GRACE :: Lung Cancer



Denise Brock

ASCO 2017 – Lung Cancer – Keytruda is Now Approved in Combination with Chemo for Advanced Non-Squamous NSCLC

H. Jack West, MD
Medical Director
Thoracic Oncology Program Swedish Cancer Institute
President & CEO, GRACE
Matthew Gubens, MD
Thoracic Oncologist
Thoracic Surgery and Oncology Clinic
UCSF Helen Diller Family Comprehensive Cancer Center
Jyoti D. Patel, MD
Director Thoracic Oncology
University of Chicago Medicine


Drs. H. Jack West, Medical Director of the Thoracic Oncology Program at Swedish Cancer Institute in Seattle, Washington and President and CEO of GRACE, Matthew Gubens, Thoracic Oncologist at the Thoracic Surgery and Oncology Clinic of the UCSF Helen Diller Family Comprehensive Center in San Francisco, California, and Jyoti Patel, Director of Thoracic Oncology at University of Chicago Medicine gathered post meeting to discuss new information from ASCO 2017 regarding lung cancer.   In this roundtable video, the doctors discuss Keytruda is Now Approved in Combination with Chemo for Advanced Non-Squamous NSCLC.


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Dr West

Why I Don’t Favor an Front-Loaded Approach for Most Advanced NSCLC Patients


To many, the recent FDA approval of a combination of chemotherapy and concurrent immunotherapy for the vast majority of patients with advanced (metastatic) non-squamous non-small cell lung cancer (NSCLC) probably seems like a great idea. This approval was based on the more favorable results for the combination of the IV immunotherapy agent Keytruda (pembrolizumab) every 3 weeks along with first line carboplatin and Alimta (pemetrexed) as a the chemo backbone, compared to the same chemotherapy alone, in a relatively small randomized trial of 123 patients, called KEYNOTE-021g. The “g” part refers to this actually being just one portion of a much larger trial comparing chemo to the same chemo with Keytruda. The other arms haven’t panned out as favorably.

Importantly, when we talk about the arm of patients getting chemo combined with immunotherapy, we aren’t talking about improving survival. Instead, we’re talking about prolonging the time before patients showed significant progression of their cancer on scans, which leads us to switch to a new treatment. This “progression-free survival”, or PFS, was the primary goal of the trial, though the gold standard of what we should really want from our treatments is improvement in how long patients live. There’s a bit of a favorable trend for that, but that’s all. There was also a significant improvement in the fraction of patients who show major shrinkage of their cancer when Keytruda is added to chemotherapy.

Still, even if survival isn’t improved, the results seem promising enough, so what’s not to like? Continue reading

Dr West

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


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.

Continue reading

Dr West

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


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

Death by “Pseudo-progression”: Knowing When to Cut Your Losses with Immunotherapy


Among the many novel concepts in managing immunotherapy is the potential for “pseudo-progression”. This unusual phenomenon is when a patient’s scans of the areas of cancer actually appear worse on early imaging, potentially even with new lesions, after starting immunotherapy, but a patient’s scans later show shrinkage of the cancer.  These patients typically feel well, often with improvement in their cancer-related symptoms (fatigue, appetite, etc.) that don’t seem to be concordant with their worse-appearing scans.

Why might this happen? Some biopsies of lesions that have grown or appeared as new in such patients help explain that the growth is from infiltration of immune cells around tumor cells, preceding the time when those tumor cells are attacked and eradicated by the immune system.  In cases where new nodules appear that then resolve with later scans, it is felt that this situation represents immune cells infiltrating a “micro-nodule” of cancer that wasn’t visible until it was surrounded by immune cells that then enlarged it enough to become newly detectable on scans.

Pseudoprogression West JAMA Oncol 2015

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