Released: January 22, 2021
Expiration: January 21, 2022
In this module, Brian A. Costello, MD/MS offers an overview on personalizing care and improving outcomes for patients with advanced renal cell carcinoma (RCC), including first-line and second-line treatments and the management of adverse events (AEs) from immunotherapy–based therapy.
The key points discussed in this module are illustrated with thumbnails from the accompanying downloadable PowerPoint slideset that can be found here or downloaded by clicking any of the slide thumbnails in the module alongside the expert commentary.
Clinical Care Options plans to measure the educational impact of this activity. Several questions will be asked twice: once at the beginning of the activity, and then once again after the discussion that informs the best choice. Your responses will be aggregated for analysis, and your specific responses will not be shared.
Before continuing with this educational activity, please take a moment to answer the following questions.
The treatment landscape for patients with advanced RCC has changed dramatically in recent years with the very active advancement in drug design and clinical trials. When we are considering first‑line treatment for patients with advanced RCC, the question always arises about the right choice for treatment.
First, one of the key things to know when deciding on therapy is the IMDC risk criteria for mRCC, otherwise known as the Heng criteria.1,2 These criteria are a simple clinical algorithm to risk-stratify patients. There are 6 different clinical criteria included in the algorithm: Favorable-risk patients meet none of the criteria, intermediate-risk patients meet 1-2 of the criteria, and poor-risk patients meet ≥ 3 criteria. The criteria include time from initial diagnosis to treatment of < 1 year, a Karnofsky performance score of < 80%, hemoglobin less than the lower limit of normal, calcium levels > 10 mg/dL, platelet counts higher than the upper limit of normal, and neutrophil counts higher than the upper limit of normal.
Using these criteria, approximately 75% to 80% of patients eligible for first-line treatment for mRCC are intermediate/poor risk.
The original data by Heng and colleagues1 show that when we risk-stratify patients using these criteria, favorable-risk patients have a higher median OS than intermediate-risk patients, who have a higher median OS than poor-risk patients.
There are many first‑line systemic therapies currently available for patients with advanced clear-cell RCC. First‑line immunotherapy‑based regimens have been available since 2018.
For favorable-risk patients, the optimal first-line generally is axitinib plus pembrolizumab. Some patients with favorable-risk features can also consider active surveillance, which I will talk more about later. Depending on patient profile and specific comorbidities, some patients might only be candidates for single‑agent treatment. In that context, a single‑agent TKI remains a reasonable choice.
If we look at intermediate-/poor‑risk patients, there are 2 recommended immunotherapy-based regimens: nivolumab plus ipilimumab and axitinib plus pembrolizumab. In patients who may not be able to tolerate these combination approaches, single-agent treatment with cabozantinib is a reasonable choice for first‑line therapy. Now, let’s consider some patient case examples and go through the data informing these treatment choices.
Let’s return to one of the patient case examples from the polling questions in the beginning of this program. This is a 64‑year‑old man who presented with gross hematuria. Imaging showed a large mass in his right kidney and a small indeterminate pulmonary nodule on his right lung, shown with the red arrow.
The first question for this patient is whether he should undergo cytoreduction for his cancer. Let’s look at the data.
The CARMENA trial was a prospective, multicenter, randomized phase III study that enrolled 450 patients with mRCC.3,4 Patients were randomized to 2 groups: one group underwent upfront nephrectomy (n = 226) followed by sunitinib 3-6 weeks later and the other group immediately began systemic therapy with sunitinib (n = 226). Patients were followed for at least 2 years, and the primary endpoint was OS. Secondary endpoints were PFS, ORR, clinical benefit, and safety.
The CARMENA trial showed that sunitinib alone was not inferior in terms of OS compared with nephrectomy followed by sunitinib.4 In fact, the median OS was 13.9 months with nephrectomy followed by sunitinib vs 18.4 months with sunitinib alone (HR: 0.89; 95% CI: 0.71-1.10).
Some people have interpreted the data from the CARMENA trial to mean that we should not consider cytoreductive nephrectomy whatsoever. However, in my practice at Mayo Clinic, the decision of whether to consider a nephrectomy is about patient selection. There were some issues with the CARMENA trial, including patient selection and the fact that sunitinib is no longer routinely used as a first‑line therapy.
In patients with minimal extrarenal disease, it makes sense to consider upfront cytoreductive nephrectomy. In these types of patients—like in our patient example—low volume extrarenal disease can potentially be slow growing and active surveillance after nephrectomy can be considered.
In patients with poor performance status, a large primary tumor, and extensive extrarenal disease, the patient should immediately begin systemic therapy and not receive nephrectomy.
What to recommend for patients with moderate extrarenal disease is more of a judgement call. We have a discussion with the patients to talk through their options. We generally recommend that patients in this category start with systemic therapy to see if there is a response, particularly now that we have impressive data from the immunotherapy combinations. This allows us to potentially shrink the size of the primary tumor prior to any surgery, and it also allows us to see whether the cancer can be controlled with systemic therapy. Then, we revisit the need for nephrectomy 6‑9 months later. For patients with a response or stable disease, nephrectomy can be considered to remove the primary tumor. If there is progressive disease by that point, the patient should not receive nephrectomy. In short, it is about patient selection for cytoreductive nephrectomy rather than having strict rules.
Going back to the 64-year-old patient case example, this patient had low volume extrarenal disease and underwent nephrectomy for pT3a clear‑cell RCC, Fuhrman grade 4, no sarcomatoid or rhabdoid features. In a patient like this, in my clinic, we will observe with periodic CT scans after surgery under active surveillance.
In this patient, 15 months postoperatively, the small pulmonary nodules were increasing in size with the largest one increasing to 1.5 cm. The patient underwent a CT‑guided biopsy, which confirmed mRCC. Laboratory values were normal and his performance status was good.
Based on this information, even though we now have biopsy‑proven disease for this patient, it is still considered indolent and is still relatively low volume, so we would have a conversation with the patient about continuing with active surveillance.
In my clinical practice, if this patient were older with comorbidities, then I would certainly counsel the patient to consider continued active surveillance. However, since this patient is 64 years of age and is an active, healthy person, I would recommend systemic therapy. Depending on individual patients’ preferences and goals for therapy, clinicians should have a conversation about continuing active surveillance even for younger patients.
Patients who have slow growing metastatic disease and low volume disease can consider deferring systemic therapy. There are patients who can benefit from active surveillance and only intervening when their disease becomes more active.
In a retrospective cohort from Duke University with 268 patients with mRCC, 22% of patients on active surveillance did not receive systemic therapy within 1 year of diagnosis, with a 5-year OS of 59%.5
Similarly, in a prospective trial of active surveillance by Rini and colleagues6 with 48 patients, the median time on surveillance was 14.9 months. This study found a median time to tumor progression of 9.4 months, with a median OS of 44.5 months.
In the prospective phase II trial by Rini and colleagues,6 enrolled patients had clinically evident mRCC of any histologic subtype with first documentation of disease up to 12 months prior. Patients were asymptomatic and had not received previous systemic therapy for metastatic disease or in the (neo)adjuvant setting. After enrollment, patients were observed and the initiation of systemic therapy was at doctor/patient discretion.
As shown here, the median observation time was 14.9 months with a median of 9.4 months to progression.6 Of the 43 patients with progression, 53% started systemic therapy and 47% continued with active surveillance for a median of an additional 15.8 months. Of the 31 patients who received systemic therapy, the median OS was 38.6 months, suggesting that active surveillance can be a powerful tool in managing patients with newly diagnosed advanced RCC.
This slide shows data from the MaRCC registry, where 504 patients (489 evaluable patients) were enrolled from up to 60 US academic and community sites and followed prospectively to define physician treatment selection of first-line therapy and reasons for treatment selection in real-world patients.7 In this study, a decision by clinicians and their patients for active surveillance was made in 143 patients (28%). Although 60% of these patients undergoing active surveillance were favorable risk, 38% were intermediate risk and 2% were poor risk.
The patients who immediately started systemic therapy had a median OS of 30 months, whereas those who went on active surveillance have not met median OS at 122 months.7
For patients with low-volume mRCC, active surveillance can be effective and powerful tool early in the disease course.7 Although the data provide an argument for active surveillance, clinical judgement of the treating oncologist is still important. The patient also has to be comfortable with observation instead of going directly to therapy. In patients for whom you may recommend active surveillance, having an in-depth discussion about the implications of each option available to them is important. Many patients will think it is counterintuitive to be diagnosed with stage IV cancer and not immediately start therapy. I stress to patients that choosing active surveillance means that we are waiting for the disease to become more active prior to treatment and not that they will never receive treatment.
For patients who are ready for systemic therapy, there are now many good treatment options for mRCC, including first‑line immunotherapy with the advent of ipilimumab plus nivolumab, pembrolizumab plus axitinib, and avelumab plus axitinib. However, there are currently no predictive biomarkers of response that are helpful for mRCC.
Again, going back to the case of the 64-year-old patient with indolent, relatively low volume mRCC, he has small pulmonary nodules increasing in size at 15 months after surgery for his primary tumor. Since this patient is 64 years of age and is an active, healthy person, I would recommend systemic therapy.
The recent phase III trials that I will highlight are CheckMate 214, which compared ipilimumab plus nivolumab vs sunitinib; KEYNOTE‑426, which compared pembrolizumab plus axitinib vs sunitinib; and the most recent phase III trial, CheckMate 9ER, which compared nivolumab plus cabozantinib vs sunitinib. All 3 of these trials had an OS benefit which led to FDA approval for first-line advanced RCC.
Other notable trials include the JAVELIN Renal 101 trial assessing avelumab plus axitinib vs sunitinib, which also led to an FDA approval.
Sunitinib was viewed as the prevailing standard of care when these trials began, and that is why it was used as the control arm for these trials.
CheckMate 214 was a randomized phase III study comparing first-line nivolumab plus ipilimumab (n = 550) to sunitinib (n = 546) in advanced RCC.8 The 48-month OS estimate was impressive, at 53.4% for nivolumab plus ipilimumab and 43.3% for sunitinib. The median OS for nivolumab plus ipilimumab has not been reached, but it is 38.4 months for sunitinib.
In KEYNOTE‑426, a remarkable 60% of patients in the pembrolizumab plus axitinib arm had an objective response, including 9% with CR and 51% with PR.9,10 An additional 23% of patients had stable disease. These response rates have never been seen for first-line treatment in the past.
Now we will shift focus to KEYNOTE‑426, a multisite, randomized phase III trial for patients with untreated advanced RCC.9 Patients were randomized 1:1 to treatment with pembrolizumab plus axitinib (n = 432) or single-agent sunitinib (n = 429).
The 24‑month OS estimate was 74% for pembrolizumab plus axitinib and 66% for sunitinib. The PFS at 24 months was also superior with pembrolizumab plus axitinib vs sunitinib (38% vs 27%, respectively).
JAVELIN Renal 101 was a randomized phase III study of 886 treatment‑naive patients with advanced RCC. Patients were treated with avelumab plus axitinib or sunitinib alone and had a median follow-up of approximately 19 months.11 In the intention-to-treat population, the median PFS for avelumab plus axitinib was 13.3 months vs 8.0 months for sunitinib alone. Median OS data are not yet mature for either arm.
The most recent phase III data we have for first-line treatment of advanced or metastatic RCC comes from the CheckMate 9ER trial.12 Patients were randomized to receive nivolumab plus cabozantinib (n = 323) or sunitinib alone (n = 328). Of importance, in this trial, nivolumab was given as a flat dose of 240 mg every 2 weeks and cabozantinib was give at a dose of 40 mg/day (as opposed to the typical dose of 60 mg/day for single‑agent cabozantinib). Sunitinib was given at the standard dose of 50 mg/day, 4 weeks on and 2 weeks off. The primary endpoint was median PFS, and secondary endpoints were OS, ORR, and safety. Patients had a median follow-up of 18.1 months.
For the primary endpoint of PFS, nivolumab plus cabozantinib was favored with a median PFS that almost doubled from 8.3 months to 16.6 months. The PFS HR showed that the risk of PD or death decreased by 49% with nivolumab plus cabozantinib and the OS HR showed that the risk of death decreased by 40% nivolumab plus cabozantinib. There was a significant response to first-line treatment with nivolumab plus cabozantinib, with an ORR of 55.7% vs 27.1% for sunitinib. PFS, OS, and response benefits with nivolumab plus cabozantinib were noted across patient subgroups (eg, IMDC risk status, PD-L1 expression level, bone metastases) in this trial.12
These data are very similar to those seen in the CheckMate214 trial with nivolumab plus ipilimumab and the KEYNOTE-426 trial with pembrolizumab plus axitinib. In January 2021, the FDA approved nivolumab plus cabozantinib as first-line treatment for patients with advanced RCC. The FDA approval included nivolumab dosing at either 240 mg every 2 weeks or 480 mg every 4 weeks in combination with cabozantinib 40 mg orally once daily.
Returning to our 64-year-old patient case example, this patient had low-volume extrarenal disease and underwent nephrectomy for pT3a clear‑cell RCC, Fuhrman grade 4, no sarcomatoid or rhabdoid features. After 15 months of active surveillance, small pulmonary nodules began increasing in size. The patient underwent a CT‑guided biopsy, which confirmed mRCC. Laboratory values were normal and his performance status was good.
Since this patient is 64 years of age and is an active, healthy person, I would recommend systemic therapy. Based on this information, this patient’s disease would be considered favorable risk, so the next question is, which of the options that we discussed would be best suited for this patient?
If we look at the CheckMate 214 data for favorable-risk patients, we see that really there is no difference in OS between nivolumab plus ipilimumab and sunitinib, whereas there is an improvement in OS for intermediate-risk and poor-risk disease.8 Furthermore, the ORR and median PFS favored sunitinib over nivolumab plus ipilimumab for favorable-risk patients.
Since this study was geared toward analysis in intermediate-risk and poor-risk patients, it was not powered to draw conclusions from the data on the favorable-risk patients. So, at this time, guidelines do not recommend ipilimumab plus nivolumab in patients with favorable risk mRCC.
Looking at the favorable-risk patients enrolled on KEYNOTE‑426, the 24‑month OS rate was similar for pembrolizumab plus axitinib and sunitinib alone.9,13 However, there was an improvement in the 24-month PFS rate favoring pembrolizumab plus axitinib (45% vs 35%, respectively). In addition, 69.6% of favorable‑risk patients receiving pembrolizumab plus axitinib had an objective response and 11.0% had a CR.
Based on these data, our 64-year-old patient with progressive mRCC started systemic therapy with axitinib plus pembrolizumab. While receiving therapy, his thyroid-stimulating hormone level increased (suggesting immune response–mediated hypothyroidism), but he otherwise tolerated treatment. Axitinib dose was increased to 7 mg twice daily and the patient developed hypertension, which is very common with axitinib and is managed by adding or adjusting antihypertensive medication as needed.
This case brings up issues around managing immune-related AEs associated with immunotherapy, along with questions on the dosing of axitinib. We will talk about immune-related AEs later, but let’s talk about axitinib dosing.
In KEYNOTE-426, axitinib was started at 5 mg orally twice daily. Patients who are otherwise healthy and fit can do well starting at this dose. However, in my clinical practice, we start patients who are older or are compromised in terms of their performance status at a lower dose, for example, 3 mg orally twice daily and work up to 5 mg twice daily as tolerated. One can increase beyond 5 mg twice daily, but one needs to be very careful about AEs. In my experience, the maximum dose that is tolerated by patients is 7 mg twice daily.
The patient in this case achieved a response to axitinib plus pembrolizumab, with regression or resolution of all lung nodules, and the plan was to continue treatment for up to 2 years.
Now, we will consider our second case. This is a 51‑year‑old man who presented with symptomatic disease: gross hematuria, weight loss, and night sweats. He underwent a radical nephrectomy and tumor thrombectomy for pT4 grade 3 clear‑cell RCC. Lymph nodes were negative and there was no evidence of metastatic disease.
At his first surveillance scan 3 months later, recurrent disease was found in the nephrectomy bed; there were new adrenal and bilobar hepatic metastases and new pulmonary nodules. Anorexia and night sweats recurred, and his bloodwork showed thrombocytosis. Based on the information we have on this patient, he has at least intermediate-risk disease based on the IMDC risk criteria. His time from initial diagnosis to need for treatment was less than 1 year, and he has a high platelet count, along with symptoms of his disease.
This patient is a candidate for therapy with either axitinib plus pembrolizumab or nivolumab plus ipilimumab, based on the current FDA approvals and information we have from the CheckMate214 and KEYNOTE-426 trials. In my practice, there are a few things I consider when selecting between these 2 treatment options for patients with intermediate-/poor-risk disease. I tend not to use nivolumab plus ipilimumab in older or unfit patients because immune‑related AEs associate with this combination can be quite detrimental to older patients, and we know that the rate of more severe immune‑related AEs requiring systemic steroids is higher with nivolumab plus ipilimumab. If patients are in their 70s or 80s, I do not use nivolumab plus ipilimumab. I would consider nivolumab plus ipilimumab for patients in their 60s, particularly if they are fit, and will certainly consider nivolumab plus ipilimumab for patients in the early 60s or younger. If you have any concerns about a patient’s ability to tolerate immune‑related AEs, then I would recommend pembrolizumab plus axitinib.
The second thing I consider is the need for a rapid response to therapy. Based on the current data, although CheckMate214 shows a potential for a durable response and long-term OS benefit with nivolumab plus ipilimumab, the data from KEYNOTE-426, suggests that pembrolizumab plus axitinib can provide a quick and potentially durable response as first-line therapy for patients with intermediate-/poor-risk RCC.
Let’s talk through the data.
Looking at the data for intermediate-/poor-risk patients enrolled on CheckMate 214, patients treated with nivolumab plus ipilimumab had a 48-month OS estimate of 50% vs 35.8% for sunitinib.8
In KEYNOTE‑426, intermediate-/poor-risk patients who received pembrolizumab plus axitinib had a 24-month OS estimate of 69% compared with 56% for those receiving sunitinib alone.9,13 These data suggest an improvement in OS for both nivolumab plus ipilimumab and pembrolizumab plus axitinib in this patient population.
Intermediate-/poor‑risk patients in CheckMate 214 had an ORR of 41.9%.8 Patients with intermediate/poor risk enrolled on KEYNOTE-426 had an ORR of 55.8% at 23 months.13,14 A small minority of patients in both trials achieved a CR, something we never really observed with single‑agent TKIs.
A looming question is whether the benefit observed from these regimens is durable. The median duration of response for nivolumab plus ipilimumab in CheckMate 214 has not been reached but was 18 months with sunitinib.15 Of importance, the duration of response curve begins to plateau for nivolumab plus ipilimumab at 24 months, whereas the curve for sunitinib continues to decline.
In the KEYNOTE-426 study, the median duration of response was 23.5 months for axitinib plus pembrolizumab and 15.9 months for sunitinib.9 The data are less mature in this trial, but by 24 months, the duration of response curve has not yet reached a plateau with pembrolizumab plus axitinib although many patients are still censored at these time points.
In the intermediate-/poor-risk cohort of patients from CheckMate 214, the PFS Kaplan-Meier curve for ipilimumab plus nivolumab had plateau by approximately 30 months. It appears that 1 in 3 patients receiving the combination immunotherapy has a relatively durable response and long-term PFS.8 There are also some patients who received single-agent sunitinib who seem to have long‑term PFS, but it is significantly less than with the immunotherapy combination.
Again, the follow-up in the KEYNOTE-426 trial is shorter, so it is difficult to determine whether PFS curves will plateau with pembrolizumab plus axitinib as was seen with nivolumab plus ipilimumab.9
This slide shows common immune‑related AEs seen with nivolumab plus ipilimumab and pembrolizumab plus axitinib.14,15 The main thing to watch for are high-grade immune‑mediated AEs that require prompt treatment.
In the intermediate-/poor-risk patient cohort from CheckMate 214, patients receiving nivolumab and ipilimumab had an improved health-related quality of life compared with sunitinib.10 This is also what we observe in everyday clinical practice.
If we look across the trials for CheckMate214 and KEYNOTE-426, the rate of immune‑related AEs of any grade was higher with nivolumab plus ipilimumab compared with axitinib plus pembrolizumab (81% vs 56%, respectively).8,9,15 In addition, 60% of patients receiving nivolumab plus ipilimumab had immune‑related AEs requiring systemic corticosteroid.
These data highlight the potential increased risk and severity of immune‑related AEs for patients receiving dual immunotherapies with a PD-(L)1 inhibitor and a CTLA-4 inhibitor compared with patients receiving a PD-(L)1/VEGF TKI combination.
Going back to our second case study, the 51-year-old patient with intermediate-risk mRCC began therapy with nivolumab plus ipilimumab and received 4 cycles of therapy, tolerated it well, and was continued on monthly nivolumab monotherapy.
Of importance, in the development of this regimen, patients initially received nivolumab every 2 weeks, but now there is a formulation for every 4 weeks to which patients can be transitioned.
Scans showed near complete resolution, but the patient unfortunately developed a seizure 8 months later and was found to have progressive central nervous system disease, leading to his death approximately 1.5 years after beginning treatment.
Given the data we discussed, how do I think about these patients? For favorable-risk patients who are candidates for combination immunotherapy, they should receive pembrolizumab plus axitinib. For patients with intermediate-/poor-risk disease, it is a bit more involved. Pembrolizumab plus axitinib is favored for patients who need to avoid immune-related AEs and for patients needing a rapid response.
To avoid chronic VEGF AEs or if there is a contraindication to a TKI, consider ipilimumab plus nivolumab—but only in patients with intermediate-/poor-risk disease. As I discussed earlier, the data do not support using this combination in favorable-risk patients.
Cytoreductive nephrectomy is still an option, as is active surveillance in selected patients with low-volume, indolent mRCC.
There are several exciting phase III trials that you should be aware of. We already mentioned CheckMate 9ER with nivolumab plus cabozantinib, which was recently FDA approved. In the first-line setting, there are also 2 other trials to keep in mind. The first is CLEAR, comparing lenvatinib plus pembrolizumab vs lenvatinib plus everolimus vs sunitinib.16 The other, COSMIC-313, is assessing cabozantinib plus nivolumab plus ipilimumab vs nivolumab plus ipilimumab.17
Although there is FDA approval for sunitinib in the adjuvant setting after resection of high‑risk localized RCC, there have been negative trials in this space using other oral TKI agents. It is unclear whether immunotherapy will have an additional benefit in the adjuvant setting, but 2 interesting trials in the adjuvant setting are underway: KEYNOTE-564 testing pembrolizumab vs placebo and CheckMate 914 using nivolumab plus ipilimumab vs placebo.18,19
With all of the recent approvals, we now have many treatment options for mRCC, which raises the question about sequencing of therapy.
Before the introduction of immunotherapy for mRCC, there were fewer choices for how to sequence therapy since only VEGF TKIs and mTOR inhibitors were available.
As I mentioned earlier, drug development for advanced RCC has been rapid. We had the first approval of immunotherapy for mRCC in 2015, with the approval of single‑agent nivolumab as a second-line therapy. In 2018, nivolumab plus ipilimumab was approved for first line. Pembrolizumab plus axitinib and avelumab plus axitinib were approved in 2019. In addition to the introduction of immunotherapy for mRCC, we have also had approval for 2 new TKIs: single-agent cabozantinib and lenvatinib in combination with everolimus.
Current approvals for mRCC include:
There are a few other available agents, including sorafenib, bevacizumab plus interferon, temsirolimus, and IL-2, but these agents are not typically used in clinical practice at this time.
This slide highlights the treatment options for second-line therapy and beyond. There are currently no good data on sequencing after immunotherapy, so I typically go from immunotherapy to a single‑agent TKI like cabozantinib.
Although the approved dosing for cabozantinib is 60 mg/day, in my experience, many patients do not tolerate this dose well. Whereas I do consider starting patients who are young and otherwise healthy on 60-mg cabozantinib, I typically begin cabozantinib dosing at 40 mg, and if the patient tolerates that dose well, I will increase the dose to 60 mg.
Because there are multiple new agents and combinations, sequencing has become much more complex. In some ways, there are no right or wrong answers to sequencing these therapies beyond first-line therapy. The gold standard now is if patients are fit enough to tolerate combination treatment, they should start first-line therapy with a combination immunotherapy and then consider options for sequencing thereafter.
We will learn more about sequencing in the years to come, but my practice generally is to mix up mechanisms of action sequentially—switch to a TKI for patients who receive immunotherapy and vice versa— because you can always go back to immunotherapy in third line and beyond.
This slide shows a number of historical trials for second‑line treatment of mRCC. The initial second‑line data came from the use of everolimus and axitinib as single agents.20-23 The improvement in outcomes was negligible, but they received FDA approval because there was nothing else with good second‑line data. Then cabozantinib, nivolumab, and combination lenvatinib plus everolimus were approved in previously treated patients.24-27
As I mentioned before, we do not have a lot of data around sequencing immunotherapy after first‑line immunotherapy. However, there is an interesting study of lenvatinib plus pembrolizumab after progression on previous immunotherapy.28 In the KEYNOTE-146/Study 111 open-label phase II trial, 104 patients were enrolled who had mRCC and had received at least 1 line of therapy, including PD after an anti–PD-(L)1 therapy. The primary endpoint was ORR at 24 weeks, and secondary endpoints were ORR, PFS, duration of response, and safety.
All patients had previous therapy with an anti–PD-(L)1 therapy either in combination or as monotherapy, 65% received previous therapy with an anti–PD-(L)1 therapy and anti-VEGF in combination or sequentially, and 37% received previous therapy with nivolumab plus ipilimumab.
What was interesting about KEYNOTE-146/Study 111 is that patients had objective responses even after previous immunotherapy.28 No CRs were observed, but 47% up to 59% of the patients had a PR, depending on previous therapy. The median duration of response was not yet reached for patients who had previous nivolumab plus ipilimumab, but for the other regimens it ranged from 9‑12 months.
Many patients receiving lenvatinib plus pembrolizumab had an impressive reduction in tumor size.28
Looking at the change in tumor size in patients who received prior anti‑VEGF therapy, there were again impressive reductions in tumor size.28
Even patients who received previous immunotherapy had a decrease in tumor size.28 Although we do not have robust data around sequencing particular immunotherapy-based treatment regimens, these data show that there is efficacy in using immunotherapy as part of treatment sequencing strategies—even if a patient received immunotherapy previously.
There are several considerations in selecting next-line treatment. It is important to use your own clinical judgement and the characteristics of the patient, but keep in mind their response to first-line agents.
In patients whose disease was controlled for at least 1 year with single-agent VEGF inhibitors, consider sequential VEGF inhibition with agents such as cabozantinib or axitinib. For patients with only a brief response to a single-agent VEGF inhibitor, consider a combination of VEGF and immunotherapy, such as axitinib and pembrolizumab. If there was no response to first-line single agent VEGF inhibition, consider switching to an immunotherapy combination with ipilimumab plus nivolumab or use nivolumab as a single agent.
For patients who have received combination of VEGF and immunotherapy but do not respond, consider switching to second-line VEGF, such as cabozantinib, or to lenvatinib plus everolimus.
As mentioned previously, any treatment with immunotherapy-based therapy may result in unique immune-related AEs that are not experienced with targeted therapy. It is important to obtain a detailed clinical history of each patient before he or she begins any treatment course to be able to monitor and detect any AEs early.29-31 These immune-related AEs can occur regardless of the type of tumor that is being treated. Therefore, there is a large body of work on how to manage these AEs to allow patients to stay on therapy for as long as possible to optimize clinical benefit.
This slide is a reminder about immune‑related AEs and their frequency.29,32 CTLA-4 has significant skin toxicity and GI toxicity, so those are important AEs to keep in mind, especially with the combination of ipilimumab plus nivolumab.
There are multiple resources available for managing immune-related AEs. In general, supportive care is important for managing mild (grade 1) irAEs.33 In patients with grade 2 or mild irAEs, immunotherapy should be held and low-dose corticosteroids may be necessary to mitigate the symptoms. For patients with grade ≥ 3 or severe immune-related AEs, immunotherapy should be held or discontinued depending on the severity of the AE, and high-dose corticosteroids with close monitoring (or inpatient care) may be necessary to mitigate the symptoms.
If symptoms resolve after steroids are introduced, the steroid dose can be slowly tapered down and discontinued after approximately 1 month.
If the AEs do not resolve with corticosteroids, consider adding other agents such as infliximab or mycophenolate mofetil, depending on the organ system affected. In this case, it is also important to involve subspecialist colleagues of the affected organ system.
Returning to the second patient case, we had a patient who began therapy with nivolumab plus ipilimumab, and at follow-up, repeat imaging showed a reduction in his metastatic burden. He returns to clinic for his third cycle of therapy and is now complaining of increased bowel movements. Typically 1-2 per day, he now experiences up to 6 loose bowel movements each day with mild cramping and urgency, although there is no blood in his stool. He has not traveled recently and has no sick contacts. Laboratory testing shows he is negative for Clostridium difficile toxin and ova and parasites.
Based on this information, he is experiencing grade 2 diarrhea or colitis. Most guidelines, including the NCCN Guidelines for Managing Immune Checkpoint Inhibitor–Related Toxicities, available as an online interactive tool here, suggest holding immunotherapy at this point and beginning treatment with prednisone/methylprednisolone at a dose of 1-2 mg/kg/day. Corticosteroid can be tapered down over a period of 4-6 weeks if the diarrhea improves to grade ≤ 1. After grade 2/3 colitis, clinicians can consider resuming the PD-(L)1 therapy after symptoms have resolved to grade ≤ 1 and, in this setting, consideration can be given to resume the CTLA-4 therapy based on clinical judgement.
As we have discussed, treatment options for patients with advanced RCC are continuing to expand as we understand more about how to use both VEGF TKI therapy and immunotherapy to control disease progression in our patients with mRCC. We now have multiple impressive first-line options for our patients with advanced RCC, including combination immunotherapy and combination TKI plus immunotherapy.
It will be exciting to learn more about how to sequence available therapies and how to incorporate additional new agents into the treatment paradigm for advanced RCC as additional clinical trials continue to read out over the coming years.
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