This article is more than 5 years old. Information may no longer be current.
More immunotherapy regimens ‘desperately needed’ for salvage treatment of advanced NSCLC
Click Here to Manage Email Alerts
NEW YORK — Results of the KEYNOTE-189 trial dramatically altered initial treatment for patients with advanced-stage non-small cell lung cancer whose tumors do not harbor targetable alterations, according to a presenter at HemOnc Today New York.
However, no data are available to guide subsequent treatment decisions for later-line therapy, Benjamin Levy, MD, associate professor of oncology at Johns Hopkins University and clinical director of Sidney Kimmel Cancer Center at Sibley Memorial Hospital, said during his presentation.
“For now, chemotherapy with immunotherapy remains the standard in my mind,” Levy said. “Novel immunotherapies or immunotherapy combinations that are rooted in science are desperately needed in this space. It is complicated and vast and will take a lot of sorting out over the next 5 to 10 years.”
The randomized phase 3 KEYNOTE-189 trial included 616 untreated patients with untreated stage IV nonsquamous NSCLC who had no sensitizing EGFR or ALK alterations.
Researchers randomly assigned 410 patients to pemetrexed plus the anti-PD-1 therapy pembrolizumab (Keytruda, Merck) and either cisplatin or carboplatin, followed by pembrolizumab and pemetrexed maintenance. The other 206 patients received pemetrexed plus placebo and either cisplatin or carboplatin, followed by maintenance with placebo plus pemetrexed.
PFS and OS assessed by blinded independent central review served as primary endpoints. Overall response rate and duration of response serve as secondary endpoints.
Patients assigned the pemetrexed-pembrolizumab regimen achieved significantly longer median PFS (8.8 months vs. 4.9 months; HR = 0.52; 95% CI, 0.43-0.64) and OS (not reached vs. 11.3 months; HR = 0.49; 95% CI, 0.38-0.64). OS did not differ significantly based on PD-L1 tumor proportion score.
“This has clearly altered the treatment paradigm for patients. We of course want to do biomarker selection to identify EGFR and ALK first but, outside of genetic aberration that is targetable, I think triplet therapy for those patients who are eligible is important.”
However, no data exist to guide second-line therapy for these patients, Levy said.
“We live in a vacuum right now, as we have no data to help us decide what to do after triplet therapy no longer works,” Levy said. “We really have our work cut out for us in terms of trying to solve this mystery.”
The REVEL trial included patients with stage IV NSCLC whose disease progressed after one platinum-based chemotherapy with or without maintenance. Prior treatment with bevacizumab (Avastin, Genentech) was allowed.
Researchers randomly assigned patients 1:1 to docetaxel plus the fully human monoclonal antibody ramucirumab (Cyramza, Eli Lilly) or placebo.
Results showed modest benefits in median PFS (4.5 months vs. 3 months; HR = 0.76; 95% CI, 0.68-0.86) and median OS (10.5 months vs. 9.1 months (HR = 0.86; 95% CI, 0.75-0.98) among patients who received ramucirumab.
“This is not [the post-KEYNOTE-189 setting. It is post-platinum doublet, but it is one of the largest bodies of work in chemotherapy-refractory patients,” Levy said. “This is an unfavorable group. These are patients who had gotten induction chemotherapy as first-line agents and had rapid progression, and there was still a meaningful benefit when adding ramucirumab to docetaxel. I’d make the argument, off of a clinical trial, that patients who are progressing or no longer garnering a benefit from [the KEYNOTE-189 regimen], we should consider taxane or taxane plus ramucirumab.”
There are “broad strategies” for overcoming immunotherapy resistance, Levy said.
These include giving patients more chemotherapy with immunotherapy, immunotherapy plus targeted agents, immunotherapy plus anti-VEGF agents, and immunotherapy combinations.
A key consideration is whether resistance is classified as primary, adaptive or acquired.
“Many of these mechanisms of resistance lead to what’s called a cold tumor,” Levy said. “The question really is, how do you take these cold tumors that are no longer responding to immunotherapy and convert them to a hot tumor. That’s’ where tremendous amount of effort is going on right now.”
Most often resistance is characterized by what is observed on CT scans performed at predetermined time points.
“Once a scan shows progression, we switch therapies,” Levy said. “I think that’s obviously a concept and strategy we have been doing for years. The question is, can we look at resistance in real time, earlier than what a scan would show?”
Monitoring circulating tumor DNA and T-cell receptor clonal expansion can allow for dynamic response assessment.
“This is an interesting way to monitor in real time what is going on at the level of the tumor microenvironment and whether the tumor is responding,” Levy said. “Stay tuned, because you will see more work like this trying to identify resistance in real time.” – by Mark Leiser
Reference:
Levy B. Is there science in salvage treatment options in NSCLC? Presented at: HemOnc Today New York; March 21-23, 2019; New York.
Disclosure : Levy reports consultant/advisory board roles with AstraZeneca, Celgene, Eli Lilly, Genentech, Merck and Takeda, and research funding from Boehringer Ingelheim and Celgene.