Pembrolizumab (Keytruda)

Unlike the other immune checkpoint inhibitors (nivolumab, atezolizumab), only pembrolizumab is approved for the first-line treatment of patients with advanced non–small cell lung cancer (NSCLC) and high levels of programmed cell death ligand 1 (PD-L1) expression (≥ 50%) in tumor cells.^1,2 Several immune checkpoint inhibitors (pembrolizumab, nivolumab, atezolizumab) are approved for treatment of patients with NSCLC after disease progression on or after platinum-containing chemotherapy.^3,4 Moreover, the U.S. Food and Drug Administration (FDA) recently approved a three-drug regimen with pembrolizumab and doublet chemotherapy (pemetrexed plus carboplatin) for the first-line treatment of patients with metastatic nonsquamous NSCLC, irrespective of tumor PD-L1 expression.⁵ To date, pembrolizumab has also been approved by the FDA for treatment of patients with various tumor types, in addition to NSCLC, including melanoma, head and neck squamous cell carcinoma, classical Hodgkin lymphoma, urothelial carcinoma, and microsatellite instability–high cancer.⁶

Evolving Data and Clinical Use

The National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology for NSCLC⁷ have been updated to include the following points about pembrolizumab:

• Pembrolizumab is recommended (category 1) for patients with advanced NSCLC and 50% or more expression of the PD-L1 and without (or unknown) genetic alterations in EGFR, ALK, BRAF, or ROS1.
• PD-L1 testing is recommended for patients with advanced NSCLC before prescribing pembrolizumab.
• Patients whose disease progresses on first-line pembrolizumab should be treated with subsequent chemotherapy, as per first-line recommendations for patients without (or unknown) genetic alterations in EGFR, ALK, BRAF, or ROS1.

Many oncologists, particularly those who treat patients with lung cancer, have some experience with pembrolizumab in the clinic. Nevertheless, few have as much experience as Ramaswamy Govindan, MD, Professor of Medicine, Anheuser Busch Chair in Medical Oncology, and Director, Section of Medical Oncology at the Washington University School of Medicine in St Louis.

According to Dr. Govindan, clinicians have to keep a number of concerns in mind when using a checkpoint inhibitor such as pembrolizumab. 

The most challenging aspect of treating patients with pembrolizumab is related to the risk for developing severe toxicities, the most common of which are pneumonitis, hepatitis, and other immune-related adverse effects (irAEs); most practitioners know how to manage these acute effects with high-dose steroid therapy. Dr. Govindan pointed out that patients with some sort of chronic autoimmune condition were generally excluded from clinical trials, but “anecdotally, checkpoint inhibitors are sometimes used in patients who have well-controlled autoimmune conditions, such as psoriatic or rheumatic arthritis; we don’t have enough data about patients with lupus or inflammatory bowel disease. The ALLIANCE for Clinical Trials is planning to formally study the use of checkpoint inhibitors in patients with existing autoimmune diseases,” Dr. Govindan reported.

Response Time and Symptom Relief

Dr. Govindan observed that newly diagnosed patients may need immediate relief from disease-related symptoms, because responses with a checkpoint inhibitor can take as long as 2 months to be appreciated. “It’s worth asking,” Dr. Govindan said, “whether we can do something simple to mitigate the patient’s symptoms until treatment takes effect.” Draining a pleural effusion will likely ease shortness of breath, and a short course of radiation can relieve a lobar collapse that is caused by a lesion pressing on the bronchi, he explained. “Sometimes a short course of radiation followed by initiation of pembrolizumab will be the best path forward.” If the patient has substantial symptomatology related to lesions that have spread to the liver, however, “it may not be as easy to relieve those,” Dr. Govindan acknowledged.

A Role for a Combination Regimen?

If the patient is highly symptomatic AND the tumor has very high PD-L1 expression, “one could make a case for a combination of chemotherapy plus pembrolizumab, if the NSCLC tumor is nonsquamous,” Dr. Govindan speculated. “We have data from the KEYNOTE 021 study (cohort G1), where the combination of pemetrexed, carboplatin, and pembrolizumab resulted in better objective response rates and better overall survival than the chemotherapy regimen alone in patients with nonsquamous NSCLC."⁸ The objective response rate when pembrolizumab was included was 55%, compared with 29% for chemotherapy alone. Likewise, median progression-free survival was 13 months (95% confidence interval [CI], 8.3 to not reached) in the pembrolizumab-containing arm versus 8.9 months (95% CI, 4.4–10.3) with chemotherapy alone.⁸ 

“The idea is that those patients will derive the benefit of immediate cytoreduction from the chemotherapy plus better, longer disease control with the checkpoint inhibitor,” Dr. Govindan explained. “I don’t have clinical experience with this combination yet, but I support the argument. It is important to keep in mind that the FDA approval for this combination is for ‘all comers’ with nonsquamous NSCLC, regardless of PD-L1 expression, as long as the tumor does not harbor EGFR mutations or ALK aberrations.”

According to Joanne Riemer, RN, BSN, a research nurse in the Upper Aerodigestive Cancer group with the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Medicine in Baltimore, patients who receive this regimen and their caregivers should anticipate the usual chemotherapy-induced adverse effects and also remain vigilant for any irAEs associated with pembrolizumab. Steroid premedication is required when pemetrexed is given to avoid or decrease skin rash, but, according to Dr. Govindan, short-term steroid use in this setting is not likely to affect the overall safety or activity of the combination regimen.

‘Newly diagnosed patients may need immediate relief from disease-related symptoms, because responses with a checkpoint inhibitor can take as long as 2 months to be appreciated.  Can we do something simple to mitigate the patient’s symptoms until treatment takes effect?’

Dr. Govindan noted that clinicians may apply current data about a pembrolizumab combination in three different ways. “For a highly symptomatic patient with nonsquamous NSCLC, the clinician could use combination chemotherapy, which has been the conventional approach for many years,” he said. “Or, if the practitioner is convinced by the data from KEYNOTE 021,⁸ he or she could consider the combination of chemotherapy with pembrolizumab, regardless of tumor PD-L1 expression.” For those who might be a little more skeptical, Dr. Govindan suggested the data might be parsed a bit by considering the combination of a checkpoint inhibitor plus chemotherapy for patients with high tumor PD-L1 expression. “In other words, patients who are eligible for checkpoint inhibition in the first line but who have significant symptoms might benefit from the addition of chemotherapy. We now have data to reassure us as to the safety of the combination.” 

Managing Toxicities: A Risk Versus Benefit Assessment

Pembrolizumab is quite well tolerated as long as patients are educated about what to look for in terms of irAEs. “They have to be educated and encouraged to report anything new or worsening to the team,” Ms. Riemer said. The AEs are varied, depending on which organ is affected by inflammation. If there is suspicion of an irAE, the diagnosis is one of exclusion: Is it an infection? Is it disease progression? “If it is none of those things, you have to consider an irAE and treat accordingly,” Ms Riemer explained.

Some irAEs are manageable without stopping therapy. If a patient develops a thyroid condition, for example, and can take medication for it, as long as pembrolizumab is providing benefit, “cancer control far outweighs the fact that the patient needs medication for a hypoactive thyroid,” Ms. Riemer observed.

For other irAEs with a checkpoint inhibitor, “You may be able to delay treatment a bit and then restart, but if the grade or severity of the AE is high, the risk associated with restarting the drug may outweigh the benefit of therapy,” Ms. Riemer said. “Although some of these effects are manageable and reversible, some can be serious and irreversible.”

Once a patient has been hospitalized and treated with high-dose steroids for a severe irAE, he or she generally is not restarted on the checkpoint inhibitor. However, Ms. Riemer explained, “we maintain a ‘risk versus benefit’ approach.” If the AE was a type of dermatitis and the patient was clearly responding in terms of cancer control, restarting treatment might be considered.⁹ “If, on the other hand,” Ms. Riemer said, “it was a grade 3 pneumonitis, it might not be prudent to go back to that treatment.”

The grade of a side effect is an important aspect of monitoring for irAEs and determining the need for treatment. “Although nurses are familiar with ‘mild,’ ‘moderate,’ or ‘severe’ as terms to characterize AEs, most are also familiar with grading systems to characterize AEs,” Ms. Riemer pointed out.

High-Dose Steroid Treatment: Slow Tapering Is Key

Ms. Riemer noted that irAEs may recur, so steroid treatment should be slowly tapered over a period of at least 4 to 6 weeks. “I have also seen the development of a different type of AE,” she noted. “So, let’s say we’ve gotten hypothyroidism under control; a few months later, the patient may develop hypophysitis, pneumonitis, or colitis.”

“Clearly, we must take seriously any side effects, such as uncontrolled diarrhea or sudden shortness of breath,” Dr. Govindan stated. Fatigue, for instance, is a common symptom. He also underscored the importance of a very gradual tapering of high-dose steroids. “Abrupt tapering of steroids should be avoided,” he warned.

Duration of Treatment With Immunotherapy

Early clinical studies of checkpoint inhibitors were designed with a 2-year cutoff.¹⁰ However, when some patients experienced disease recurrence after 2 years, they were allowed to resume treatment.  Subsequent studies¹¹ do not have the 2-year cutoff.

“It’s possible we are dosing patients longer than we need to,” Ms. Riemer said, “but we don’t know the optimal duration yet. Ongoing studies, such as CheckMate 153, may shed light on the benefits and risks of different durations of treatment.¹¹ Anecdotally, I have patients on a checkpoint inhibitor for more than 4 years.” She also noted that an educated immune system may keep fighting cancer, even after treatment has stopped. In other words, data suggest that patients continue to derive benefits from immune checkpoint inhibitors even after treatment has ended.

Supporting Patients on Immunotherapy: The Nurse’s Role

Supporting patients on immunotherapy is quite different from the nurse’s role when patients receive chemotherapy, explained Ms. Riemer.“With chemotherapy, our mindset is to help patients march through their treatment course. But with immunotherapy, it’s very important to evaluate any side effects to determine whether they could possibly be irAEs.”

Although the oncologist determines whether a symptom may be immune-related, the nurse is usually the person who educates the patient about what to look for and what to report. Together with the patient, the nurse is often the first to raise a red flag. If patients have not been well educated, they may misinterpret or dismiss important symptoms.

Ms. Riemer explained that all informational and educational materials used in a clinical trial are approved by the institutional review board. However, in the community setting and “with our standard-of-care patients, we’re all still grappling with the question of what are the best educational tools.” 

“As a research nurse, I worked with checkpoint inhibitors several years before they were approved.” Seeing a need in the nursing community, Ms. Riemer is developing a handbook to help nurses understand how these drugs work and what kinds of questions to ask patients “to tease out whether side effects could be immune-related.”  [Editor’s Note: See http://accc-iclio.org¹² and https://www.ons.org/practice-resources/cancer-therapies/immunotherapy-resources¹³ for useful resources.]

“If patients don’t know that a symptom is something they should report, they may wait to see whether it will resolve before their next scheduled visit,” Ms. Riemer noted. Without specific education, patients are likely to ascribe gastrointestinal symptoms to something they ate or shortness of breath and coughing to a virus that’s “going around” rather than to their cancer treatment.

Although pembrolizumab is administered every 3 weeks, some patients may benefit from more frequent contact.  “Some patients are reticent to ‘complain,’ so I follow up with them proactively,” Ms. Riemer said. “Other patients call every other day, so I can be pretty certain I will hear about any problems promptly.” Ms. Riemer observed that “there probably needs to be some sort of standard surveillance, but we don’t know yet what the optimal form or frequency should be.” 

Reinforcing Education at Every Visit: “Can I see your ID card?”

Ms. Riemer urges cancer care teams that provide treatment documentation to check with patients at every visit about whether they have their drug identification cards with them. “At Johns Hopkins, we ask, ‘Can I see your ID card?’ First of all, you are ensuring that the physical card is intact, but you are also highlighting the importance of knowing what drug is being taken, what the potential side effects are, and how to get in touch with the team if any symptoms emerge. It’s obviously also an opportunity to replace the card if the patient has lost or misplaced it.” If the patient visits a primary care provider or an emergency department, “we want that practitioner to call the cancer care team while the patient is in the office,” Ms. Riemer emphasized.

Building a Consultant Team

The Johns Hopkins team, according to Ms. Riemer, is trying to assemble an immuno-oncology tumor board, which would bring together different specialists with experience using immunotherapy. “Ideally, we will build a team of consultants that can quickly respond if symptoms emerge.” Ms. Riemer encourages community practitioners to find out who they can call on, if they need an endocrinologist or rheumatologist, for instance. It is important to establish the structure for these networks before they are needed, she said, and to know how to access them rapidly.

Dr. Govindan underscored the need “for us as oncologists to talk with and educate our colleagues in other specialties about the types of AEs that may be associated with our therapies. For instance, if I consult with a dermatologist about a rash in a patient on erlotinib, I need to first educate my colleague about erlotinib.”

In the face of rapidly emerging data, new findings, and updated guidelines, Dr. Govindan urges clinicians who treat patients with advanced NSCLC to become familiar with the AEs of checkpoint inhibitors, to assemble an expanded team of colleagues in other specialties, and to make the effort to keep up with the literature as it evolves.

Disclosures

Ramaswamy Govindan, MD, has served as a consultant for INC Research and AbbVie; he has served on advisory boards for AbbVie and Inivata; and has received honoraria from AbbVie and Genentech.

Joanne Riemer, RN, BSN, has served as a consultant, as well as on nursing and advisory boards for Merck Sharp & Dohme Corp, Merck, AstraZeneca, and Bristol-Myers Squibb.

References

1. Food and Drug Administration. FDA approves Keytruda for advanced non-small cell lung cancer. Available at https://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm558048.htm. Accessed July 21, 2017.
2. Food and Drug Administration. Pembrolizumab (Keytruda) checkpoint inhibitor. Available at https://www.fda.gov/drugs/informationondrugs/approveddrugs/ucm526430.htm. Accessed July 12, 2017.
3. Food and Drug Administration. FDA expands approved use of Opdivo in advanced lung cancer. Available at http://www.esmo.org/Oncology-News/FDA-Expands-Approved-Use-of-Nivolumab-in-Advanced-Lung-Cancer. Accessed February 25, 2017.
4. Food and Drug Administration.Atezolizumab (Tecentriq). Available at https://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm525780.htm. Accessed February 25, 2017.
5. Food and Drug Administration. Pembrolizumab (Keytruda) 5-10-2017. Available at https://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm558048.htm. Accessed July 13, 2017.
6. Merck & Co. Keytruda (pembrolizumab). Full prescribing information. Available at https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/125514s012lbl.pdf; https://www.merck.com/product/usa/pi_circulars/k/keytruda/keytruda_pi.pdf. Accessed July 14, 2017.
7. Ettinger DS, Wood DE, Aisner DL, et al. NCCN Clinical Practice Guidelines in Oncology Non-Small Cell Lung Cancer, v8.2017–July 14, 2017. Available at https://www.nccn.org/professionals/physician_gls/default.aspx. Accessed July 14, 2017.
8. Langer CJ, Gadgeel SM, Borghaei H, et al. Carboplatin and pemetrexed with or without pembrolizumab for advanced, non-squamous non-small-cell lung cancer: a randomised, phase 2 cohort of the open-label KEYNOTE-021 study. Lancet Oncol 2016;17:1497–1508.
9. Santini FC, Rizvi H, Wilkins O, et al. Safety of retreatment with immunotherapy after immune-related toxicity in patients with lung cancers treated with anti-PD(L)-1 therapy [Abstract 9012]. J Clin Oncol 2017;35(suppl).
10. A study of MDX-1106 in patients with selected refractory or relapsed malignancies (MDX1106-01). Available at https://clinicaltrials.gov/ct2/show/NCT00441337. Accessed July 17, 2017.
11. A safety trial of nivolumab in patients with advanced or metastatic non-small cell lung cancer who have progressed during or after receiving at least one prior chemotherapy regimen (CheckMate153). Available at https://clinicaltrials.gov/ct2/show/NCT02066636. Accessed July 17, 2017.
12. Institute for Clinical Immuno-Oncology. Available at http://accc-iclio.org. Accessed July 14, 2017.
13. Oncology Nursing Society. Immunotherapy Resources. Available at https://www.ons.org/practice-resources/cancer-therapies/immunotherapy-resources. Accessed September 18, 2017.