can occur after ALK-positive lung cancer is treated with crizotinib (Xalkori, Pfizer).

A trial that tested the efficacy of alectinib (Alecensa, Genentech) vs. crizotinib for treatment-naive advanced ALK-positive NSCLC showed significantly longer PFS in the alectinib group (HR = 0.47; 95% CI, 0.34-0.65).

The results persisted among patients with CNS metastases at baseline (HR = 0.4; 95% CI, 0.25-0.64) and patients without CNS metastases at baseline (HR = 0.51; 95% CI, 0.33-0.8).

“There was a dramatic improvement in PFS, and we now know that the PFS lasted about 30 months. ... There is also some difference in OS,” Ready said. “The main thing about alectinib is it has very good penetration to the brain, whereas crizotinib has modest penetration to the brain. So not only do you get better systemic control of the disease, you get better CNS control over the disease.”

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Ready said the challenge moving forward will be helping patients after tyrosine-kinase inhibitors fail.

“Many of the patients are younger,” Ready said. “When you take a step back and realize that the [patient] is a 40-year-old woman who is a schoolteacher with young children at home, a survival of 3, 4 or 5 years is not enough.” – by John DeRosier

 

Reference:

Ready NE. Molecular therapy: Non-small cell lung cancer. Presented at: HemOnc Today New York; March 21-23, 2019; New York.

Ramalingam S, et al. Abstract LBA2_PR. Presented at: European Society for Medical Oncology Congress; Sept. 8-12, 2017; Madrid.

Katayama R, et al. Clin Cancer Res. 2015;doi:10.1158/1078-0432.CCR-14-2791.

 

Disclosure s : Ready reports advisory roles with, as well as honoraria or research funding from, AbbVie, AstraZeneca, Bristol-Myers Squibb, Celgene, G1 Therapeutics, Merck and Novartis.

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