Pembrolizumab’s approval in this setting does not mean clinical value for Adjuvant Therapy for Resected NSCLC
By Jack West, MD
Hi, I’m Dr. Jack West, and I’m a thoracic oncologist and associate professor at the City of Hope Comprehensive Cancer Center in the Los Angeles area. I wanted to take a minute to talk about the very recent FDA approval of pembrolizumab in the adjuvant setting for to treat patients with resected stage 1B to stage IIIA non-small cell lung cancer, and specifically how much or how little this FDA approval should translate to clinical use, or should we presume the FDA approval, is tantamount to clinical utility because I think this is an important question, and one in for which many clinicians, both general oncologists and even presumed expert thoracic oncologists infer that the FDA approval means that this should be a standard of care, if not the standard of care. And I think it’s important to put this in context.
So first, we have FDA approvals for chemo and nivolumab based on the Checkmate 816 trial. This is preoperative therapy to treat patients with stage one B to three a disease, and there has been a very strong demonstration of an improvement in event-free survival and preliminary overall survival, also looks quite favorable, though still immature. And we also have an FDA approval for adjuvant atezolizumab based on the IMpower010 trial. That shows a suggestion, a strong suggestion of a benefit for overall survival in the patients with high PD-L1 of 50% or higher. That is really not present for the patients with low PD-l1. The approval by the FDA for adjuvant atezolizumab is for PD-L1 or higher. The approval for chemo NIVO is irrespective of PD-L1 level. And then we have this approval for adjuvant pembrolizumab. This is based on the PEARLS trial, also known as KEYNOTE-091, and this showed a disease-free survival benefit of in the range of 0.78 for the broad population. This across the entire spectrum of PD-L1 and across stages from 1B to 3A. What’s quite interesting and frankly head scratching about the results, is that there’s no clear pattern that makes biological sense about how the subgroups work out. You have lower benefit in patients with stage three a disease than with lower stage disease. You have less benefit. With DFS (disease free survival) for patients with high PD-L1 than with low PD-L1. And and again, it’s a little higher for low PD-L1 than for negative PD-L1. But the overall pattern, there’s no evidence of any benefit at all for DFS (disease free survival) in patients with squamous histology, and this is really inconsistent with just about everything we’ve ever seen with immunotherapy, at least in the advanced disease setting. So what do we make of all this? And I should say that there’s just a slight tiny hint of a possible mild overall survival benefit. Very early, very preliminary, but the hazard ratio is only in the range of 0.9 for this broad population with adjuvant pembrolizumab.
So should we use it? I would, what I’ve heard from many of my community oncology colleagues and some of my lung cancer specialist colleagues is the FDA has approved this, so we should really be using it. And I think that this is a very inappropriate conclusion to make. Why? Because the FDA has specifically said that they are abrogating themselves of any responsibility that what they’re approving should imply that this is clearly beneficial. Their approvals, they are saying is to give clinicians the option of doing these and putting it in the laps of the clinicians to make the hard decisions about whether the things that they’re approving are clinically appropriate and that arguably makes sense. The challenge, though, is that the end user, the physician, is often inferring that if it’s FDA approved, it should be used. And so both sides are really deflecting the hard decisions of should this be used, even if it could be used, and assuming that the other party has done the hard work of deciding that it should be done. And we see this far too often that FDA approval is presumed to mean clinical utility. But here we have an agent that has a modest, not incredibly compelling, DFS (disease free survival) benefit. We might argue, that we need to see overall survival. But on the other hand, we accept generally the DFS (disease free survival) benefit of osimertinib in the adjuvant setting to treat patients with an EGFR mutation based on the ADAURA trial. But when we were talking about FDA approval and use of this with DFS (disease free survival), but not OS (overall survival), that was in the context of a hazard ratio for DFS (disease free survival) of 0.2, which is astonishing. Years ago, 20 some years ago, when we were actively debating whether adjuvant chemotherapy should be used, we didn’t think for a minute about doing it based on DFS (disease free survival) alone, but entirely based it on waiting to see a consistent improvement in overall survival. We did not do that with ADAURA because it had a huge improvement in DFS (disease free survival), but now with IMpower010 and adjuvant atezolizumab as well as with adjuvant pembrolizumab, we’re talking about disease-free survival benefits that are okay, but not astonishing, particularly with adjuvant pembrolizumab ratio of 0.78 is, hmm, it’s possible on a good day, but that is not something that we should presume is extremely likely to translate to an overall survival benefit. Should we think about adjuvant pembrolizumab and any other FDA approved option. Yeah, it’s worth thinking about and it’s worth discussing with a patient and I think it’s an appropriate place for shared decision making, but shared decision making doesn’t mean just dropping it in front of the patient and saying you could do this FDA approved therapy or not. What do you think? Rather, it’s appropriate for us to inject and carefully discuss our own interpretation of the data. And how we conclude the balance of risks and benefits for a patient. So in many cases, that would be discussing but recommending against adjuvant pembrolizumab (brand name KEYTRUDA) if we say, “Hey, it’s an option.” But this is a therapy that has a potentially significant side effect(s) and often very long lasting, even possibly permanent side effects. It entails taking an extra year of treatment in the infusion center after you’d otherwise be done. We don’t have any hint of a survival benefit, it costs the system $200,000 or more in the US, so is it likely to have benefits that outweigh the risks and potential harms? I would say very questionable, if not likely harms exceed benefits and you can discuss it with a patient, but a very thoughtful patient would say thank you. I hear that, but I politely decline. Similarly many experts look at the data with consolidation durvalumab and are highly disinclined to recommend it in the stage 3 unresectable setting, for patients with an EGFR mutation where there seems to be no clear benefit. Maybe even for patients with PD-L1 less than 1%. And this is what many, if not most of the real experts in the field feel if you have an approval by the FDA that includes these patients, but that doesn’t mean that we want to give it, and our job should be to talk about it with our patients and make them understand why FDA approval is not the same as clinical value. And so I would say that this setting of adjuvant pembrolizumab is a clear example of the dissociation between an FDA approval and clinical utility and why you should not, think of this as anything close to a mandate or even a strong suggestion when it is meant by the FDA as just permission to do this but something that very likely may have harms that exceed the anticipated benefits.
Thanks very much. I’d be very happy to answer any questions, comments, if people have them.
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What is pembrolizumab?
The programmed death receptor 1 (PD-1) was discovered in 1992 and is a member of the B7-CD28 superfamily [1]. On activated T (CD8+ and CD4+) cells, B cells, monocytes, natural killer T cells, and antigen-presenting cells (APC), including dendritic cells, it is expressed. Development of PD-1-deficient mice indicated that this receptor has an immune-regulatory role in generating peripheral tolerance [1–3] and influencing the amplitude of the antigen-specific immunological response to infection [4–6] and malignancy [7–9]. Infection- or tumor-induced inflammatory cytokines promote the expression of programmed death receptor ligand 1 (PD-L1) and programmed death receptor ligand 2 (PD-L2) on a variety of cell types, including APC. The PD-1/PD-L1/PD-L2 relationship inhibits autoimmune as well as antitumor and anti-infectious immunity [10]. Lymphocyte activation is dependent upon antigen recognition by specific T-cell antigen receptors (assisted by APCs) and subsequent modulation by stimulatory and inhibitory signals from T-cell co-receptors. Co-stimulatory receptors include CD28, ICOS, 41BB, and OX40, whilst CTLA-4, VISTA, Tim-3, and PD-1 are co-inhibitory. There are dynamic interactions between the APC, tumor cell, and T cell that determine whether T-cell activation can occur and, if so, its amplitude and duration. The role of the numerous co-stimulatory or co-inhibitory molecules in regulating this interaction is not yet fully understood and may vary between and within tumor lesions of different patients. In addition, the role of monocytes and macrophages in this interaction is being investigated.
In oncology, the effective development of therapeutic drugs targeting the PD-1/PD-L1 axis represents a significant therapeutic step. In this article we cover the development of pembrolizumab, the first anti–PD-1 agent to be approved by the US Food and Drug Administration (FDA) (FDA). Pembrolizumab is also approved for use in melanoma in Australia, Israel, Korea, Macau, and the United Arab Emirates and was recently recommended for approval in the European Union.
What are the Side Effects of Pembrolizumab?
KEYTRUDA caused the biggest side effects (20%): fatigue (28%), diarrhea (26%), rash (24%), and nausea (21%).
In KEYNOTE-054, KEYTRUDA was given as a single therapy to stage III melanoma patients. In KEYNOTE-716, KEYTRUDA was given as a single therapy to stage IIB or IIC melanoma patients, and the side effects were similar to those seen in 1011 stage III patients in KEYNOTE-054.
20% of 405 metastatic nonsquamous NSCLC patients who received KEYTRUDA, pemetrexed, and platinum chemotherapy in KEYNOTE-189 discontinued treatment due to adverse effects. Fatigue (29%), diarrhea (24%), and rash (24%).
MSI-H or dMMR CRC patients who received KEYTRUDA monotherapy had similar adverse effects to melanoma or NSCLC patients.
In KEYNOTE-811, 6% of 217 patients with locally advanced unresectable or metastatic HER2+ gastric or GEJ adenocarcinoma terminated KEYTRUDA due to side events. Compared to the standard of treatment, diarrhea (53%) and nausea (49%) were 5% higher in the KEYTRUDA arm than placebo.
Fatigue/asthenia, nausea, constipation, diarrhea, decreased appetite, rash, vomiting, cough, dyspnea, pyrexia, alopecia, peripheral neuropathy, mucosal inflammation, stomatitis, headache, weight loss, abdominal pain, arthralgia, myalgia, and insomnia were the most common adverse reactions (20%) in chemotherapy patients taking KEYTRUDA.
Gastric cancer patients who received KEYTRUDA monotherapy had similar side effects as melanoma and NSCLC patients.
In KEYNOTE-590, 15% of 370 patients with metastatic or locally advanced esophageal or GEJ carcinoma (tumors with epicenter 1 to 5 cm above the GEJ) who were not eligible for surgical resection or final chemoradiation terminated KEYTRUDA due to side events. Nausea (67%), fatigue (57%), decreased appetite (44%), constipation (40%), diarrhea (36%), vomiting (34%), stomatitis (27%), and weight loss (24%).
KEYTRUDA monotherapy had similar side effects in esophageal cancer patients as in melanoma and NSCLC patients.
In KEYNOTE-826, when KEYTRUDA was administered in combination with paclitaxel and cisplatin or carboplatin, with or without bevacizumab (n=307) to patients with persistent, recurrent, or first-line metastatic cervical cancer regardless of tumor PD-L1 expression who had not been treated with chemotherapy except as a radio-sensitizing agent, fatal adverse reactions occurred in 4.6% of patients, including 3 cases of hemorrhage, 2 cases of pulmonary embolism, and 50% of patients taking KEYTRUDA with chemotherapy and bevacizumab had serious side effects, including febrile neutropenia (6.8%), urinary tract infection (5.2%), anemia (4.6%), and severe kidney injury and sepsis (3.3% each). 15% stopped using KEYTRUDA due to side effects.
Jack West, MD – About The Author, Credentials, and Affiliations
Jack West, MD, is an Associate Clinical Professor in Medical Oncology, a thoracic oncology specialist, and the Executive Director of Employer Services at the City of Hope Comprehensive Cancer Center. In the past, he was the Medical Director of the Thoracic Oncology Program at the Seattle Swedish Cancer Center.
Dr. West earned an MPhil in Experimental Biology from Cambridge University on a Fulbright Scholarship and a medical degree from Harvard Medical School, where he also did research as a Howard Hughes Medical Student Fellow. His postdoctoral training included an internship and residency in internal medicine at the Harvard-affiliated Brigham and Women’s Hospital in Boston, Massachusetts, and then a fellowship in medical oncology at the Fred Hutchinson Cancer Research Center/University of Washington in Seattle, Washington.
Late in 2002, he moved to Seattle to work as the Medical Director of the Thoracic Oncology Program at the Swedish Cancer Center. For more than 16 years, he did a wide range of clinical care, research, and other things. During the month of March 2019, he moved to the Los Angeles area to focus on coming up with new ways to use remote case evaluations and telemedicine consultations to provide sub-specialist expertise over a larger area.
He has written hundreds of articles and led many CME programs, clinical trials and symposia abroad on thoracic oncology, creative ways to teach, and the use of social media in cancer care.
Reference
- SpringerLink – Pembrolizumab. SprinterLink, August 18, 2015
- Merck – Merck’s KEYTRUDA® (pembrolizumab) Showed Statistically Significant Improvement in Disease-Free Survival Versus Placebo as Adjuvant Treatment for Patients With Stage IB-IIIA Non-Small Cell Lung Cancer Regardless of PD-L1 Expression. Merck, January 10, 2022