With commentaries by
Laura Wood, RN, MSN, OCN Cleveland Clinic Taussig Cancer Center Cleveland, OH
Virginia Seery, MSN, RN, ANP-BC, AOCNP Beth Israel Deaconess Medical Center Boston, MA
Megan Price, MSN, APRN, FNP-C Texas Oncology - Baylor Charles A. Sammons Cancer Center Dallas, TX
Each year in the United States there are approximately 76,000 new cases of kidney cancer and almost 14,000 kidney cancer–related deaths.1 Men have a two-fold higher risk of kidney cancer than women, with respective lifetime risks of 2.02% and 1.03%. Compared with other races and ethnicities, kidney cancer prevalence is higher among indigenous and black Americans. The average age at time of diagnosis is 64 years, with most patients diagnosed between age 65 and 74 years, and very few patients diagnosed younger than age 45. Nine of 10 cases of kidney cancer are renal-cell carcinoma (RCC).1
The treatment paradigm for RCC has changed significantly over the past 2 decades and continues to evolve. While immunotherapies such as interleukin-2 and interferon-α were once mainstay treatments, these were largely displaced in 2006 when the US Food and Drug Administration (FDA) approved sunitinib as the first tyrosine kinase inhibitor (TKI) for RCC.2,3 Now, more advanced TKIs such as cabozantinib are being paired with monoclonal antibodies, such as nivolumab, to push first-line efficacy benchmarks higher than ever.2,4
Longer survival is clearly good news for patients; but for oncology healthcare providers, recent and emerging therapies present unique characteristics that may influence clinical decision-making and communication strategies. During treatment planning, a number of factors need to be discussed with patients, including safety, efficacy, and health-related quality of life (HRQOL); and after a treatment is selected, patients may need help overcoming practical challenges, such as medication adherence, cost, and access.
Due to prolonged durations of survival, HRQOL is becoming increasingly important for patients with advanced RCC.5 In conjunction with response and survival data, HRQOL offers a comprehensive picture of daily life when taking particular treatments, which is essential for patients on long courses of therapy.6 To achieve comparable levels of HRQOL reported by clinical trials, healthcare providers need to collaborate with patients to create detailed adherence strategies and planned responses to suspected adverse events (AEs).
This article offers an overview of first-line combination therapies for advanced RCC with an emphasis on HRQOL, communication strategies to optimize adherence, ways of overcoming barriers to access, and AE management strategies. Following each section, commentary is provided by 3 leading oncology advanced care practitioners who offer practical tips for success when helping patients with advanced RCC navigate their treatment journey.
Commentary by Virginia Seery, MSN, RN, ANP-BC, AOCNP: There has been tremendous progress over the past 15 to 16 years in the treatment of advanced kidney cancer. We went from having only interleukin-2 and interferon to the FDA approval of VEGF-targeted therapies, mTOR inhibitors, and now on to immunotherapy. Now we’re seeing combinations of these drugs getting approved for use in advanced kidney cancer.
The wonderful progress has made this a very exciting time to be working in renal-cell carcinoma oncology. It’s very fulfilling to see patients getting improved benefit along with tolerable side effects and overall better quality of life.
Commentary by Laura Wood, RN, MSN, OCN: There are a lot of new treatment options coming out for patients with advanced kidney cancer. It’s really about doing everything possible to help a patient and caregiver make the best out of whatever treatment they’re starting.
With previous therapies we treated until we lost efficacy. We never used to talk about drug holidays because we were afraid we would lose the effectiveness. Now, with immunotherapy, I have patients who have been on therapy for several years, either because they achieved a very strong response and had side effects that required treatment interruption, or they’ve completed a 2-year treatment plan, and now we are monitoring their disease to reinitiate treatment at the time of disease progression.
That’s been a learning curve for us in the oncology field, as well as a very strong and sometimes challenging conversation with patients who do not want to stop their therapy. We’re trying to balance efficacy and quality of life.
When discussing treatment options with patients and caregivers, it’s best to foster open communication from the start. Patients and caregivers should know that they can ask about any aspect of their treatment journey, either medical or nonmedical, and feel welcome sharing their emotions and concerns.
Once a trusting environment is established, it is necessary to determine each patient’s knowledge base. What is their medical literacy? How much do they know about RCC and treatment options? It can also be helpful to ask about past experiences with cancer. Patients may have expectations based on the experiences of their friends or family, and these may poorly represent their own situation, as treatments vary between cancer types, and cancer treatments in general have changed substantially over the years.
After establishing familiarity with baseline knowledge, the next step is to determine health goals, with an emphasis on HRQOL. Keep in mind that health goals can change over time. For example, a patient receiving first-line therapy is more likely to be focused on reducing tumor burden to improve symptoms of disease, whereas a patient starting later lines of therapy may wish to minimize toxicity associated with aggressive treatment.
The first discussion of treatment options should begin broadly, with little or no mention of specific drug names. This can be a highly emotional time for patients, possibly making it difficult to think clearly or remember complicated details. Instead of relying on memory, patients and caregivers may benefit from taking notes during the discussion and writing down any questions that come up afterwards.
During follow-up, advanced care practitioners can expand upon this first discussion by addressing initial questions and concerns, then reviewing specific drug recommendations. Because an oncologist has typically already discussed efficacy differences between treatment options, advanced care practitioners can explore differences in HRQOL outcomes.
Commentary by Virginia Seery, MSN, RN, ANP-BC, AOCNP: As soon as I meet a patient, I try to make them feel comfortable with asking me anything or talking to me about anything. I believe, as nurses, sometimes patients or families are more likely to come to us when they might be a little more hesitant to reach out to the doctor about issues.
Often, if we’re thinking about first-line treatment options, these patients are typically either newly diagnosed or adjusting to a new stage IV diagnosis, so this is an incredibly stressful time. I try to provide a general overview of different first-line therapies including targeted therapy, immunotherapy, or a combination.
You have to be able to read the patient and family, then gauge where they are with their understanding and acceptance of the diagnosis and how much information they can take in. They may not remember much of what is said initially, so providing written materials to highlight and supplement what you tell them is incredibly important.
Along that line, if a patient or family member is asking higher level questions, then I know they’ve done some research or have some background and have a better understanding of options. If that’s the case, I’ll go into more detail on the potential therapies, the response rates, and the potential side effects.
I can’t stress enough how important it is to meet the patient and the family where they are in their understanding and acceptance, and try to work off that when you decide how much you teach them or talk with them in the first meeting. They can be very overwhelmed because this truly is a life-changing diagnosis for them.
Commentary by Laura Wood, RN, MSN, OCN: I think an important piece of patient education is how to break up information into critical pieces at a pace that the patient and the caregiver can absorb the information. I use a lot of written resources to hit the highlights. There’s written information for them to take home to review at a later point in time. I may have written information that I’m not even addressing that goes in their education packet.
Commentary by Megan Price, MSN, APRN, FNP-C: One thing that we do at our institution that I think is very helpful is have a treatment review and coordination visit following the initial consult—whether it’s via telemedicine or in person—after they’ve had time to review the initial information given to them at the consult visit. We also will go through the side-effect discussion of a particular treatment regimen.
I know time is of the essence sometimes, so these kinds of visits don’t happen in every institution or for every patient. We really try to incorporate them, because the questions start flooding in when patients go home from their first visit and start talking to their family. I have found these follow-up visits very helpful, and the patients have benefited from them immensely, as well.
Combination therapies are now the most common first-line treatment for patients with advanced RCC.7 To date, 4 frontline combos have been approved by the FDA: ipilimumab/nivolumab, pembrolizumab/axitinib, avelumab/axitinib, and nivolumab/cabozantinib.8-11 Of these, ipilimumab/nivolumab is an immunotherapy doublet, while the other combinations involve an immunotherapy and a TKI.
Although comparisons across clinical trials are limited by differences in patient populations and variations in care delivered, they can still offer a general sense of expected benefits.12 Table 1 offers a brief summary of phase 3 efficacy outcomes for the 4 FDA-approved combination therapies for advanced RCC, including objective response rate (ORR), progression-free survival (PFS), and overall survival (OS).13-17
Although it appears that pembrolizumab/axitinib was associated with the best ORR, at 60%, a closer look shows that the sunitinib group in that particular trial had a relatively high response rate, at 40%, compared with approximately 27% for sunitinib-treated patients in the other 3 trials.13 This difference in control groups suggests that the patient population in the pembrolizumab/axitinib trial may have had more favorable characteristics than patients enrolled in the other trials. The similar outcomes in sunitinib groups across the other 3 trials allow for more reliable comparisons of efficacy; namely, that nivolumab/cabozantinib had the best ORR, at 55.7%.4
A similar pattern appears in a comparison of median PFS rates. In the pembrolizumab/axitinib trial, patients in the sunitinib (control) arm had a median PFS of 11.1 months, compared with approximately 8 months in the control arms of the other trials.4,13-15 The 15.4-month median PFS for pembrolizumab/axitinib should be considered in this context.15 At 16.6 months, the median PFS for nivolumab/cabozantinib stands out as the clear leader in the field, while avelumab/axitinib and nivolumab/ipilimumab trail behind at 13.3 months and 11.6 months, respectively, with the caveat that these nivolumab/ipilimumab findings are exclusive to intermediate- and poor-risk patients.4,13,14
Due to the recency of the pembrolizumab/axitinib and nivolumab/cabozantinib trials, a comparison of OS across all trials is not yet possible. Although pembrolizumab/axitinib appears to have a greater survival benefit than nivolumab/ipilimumab based on 2-year OS rates of 74% and 66%, respectively, the control groups are again dissimilar, with a 14% gap between rates of survival, casting some doubt on the legitimacy of a direct comparison.16,17 The intermediate- and poor-risk profile of the nivolumab/ipilimumab population further distorts the picture.
Beyond the challenges presented by cross-trial comparisons, conventional efficacy data do not necessarily reveal the average patient experience undergoing each treatment regimen. For this, patient-reported outcomes for HRQOL are more helpful. And because patients with advanced RCC may be on therapy for years, these outcomes are becoming increasingly important.5
HRQOL was measured variously by 4 patient-reported instruments in the previously described phase 3 trials (Table 2)18-21:
Among the above metrics, the FKSI-19 is the most specific to kidney cancer.22 This validated assessment tool was developed in conjunction with the National Comprehensive Cancer Network and aligns with FDA guidance.23 It is a 19-item questionnaire that addresses 4 domains: disease-related symptoms-physical, disease-related symptoms-emotional, treatment side effects, and function/well-being (FWB).22
The FACT-G is a 27-item instrument designed to measure HRQOL across cancer types. Like the FKSI-19, the FACT-G measures FWB.18 The FACT-G also evaluates physical well-being, social and family well-being, and emotional well-being.18
The EQ-5D-3L is a comparatively broad instrument that assesses general health status in 5 domains: depression and anxiety, mobility, pain and discomfort, self-care, and usual activities.18 It also asks patients to self-rate their global health on a scale from 0 to 100, with zero being the worst health imaginable and 100 being the best health imaginable (visual analog scale [VAS]).18
The EORTC QLQ-C30 also measures general quality of life (QOL).19 It groups scoring into 8 symptom scales (nausea/vomiting, pain, diarrhea, fatigue, constipation, sleep disturbance, dyspnea, appetite loss) and 5 functioning scales (social, emotional, cognitive, role, and physical).19 Like the EQ-5D-3L, the QLQ-C30 asks patients to self-report 1 global health score.19
In the CheckMate 214 trial, patients received nivolumab/ipilimumab and self-reported HRQOL at baseline and scheduled visits using the FKSI-19, FACT-G, and EQ-5D-3L (Table 2).18 At week 103, compared with sunitinib, nivolumab/ipilimumab significantly improved FKSI-19 and FACT-G, with differences in mean change from baseline of 7.14 and 9.09, respectively.18 Most subdomain scores favored nivolumab/ipilimumab over sunitinib; however, several domains favored sunitinib, including FACT-G social and family well-being and functional well-being; and FKSI-19 disease-related symptoms and functional well-being.18 While EQ-5D-3L VAS (patient self-reported overall health) score improved to a greater degree in the nivolumab/ipilimumab group than the sunitinib group (difference in mean change, 3.67), this difference was not significantly different at week 103.18
The KEYNOTE-426 trial, which evaluated pembrolizumab/axitinib versus sunitinib, reported HRQOL outcomes at week 30 using QLQ-C30 global health status, EQ-5D-3L VAS, and FKSI–disease-related symptoms.19 For each, small differences in mean change between groups favored sunitinib; however, these differences were insufficient to meet criteria for minimally important difference.19
The JAVELIN Renal 101 trial, which evaluated avelumab/axitinib versus sunitinib, measured HRQOL via FKSI-19 and EQ-5D-3L.20 Neither instrument revealed significant changes between groups, and exact scores have not been released.20
The CheckMate 9ER trial, which tested nivolumab/cabozantinib versus sunitinib, measured HRQOL using FKSI-19 and EQ-5D-3L VAS.21 At week 91, patients treated with nivolumab/cabozantinib reported significantly greater increases in scores than patients treated with sunitinib.21 The mean intergroup differences for FKSI-19 and EQ-5D-3L VAS were 2.90 and 3.26, respectively.21 These findings suggest that combination therapy with nivolumab/cabozantinib improved both kidney cancer–related QOL and overall HRQOL.
A comparison of HRQOL outcomes across trials suggests that, of the 4 available combination therapies, only nivolumab/ipilimumab and nivolumab/cabozantinib are associated with statistically significant improvements compared with sunitinib monotherapy (Table 2).18-21 Compared with nivolumab/cabozantinib, nivolumab/ipilimumab was associated with greater changes in kidney cancer– and general cancer–related HRQOL (FKSI-19 and FACT-G); however, a significant difference in general health was not reported (EQ-5D-3L VAS).18,21
This overview of HRQOL outcomes across trials offers a more comprehensive understanding of what it may be like for a patient to take these medications, allowing for a more nuanced discussion of treatment options. Comparing the median PFS of pembrolizumab/axitinib with nivolumab/cabozantinib, for instance, shows respective outcomes of 15.4 months and 16.6 months, suggesting a slight improvement in disease control for patients taking nivolumab/cabozantinib.15,16 Incorporating HRQOL tilts the scale in further toward nivolumab/cabozantinib, as this combination was associated with both significantly improved disease-related HRQOL and overall HRQOL.19,21 The HRQOL data for nivolumab/cabozantinib are particularly compelling in this comparison, as they were measured all the way to week 91, compared with week 30 for pembrolizumab/axitinib, suggesting greater support for QOL over time.19,21
Commentary by Laura Wood, RN, MSN, OCN: I’m learning more and more about the value of quality-of-life data. Because we’re really looking at it from the patient’s eyes—it’s what they’ve experienced.
The interesting thing in the CheckMate 9ER data is that they did not see deterioration in quality of life in spite of a fairly significant toxicity profile. Even dealing with those high percentages of side effects, quality of life was maintained. That’s an important factor.
Commentary by Megan Price, MSN, APRN, FNP-C: The quality-of-life data are really a surrogate for overall tolerance. It’s what we need to feel justified in treating the patients safely while respecting that quality of life ultimately is the biggest issue. Even when we’re seeing improved progression-free survival and overall survival data, if it doesn’t correlate to improved quality of life overall, that doesn’t help the patient. When we see a nice separation in survival curves, it’s fantastic, but when we actually see that a patient can function and can go to life events, like weddings, that is the exciting data for us. That’s why we’re all in this field, to be completely honest.
Quality-of-life data from clinical trials for these combinations should be the largest focus for us when we’re looking at incorporating them into real-world practice, because quality-of-life data do correlate secondarily, of course, to the primary end points as well.
When a treatment is selected, advanced care practitioners should emphasize the importance of adherence, which strongly predicts a better disease course among patients with RCC.24 Adherence is most likely to be achieved when patients create personalized treatment goals that are SMART (specific, measurable, achievable, realistic, and time-bound).25
It is particularly important to create SMART goals for taking oral medications. In this, some guidance may be necessary. For example, if a patient says that they plan on taking their oral medication once daily, they should be asked to pick a specific time or part of the day to do this, such as 7 PM or upon waking, and stick to that schedule.
Patients should be advised to notify their healthcare provider immediately if they are running into any issues during treatment. New symptoms may or may not be AEs, so it’s better that the healthcare team knows about them as soon as possible, allowing for further investigation, and if necessary, treatment modification. Although adherence is necessary to achieve best outcomes, dosage modifications or drug holidays may be needed, particularly when patients are taking medications for years.
Beyond SMART goal-setting, it’s important for patients to have clear expectations about their treatment journey because appropriate expectations have been shown to improve QOL, side-effect burden, and adherence.26 Common AEs should be discussed prior to starting therapy, including time windows in which they are most likely to occur, and overlapping toxicities. This latter point is important for combination therapies because it helps patients understand that suspected AEs may require some troubleshooting. One drug may need to be stopped, and possibly the other, before a clear source of the new symptom can be identified. To help with this, patients can log their treatments, symptoms, and if applicable, clinical signs (eg, blood pressure) in a diary or calendar. Honesty should be encouraged, as knowledge of missed doses may guide future clinical decisions.
Commentary by Megan Price, MSN, APRN, FNP-C: For adherence with oral oncolytics, written materials are very important to give patients a foundation to build on.
Outside of written materials, establishing rapport and trust with the patient is essential for making sure that there’s honest communication. You may tell them, “Please, let us know if you’re having side effects, because if we need to dose reduce, we can do that.” Explaining why we want to know about adherence is very important. It’s also important to explain why they need to take their medication every day—they need to know about building up therapeutic levels in their system. It’s about giving patients a foundation of information so that they understand why we need them to be adherent, but also keeping that door open, so they feel comfortable telling us if they’ve skipped or missed a dose.
We’ve all seen diaries on oral oncolytics. We want to make sure that what patients are writing down is true. Because a lot of patients are scared of disappointing someone, speaking to them human to human and making sure they feel comfortable coming to you with a concern is probably the most important aspect of adherence, when you’re talking about oral therapies.
During the treatment-planning process, advanced care practitioners and navigators should identify barriers to access, which can vary broadly, encompassing both medical and nonmedical obstacles to care. Medical obstacles may include the need for home care or medical equipment, challenges with prior authorization, high costs of care, and other issues. Nonmedical barriers can also vary widely, including practical issues such as lodging or transportation.
Early on, patients should know that their oncology care team can help with nonmedical issues, or at least put patients in touch with helpful resources. For this to be possible, advanced care practitioners and navigators need to familiarize themselves with available resources, both inside and outside of their treatment center. Resources may include pharmacists and pharmacy technicians, social workers, or even a patient’s family and friends. When medical costs stand in the way of care, patient assistance programs can be invaluable, either through drug companies, patient advocacy groups, or independent organizations.
After identifying barriers to care and putting patients in touch with appropriate resources, adequate follow-up is essential to ensure resolution.
Commentary by Laura Wood, RN, MSN, OCN: Helping patients navigate the financial aspects of their treatment plan can be very challenging. It’s a matter of networking with my peers to know what’s available and what’s out there to reach out to, and working with the specialty pharmacy to see what resources are available. Our institution is very good about assisting us with the forms that need to be completed for financial assistance access.
The pharmaceutical companies may have access to care programs that patients may qualify for. As a clinical trial coordinator, there is the Lazarex Cancer Foundation—it’s a foundation that financially supports patients to participate in clinical trials. That’s a resource that I’m proud to be able to share with patients. That may help them with some of those out-of-pocket expenses and travel expenses needed for clinical trial participation.
Commentary by Virginia Seery, MSN, RN, ANP-BC, AOCNP: At our academic medical center, we are very lucky to have resources that can help us overcome barriers to access. We work closely with case managers to help us explore available options for the patient, whether that would be something related to home care or durable medical equipment needs, or getting financial assistance with hotel rooms or with medication coverage.
We also are blessed to have pharmacy technicians who assist us a great deal with obtaining prior authorizations or looking for additional funding for medications to help patients pay copayments. This is incredibly helpful to us, as clinicians.
Clearly, not all practices or centers will have these luxuries. In that case, I think you need to expand out and look for social work assistance to see if they can help you with patient assistance programs, either through the drug company or through other independent funding sources.
Combination therapies for patients with RCC have been associated with a broad range of AEs, making them challenging to predict, both in terms of type and timing.27 If a patient reports a possible AE, they should first be praised for reporting the possible issue to increase the likelihood of this behavior in the future.
If an AE is confirmed, patients and clinicians will need to weigh the balance between drug efficacy and QOL. Possible solutions will also need to be discussed, such as an additional medication (eg, antidiarrheal), supportive care, dose reduction or interruption, or switching to a new regimen. Collaboration with other specialists may be required.
At the beginning of this process, patients should be reminded that confirming an AE, and finding the optimal solution, can sometimes be a process of trial and error. They should also be reassured that excellent results are still possible if a treatment modification or interruption is needed.
If interventions are implemented, an advanced care practitioner should follow up within a few days to see if the patient is feeling better.
Commentary by Laura Wood, RN, MSN, OCN: If a patient develops a new side effect or issue, I urge them to contact us sooner rather than later. In this way, we can manage it before it becomes a major problem, with the goal of, of course, continuing their treatment. If a side effect escalates, sometimes therapy needs to be held. Quality of life is an important factor for patients. Maximizing this is extremely important.
Patients need to know how we manage side effects. They need to know who to reach out to and we need to know how to get in touch with them, Monday through Friday. They also need to know who to call after clinic hours, and on weekends or holidays, so that we can stay on top of managing those side effects.
If we’ve got a side effect that we didn’t previously discuss in detail, I will have that patient go back to their education folder, pull out that particular education sheet, and then we can review it together because it’s more relevant at that point in time.
Commentary by Virginia Seery, MSN, RN, ANP-BC, AOCNP: When we first started using checkpoint inhibitors, some patients would come in with a side effect, and we would understand that they were only really telling us the tip of the iceberg. They had been having this side effect for some time, but didn’t want to fess up to it, because they were very fearful about us stopping their treatments.
It takes education and communication to help patients understand that it is in their best interest, if necessary, to hold treatment to get control of a side effect. Then we may be able to restart treatment.
We have so many patients today who are doing well and have been off immune checkpoint inhibitors for years. Whether that means they have had a complete response, tumor regression, or even stable disease, that is still a win in our eyes, and I think it takes changing a patient’s mindset sometimes to understand that.
As treatments for advanced RCC grow increasingly effective, some patients will be on therapy for years. HRQOL is therefore an essential focus throughout the treatment journey, starting with drug selection, and if needed, when discussing adjustments to treatment regimens. This emphasis on each patient’s QOL moves away from pure statistics and toward a more personalized approach.
Instead of asking, “Which drug has the longest median PFS?” clinicians may first need to ask, “Who is my patient and what are their goals?” Throughout this shared decision-making process, collaboration is essential—between clinicians and patients, and with other stakeholders. Ultimately, it is advanced care practitioners and navigators, through aptitude in both medicine and communication, who bring the promise of new medications to the real world, unlocking each treatment’s full potential.
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