The New England journal of medicine 2018-11-22
Pembrolizumab plus Chemotherapy for Squamous Non-Small-Cell Lung Cancer.
Abstract
Background
Standard first-line therapy for metastatic, squamous non-small-cell lung cancer (NSCLC) is platinum-based chemotherapy or pembrolizumab (for patients with programmed death ligand 1 [PD-L1] expression on ≥50% of tumor cells). More recently, pembrolizumab plus chemotherapy was shown to significantly prolong overall survival among patients with nonsquamous NSCLC.
Methods
In this double-blind, phase 3 trial, we randomly assigned, in a 1:1 ratio, 559 patients with untreated metastatic, squamous NSCLC to receive 200 mg of pembrolizumab or saline placebo for up to 35 cycles; all the patients also received carboplatin and either paclitaxel or nanoparticle albumin-bound [nab]-paclitaxel for the first 4 cycles. Primary end points were overall survival and progression-free survival.
Results
After a median follow-up of 7.8 months, the median overall survival was 15.9 months (95% confidence interval [CI], 13.2 to not reached) in the pembrolizumab-combination group and 11.3 months (95% CI, 9.5 to 14.8) in the placebo-combination group (hazard ratio for death, 0.64; 95% CI, 0.49 to 0.85; P<0.001). The overall survival benefit was consistent regardless of the level of PD-L1 expression. The median progression-free survival was 6.4 months (95% CI, 6.2 to 8.3) in the pembrolizumab-combination group and 4.8 months (95% CI, 4.3 to 5.7) in the placebo-combination group (hazard ratio for disease progression or death, 0.56; 95% CI, 0.45 to 0.70; P<0.001). Adverse events of grade 3 or higher occurred in 69.8% of the patients in the pembrolizumab-combination group and in 68.2% of the patients in the placebo-combination group. Discontinuation of treatment because of adverse events was more frequent in the pembrolizumab-combination group than in the placebo-combination group (13.3% vs. 6.4%).
Conclusions
In patients with previously untreated metastatic, squamous NSCLC, the addition of pembrolizumab to chemotherapy with carboplatin plus paclitaxel or nab-paclitaxel resulted in significantly longer overall survival and progression-free survival than chemotherapy alone. (Funded by Merck Sharp & Dohme; KEYNOTE-407 ClinicalTrials.gov number, NCT02775435 .).
Related Questions
Are you dose reducing/omitting IV dexamethasone as a pre-medication for anti-emesis in patients with MIBC when using durvalumab/gemcitabine/cisplatin?
In my practice, we routinely give IV dexamethasone on the day of treatment. The question is whether or not to give extended dex on days 2-4 to prevent delayed nausea.The NIAGARA protocol did permit dex on the day of the treatment but did state "investigators should attempt to limit the use of steroi...
Would you consider using IO alone for lung cancer patients with PD-L1 <1% but who have high TMB?
The brief answer here is a resounding no. A more extended version might include a statement that this would be a case of not seeing the forest for the trees.And the tree here is the FDA approval of pembrolizumab in a tissue-agnostic fashion for patients with advanced TMB >10 mutations/Mbase- likely ...
How do you approach patients with metastatic SCC of the larynx, PD-L1 <1, unable to tolerate 5-FU based chemotherapy due to grade 4 esophagitis/mucositis?
For patients with PD-L1 zero metastatic head and neck squamous cell cancers, standard of care is platinum/5-FU/Pembrolizumab for first-line management. The mucositis from 5-FU can be very difficult for patients to tolerate, so if dose reductions do not meaningfully allow for tolerability, I switch t...
How do you schedule IV/PO Dexamethasone if giving immunotherapy concurrently with chemotherapy in patients with NSCLC?
We follow the methods listed in the clinical trial publications. For instance, KEYNOTE-189 followed standard steroid pre-medications for pemetrexed, and KEYNOTE-407 did the same for paclitaxel. Since the monoclonal antibodies tend to have long half lives and steroid premeds are given for such a shor...
What factors do you take into account for recommending chemo/IO vs IO/IO vs CheckMate 9LA regimen in front line therapy for PD-L1 negative advanced squamous cell carcinoma?
As others have noted, the HR for the squamous subset of NSCLC seems to suggest that these patients benefit most from combined ICI, seen in both the CM227 and 9LA studies (with the caveat that comparator is chemotherapy alone which is now outdated.) In CM227, the HR for nivo-ipi vs chemo was 0.53 in ...
What is your preferred first line regimen for PDL1-negative squamous cell lung cancer?
Firstly, I think clinical trials, where available, should be considered for all patients particularly those with squamous and/or PD-L1 negative tumors as the benefits from chemo-IO in this setting have not been as striking as in PD-L1 positive or non squamous tumors, we have more work to do to impro...
How do you decide between checkpoint monotherapy versus chemo-immunotherapy approach for patients with PD-L1 High (>50%) NSCLC?
At this point, there are no prospective trials comparing checkpoint monotherapy and chemo-immunotherapy for patients with PD-L1 high NSCLC. The ongoing prospective INSIGNA trial will answer this question. If one does a cross trial comparison of pembrolizumab for patients with PD-L1 of >50% and chemo...
How do you proceed with treatment of a patient with stage IIIB NSCLC who progresses DURING treatment with concurrent weekly carboplatin/paclitaxel and radiation?
I have been looking at this question for a little over a week, and struggling to know how to answer this. The relevant trials for a patient with PDL1 somewhere between 0 and 49% (KEYNOTE-189, KEYNOTE-407, KEYNOTE-042, CheckMate 227, and 9LA) would have excluded patients who received either adjuvant ...
Does the final report and approval of CHECKMATE 227 (ipi/nivo) regimen change your first line recommendations for patients with PDL1 TPS < 1%?
Not at this point. There are many factors that should be considered when treating patients with a PD-L1 < 1%. A recent analysis (page 372, MA25.01) of KEYNOTE 407, 021, and 189 indicated that patients receiving chemotherapy + pembrolizumab had improved survival compared to those receiving chemothera...
Do you always use platinum/5-FU as the chemo backbone with pembrolizumab for recurrent/metastatic H&N cancer?
I prefer to use carbo/taxol with pembrolizumab as well but there is no data to support this and I am having a hard time getting insurance providers to approve. It would be amazing if we can use Mednet platform to create guidelines that might help this cause. Also, I tend to do chemo+pembro for all p...
How are you treating patients who progress while on durvalumab after definitive chemoradiation for stage III NSCLC?
I usually recommend a bx to confirm the presence of metastatic disease. I ensure that all other biomarker information is available, including PD-L1 is obtained, of not performed already. In the absence of actionable/ targetable mutations, I offer patients a KN189/KN407 type regimen at the time of pr...
Does Keynote 189 establish combination chemoimmunotherapy as the standard of care for Stage IV lung adenocarcinoma?
If the Insigna trial is available, to me that is the best way of addressing this. Otherwise I would not. To me KN189/407 represents the current standard of care in the US relative to KN42 which appears inferior. For those that make argument about patient with poor performance status etc for KN42, th...