GRACE :: Lung Cancer

PD-L1

Denise Brock

Lung Cancer Video Library – What is the role for PD-L1 testing after first line treatment for advanced NSCLC in initial diagnosis today

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GRACE Cancer Video Library - Lung

 

Dr. Jared Weiss

We are pleased to have Dr. Jared Weiss, Associate Professor at UNC-Chapel Hill in Clinical Research, and the Thoracic Oncology Program at UNC Lineberger, bring us further updates for our 2017 Lung Cancer Video Library.

In this latest video, Dr. Weiss discusses What is the role for PD-L1 testing after first line treatment for advanced NSCLC in initial diagnosis today.


 

 

 

 

 

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Denise Brock

Lung Cancer Video Library – Is There A Role For PD-L1 Testing After First Line Treatment For Advanced Non-Small Cell Lung Cancer (NSCLC) In Those Previously Untested

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GRACE Cancer Video Library - Lung

 

Dr. Jared Weiss

We are pleased to have Dr. Jared Weiss, Associate Professor at UNC-Chapel Hill in Clinical Research, and the Thoracic Oncology Program at UNC Lineberger, bring us further updates for our 2017 Lung Cancer Video Library.

In this latest video, Dr. Weiss discusses Is There A Role For PD-L1 Testing After First Line Treatment For Advanced Non-Small Cell Lung Cancer (NSCLC) In Those Previously Untested.


 

 

 

 

 

How Did You Like This Video?

Please feel free to offer comments and raise questions in our Discussion Forums.


 We would like to thank the following companies for their support of this program

 

                

 

 

                        

 

 
 

 

 


  


Dr West

Imprecision Medicine: Why Keytruda (Pembrolizumab) + Chemo for PD-L1+ NSCLC isn’t Ready for Prime Time

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Let me start by saying that I’m a fan of the immune checkpoint inhibitor Keytruda (pembrolizumab) and consider it the new standard of care as a single agent (monotherapy) first line treatment for the subset of about 28-30% of patients with advanced NSCLC, either squamous or non-squamous, whose cancers have high level expression of PD-L1, defined as 50% or more cancer cells staining on the companion test for Keytruda (an antibody called 22c3).  It can lead to some terrific and long-lasting responses, but it works well only in a minority of patients; in fact, even in the cherry-picked population of patients with cancers that show high PD-L1 expression, the response rate is a little less than 50%, and it’s below 20% in patients with low or no PD-L1 expression. Merck just announced that the FDA has accepted a “supplemental Biologics License Application” (sBLA) that would broaden the FDA approval for Keytruda in NSCLC to all non-squamous NSCLC patients without an EGFR mutation or ALK rearrangement and without regard to PD-L1 expression, giving Keytruda in combination with chemotherapy (carboplatin and Alimta (pemetrexed)).  I think the evidence we have with this combination is encouraging and worthy of further study, but it shouldn’t be enough to lead to broad use as requested in the FDA filing. I think it’s a premature money grab that isn’t necessarily better for patients and is definitely bad for broad society. Let me explain why.

The evidence behind this strategy is from a cohort of patients (cohort G) from a larger study, KEYNOTE-021) of patients randomized to various chemo combinations with or without Keytruda. This particular trial did not have a threshold requirement for PD-L1 and enrolled 123 patients with a good performance status and advanced NSCLC to receive either carboplatin/Alimta alone or the same chemo with Keytruda at a fixed dose of 200 mg IV every 3 weeks. Patients who hadn’t progressed after 4 cycles would continue to receive maintenance Alimta (for the chemo only arm) or Alimta/Keytruda (for the chemo/immunotherapy arm) until progression or prohibitive side effects.

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Dr West

First Line Immunotherapy for Advanced Non-Small Cell Lung Cancer: A Great Option for Some, but Not for All

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General-Campaign-Logo-300x300Several weeks ago, at a very crowded plenary session for the European Society of Medical Oncology (ESMO) in Copenhagen, Denmark, results with first line immunotherapy compared to standard first line chemotherapy for patients with advanced non-small cell lung cancer (NSCLC) were presented that simultaneously ushered in a new era for testing for PD-L1, the leading predictive marker for sensitivity to immunotherapy, and indicated both the new promise and limitations of PD-1 immune checkpoint inhibitors such as Keytruda (pembrolizumab) and Opdivo (nivolumab). In fact, the remarkably different results from two similarly designed trials leave us in a new world, but also one in which further change is coming.

First, let’s discuss the positive results for first line. The KEYNOTE-024 trial, which enrolled 305 patients with high level expression of the PD-L1 antibody marker known as 22C3 (>50% of tumor cells staining positive, seen in about 30% of patients with advanced NSCLC overall), randomized patients to either first line treatment with standard chemotherapy with any of several chemotherapy doublets or Keytruda at a new fixed dose of 200 mg IV every 3 weeks. Notably, patients with an EGFR mutation or ALK rearrangement were excluded from the trial, based on evidence that these patients are far more likely to benefit from the targeted therapies against their driver mutations than either chemotherapy or immunotherapy. Patients assigned to Keytruda were to continue until significant side effects or progression. Patients who were assigned to chemotherapy could receive maintenance Alimta (pemetrexed) if they had not demonstrated progression after 4-6 cycles of initial doublet chemotherapy; patients on the chemotherapy arm were eligible to cross over to receive Keytruda as second line therapy. 

The trial demonstrated a highly significant improvement in progression-free survival (PFS); the median PFS (the time when half of patients have progressed and half have not) being 10.3 months for the first line Keytruda recipients vs. 6.0 months for the first line chemo patients. The differences became more pronounced with longer follow up, so that by 1 year from the start of treatment, 48% of patients assigned to Keytruda still hadn’t progressed, while 15% of the patients starting on chemo hadn’t progressed. In terms of response rate, the probability that measurable cancer will shrink significantly, it was significantly better with Keytruda – 45% vs. 28%.  As is typical with immunotherapy trials, chemotherapy caused more side effects, though a minority of patients will have challenging and even rarely serious side effects with immunotherapy.

Both groups of patients did relatively well in terms of overall survival (OS), but a higher proportion of those starting with Keytruda remained alive a year into the trial (70% vs. 54%). Based on these differences in efficacy favoring Keytruda, the Data Safety Monitoring Committee following the trial recommended stopping the trial because it would have been considered unethical to continue to randomize patients to chemotherapy in light of the emerging findings. Notably, however, while this survival benefit was seen despite the built-in crossover of chemo patients to Keytruda, only about half of the progressing patients had received immunotherapy, a low proportion that is unexplained, disappointing, and partly challenges the idea that it is critical to get immunotherapy first, because too many patients assigned to first line chemo failed to ever get immunotherapy, despite the fact that this is a treatment that has been repeatedly proven to improve survival as a second line therapy.

With that presentation and the simultaneously published article in the New England Journal of Medicine, the standard of care for advanced NSCLC changed, as indicated by the remarkably quick update in the NCCN guidelines (the leading treatment recommendations put forth by a group of cancer experts as defining our best treatment) and a new approval for Keytruda as first line therapy, specifically for patients with high level expression of PD-L1. This means that it is now necessary to have the tumors of newly diagnosed patients with advanced squamous or nonsquamous NSCLC tested for PD-L1, and for the 30% of patients with high level expression of PD-L1, to favor single agent Keytruda.

But despite this clear victory for immunotherapy in advanced NSCLC, this doesn’t mean that most or all patients should get immunotherapy as initial treatment. Though some provocative data came out looking at chemo combined with immunotherapy as first line therapy, that relatively small trial didn’t show a survival benefit compared with first line chemo followed by immunotherapy. We need to also remember that the trial excluded patients with an EGFR mutation or ALK rearrangement, as the oral targeted therapies for these patients are remarkably effective, and we’ve seen disappointing (though still very limited) results with immunotherapy overall in these populations.  Importantly, we must remember that good results with first line Keytruda are seen thus far only in the high PD-L1 expression group, the 30% of patients with the best probability of benefit from immunotherapy, and that we can’t presume that immunotherapy would be better for the 70% of patients with a lower probability of benefiting greatly from immunotherapy.

And that brings us to the humbling results of the Checkmate-026 trial of Opdivo vs. chemotherapy, which I’ll cover in a post later this month.


Dr West

Is immunotherapy the wrong choice for some lung cancer patients?

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Amidst all of the glowing reports about immunotherapy for lung and many other cancers, it would be understandable for patients and physicians to be tempted to rush toward prioritizing immunotherapy as the first treatment strategy to pursue. In fact, a highly publicized trial called KEYNOTE-024 was just presented at the ESMO meeting in Copenhagen and demonstrated a significant improvement in progression-free and overall survival over standard chemotherapy doublet treatment as the first line approach for patients with high level expression of the PD-L1 protein on their tumor (about 30% of patients).  But there is also converging evidence that some patients are consistently less likely to benefit from immunotherapy — specifically, those patients with an EGFR mutation and perhaps others with another “driver mutation” such as an ALK or ROS1 rearrangement.  This is an important issue to know, because I and some other lung cancer specialist colleagues see patients with one of these highly targetable lesions sometimes being mistakenly recommended immunotherapy over the optimal targeted therapy for their cancer, or patients deflect a recommendation for an EGFR or ALK inhibitor in favor of immunotherapy based largely or completely on the hype around the latest new idea in cancer treatment.

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