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Immunotherapy

Luis E Raez

More Immunotherapy Agents are in Development for Lung Cancer

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Luis E. Raez, MD, FACP, FCCP

Luis E. Raez, MD, FACP, FCCP, Chief of Hematology/Oncology and Medical Director of Memorial Cancer Institute (Miami, FL) Clinical Associate Professor of Medicine, Herbert Wertheim College of Medicine, Florida International University

In the last 2 years we were very happy to have seen: nivolumab, pembrolizumab and recently atezolizumab approved for non-small cell lung cancer (NSCLC). If you remember all of them are approved for second line therapy of NSCLC and pembrolizumab has been moved and approved already for first line NSCLC therapy if the tumor expresses PDL-1 immunohistochemistry staining (IHC) more than 50%. All of these agents block the interaction between the receptor PD-1 present in T lymphocytes and the ligand PDL-1 present in tumor cells and they are called “checkpoint inhibitors”. Some of them like atezolizumab block the PDL-1 ligand and the others are PD-1 inhibitors, there are no clear differences among them other than the current FDA indications. Soon we will know if there are differences in these 2 types of inhibitors among themselves regardless effectivity or toxicity. However these are not the only agents, we have more PDL-1 inhibitors in development like: avelumab (also known as MSB0010718C) that is in priority review for urothelial cancer but results from the JAVELIN trial were recently reported in December in Vienna during the 17th International Association for the Study of Lung Cancer (IASLC) Annual Meeting showing good responses and toxicity profile similar to the other inhibitors. The same happened with another anti-PDL-1 called durvalumab that was also presented at the IASLC meeting too with similar outcomes. But not only anti PD-1/PDL-1 antibodies are considered check point inhibitors we also have to remember that we have anti-CTL4 antibodies called ipilimumab and tremelimumab; none of them are approved for lung cancer yet but the first is already commercially available for melanoma. The importance of these anti-CTL4 antibodies is in the fact that they stimulate the immune response by a different mechanism of the PD-1/PDL-1 inhibitors then the great interest from the research community in combining these 2 different type of drugs to try to enhance the immune response as already has happened successfully in melanoma where the combination of ipilimumab + nivolumab is becoming standard. Other investigators are already combining durvalumab with tremelimumab for NSCLC, the first phase I study was published in the journal “Lancet” in February 2016 where they showed a manageable tolerability profile, with antitumour activity irrespective of PD-L1 status. During World Lung IASLC conference in December 2016 the combination of ipilimumab + nivolumab was presented showing good tolerance for the patients and enhancing the immune response of single agent nivolumab and the final paper was published also in “Lancet” in January 2017.

But this story even gets better: while some pharmaceutical companies are developing similar check point inhibitors to the 2 types described (anti PD-1/PDL-1 and anti-CTL4) other companies are exploring other targets and checkpoints so there is a large list of potential candidates that can be targeted with  the hope to achieve an immune response like: A2AR, B7-H3, also called CD276, B7-H4, also called VTCN1, BTLA also called CD272, IDO, short for Indoleamine 2,3-dioxygenase; KIR, short for Killer-cell Immunoglobulin-like Receptor, LAG3, short for Lymphocyte Activation Gene-3, TIM-3, short for T-cell Immunoglobulin domain and Mucin domain 3, and VISTA (protein), Short for V-domain Ig suppressor of T cell activation, among others.

The future is very exciting these days for the possibilities that is bringing to our NSCLC patients.


 Luis E. Raez, MD, FACP, FCCP is the Chief of Hematology/Oncology and Medical Director at Memorial Cancer Institute. He is also the Oncology Research Director of Memorial Healthcare System and Director of the Thoracic Oncology Program, Clinical Associate Professor of Medicine at Florida International University and Visiting Professor of Medicine at Cayetano Heredia University in Peru. He is also an Affiliate Associate Professor of Clinical Biomedical Science for Florida Atlantic University.


 

 

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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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Dr West

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

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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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Dr West

OAK trial with Tecentriq (atezolizumab) is positive: How a “me too” result may change the landscape in advanced NSCLC

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With positive trials of two immune checkpoint inhibitors, Opdivo (nivolumab) and Keytruda (pembrolizumab), in second line NSCLC and compared with Taxotere (docetaxel), it should come as a surprise to nobody that another checkpoint inhibitor, Tecentriq (atezolizumab) has also proven superior to Taxotere in the OAK trial of previously treated NSCLC patients, as reported in a press release today.  Perhaps the biggest surprise is that this result actually has the potential to shake up the field even with Tecentriq as a late third entrant into the race.

The trial in question is called OAK, which is a very straightforward head to head phase III trial of Tecentriq, a PD-L1 inhibitor, vs. standard Taxotere in 1225 patients who had received one or two lines of prior chemotherapy and were not restricted by level of PD-L1 expression.

OAK trial image

This trial is very similar to trials with the PD-1 inhibitor Opdivo in patients with previously treated squamous NSCLC (Checkmate 017) and another with Opdivo in previously treated non-squamous NSCLC (Checkmate 057), without restriction by PD-L1 status. Both of those trials demonstrated a significant improvement in overall survival compared with Taxotere, leading to the approval of Opdivo in previously treated patients with advanced NSCLC, regardless of PD-L1 status.  In addition, the Keynote-010 trial of the PD-L1 inhibitor Keytruda vs. Taxotere also demonstrated a very similar survival benefit but was restricted to patients with PD-L1 expression.  At this time, the approval of Keytruda is only specifically for patients who test positive for PD-L1 with a threshold level of >50% expression, based on an earlier trial with Keytruda that demonstrated clearly greatest benefit in the much smaller minority of patients with high level PD-L1 expression using a 50% cutoff (about 28% of patients).

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