Targeted Oncology

UT Health San Antonio MD Anderson Cancer Center

: What were the results of the COMFORT I (NCT00952289) and COMFORT II (NCT00934544) studies of ruxolitinib (Jakafi)?

 The COMFORT studies are a decade old in data, but they compared ruxolitinib with placebo or best alternative therapy.

[Ruxolitinib was] unequivocally effective for helping to improve splenomegaly and symptoms in in the majority of the patients.

 There’s about half that met the formal response criteria, but it’s pretty much a continuous variable. Almost all patients’ spleens shrink to some degree. We found over time, if that’s over 10%, they probably have both symptomatic benefit and a survival benefit.

And there was the [COMFORT II study of] ruxolitinib compared with best alternative therapy. So, it was much better than hydroxyurea or other options that physicians could use.

Symptomatically, patients felt quite a bit better.

 Having had been involved with 20 to 30 trials before ruxolitinib, it was striking to see what the difference was. Patients felt much better in a much shorter amount of time, and it helped not only 1 symptom but multiple types of symptoms.

There was a difference compared with best alternative therapy [including hydroxyurea].

What are the overall survival (OS) outcomes for patients who received ruxolitinib for myelofibrosis?

One of the things we’ve found over time is that patients live longer.

 The study was not a survival study; it would have been impractical to do so. But, caring for many of these patients, there’s no question that they’re living longer. It’s not a cure, and there’s no plateau on the [Kaplan-Meier] OS curve, although there are some long-term survivors. I’ve had some patients that have been on [ruxolitinib] since 2007, and these are individuals that we would have expected an OS of just 2 to 3 years. That’s the exception, but there are some extremely long-term survivors.

Now, why did they live longer? It’s probably a range of [factors]. It may be less risk of progression, less inflammation in the bone marrow that’s conducive to additional mutations developing, and less debilitation.

How is spleen response related to survival outcomes?

We have found that survival is probably tied to some degree with the quality of their response, and that having a spleen response matters.

 I don’t think that this is telling us that just because the spleen shrinks, patients live longer. I think that this is kind of a biomarker, if you would, of a response to a Janus kinase (JAK) inhibitor. If they respond, then they’re likely to live longer, and that corresponds to a smaller spleen, but I don’t think that they live longer solely because of the improvement in the spleen.

We have learned over time that dose matters, and that lower doses of ruxolitinib help a bit with symptoms, but are probably inadequate for giving this improvement in survival phenomenon.

What does the phase 1b EXPAND study (NCT01317875) show about patients with low platelet counts?

Over time, we have learned that if patients have lower platelet counts, it can be overcome by starting at a low dose and then increasing the dose. I see sometimes in the patients that I see, is that patients went down to a low dose, or started on a low dose because their platelets were low, but the dose has not been subsequently increased. So, they started on 5 mg twice a day, they feel a little bit better, the spleen’s a little bit smaller, and they remain on that dose. This study helped to show that you can increase the dose, and by increasing the dose it may make an impact in terms of their outcome.

Were serious adverse events observed in the EXPAND study?

With low platelet counts—again, the rate of AEs was not problematic. If platelets counts are low, they’re going to drop a little bit further, but what we don’t see really are risks, any significant risk of hemorrhage or things that really would be a true outcome in terms of the lower counts.

Do you recommend increasing the dose if the patient’s platelet count is under 50,000/μL?

Yes, but after time. So, I find that if they’ve been on the dose for about 8 weeks or so, and the counts are holding OK, if you increase the dose further their platelets won’t typically [continue] to go down. The phenomenon is that they tend to drop at first, but then afterwards they don’t continue to drop in a dose-dependent fashion.

So, I’ve had some patients with an aggressive disease, where I have them on ruxolitinib and azacitidine [Vidaza] for acute leukemia and myelofibrosis. I may try to push the dose in terms of how they’re doing, and quality of life, and sometimes I can push that if their platelets are [30,000/μL to 35,000/μL], and the platelets won’t necessarily continue to go down. What they were able to see is that the response rates, even in these lower platelet groups, were pretty good by being able to push the dose.

1. Verstovsek S, Mesa RA, Gotlib J, et al. A double-blind, placebo-controlled trial of ruxolitinib for myelofibrosis. 

2012;366(9):799-807. doi:10.1056/ NEJMoa1110557

2. Harrison C, Kiladjian JJ, Al-Ali HK, Gisslinger H, et al. JAK inhibition with ruxolitinib versus best available therapy for myelofibrosis. 

2012;366(9):787-98. doi:10.1056/NEJMoa1110556

3. Verstovsek S, Gotlib J, Mesa RA, et al. Long-term survival in patients treated with ruxolitinib for myelofibrosis: COMFORT-I and -II pooled analyses. 

2017;10(1):156. doi:10.1186/s13045-017-0527-7

4. Palandri F, Palumbo GA, Bonifacio M, et al. Durability of spleen response affects the outcome of ruxolitinib-treated patients with myelofibrosis: Results from a multicentre study on 284 patients. 

 2018;74:86-88. doi:10.1016/j.leukres.2018.10.001

5. Palandri F, Palumbo GA, Bonifacio M, et al. Baseline factors associated with response to ruxolitinib: an independent study on 408 patients with myelofibrosis. 

. 2017;8(45):79073-79086. Published 2017 Jun 27. doi:10.18632/oncotarget.18674

6. Menghrajani K, Boonstra PS, Mercer JA, et al. Predictive models for splenic response to JAK-inhibitor therapy in patients with myelofibrosis. 

. 2019;60(4):1036-1042. doi:10.1080/10428194.2018.1509315

7. Vannucchi AM, Te Boekhorst PAW, Harrison CN, et al. EXPAND, a dose-finding study of ruxolitinib in patients with myelofibrosis and low platelet counts: 48-week follow-up analysis. 

. 2019;104(5):947-954. doi:10.3324/haematol.2018.204602

8. Guglielmelli P, Kiladjian J, Vannucchi AM, et al. The final analysis of EXPAND: a phase 1b, open-label, dose-finding study of ruxolitinib (RUX) in patients (pts) with myelofibrosis (MF) and low platelet (plt) count (50 × 109/L to < 100 × 109/L) at baseline. 

. 2020;136(suppl 1):4-5. doi:10.1182/blood-2020-137742

Articles

During a live virtual event, Ruben Mesa, MD, discussed the clinical trials and challenges of using ruxolitinib for patients with myelofibrosis. 

Part 2: Maximizing Efficacy and Survival With Ruxolitinib for Myelofibrosis

I would strongly consider sacituzumab [Trodelvy], because [the patient is failing treatment] in less than 12 months from active chemotherapy.

I agree with sacituzumab in this setting, as she had early progression within less than 12 months, and she qualifies for its labeled indication.

[In my opinion], unfortunately, this patient is not curable. I think sacituzumab is still [the correct choice to me] and she has got a good performance status. Capecitabine is also a great drug choice.

I love the idea of capecitabine, but I’m also thinking this patient might do potentially better with eribulin [Halaven], because that in a clinical trial, I thought, performed better than capecitabine.

 I could potentially use capecitabine at a time when the patient is a little bit more beat up and looking for something that was a little easier to go with, but I totally love the idea of capecitabine. I’d have to have a good conversation with the patient that that might not, survival-wise, be the best bet, potentially.

What do you think the response rate to capecitabine in this setting would be?

This is a patient who obviously has a very poor prognosis, and who relapses so quickly after dose-dense [chemotherapy treatment]. I think it is unlikely that she would have a response, but the issue with what we do is that we don’t have good markers of who is going to respond to which therapy, and I think we all recognize that that’s where we’re trying to get to. However, I think she probably has a small chance of responding to capecitabine, but I understand the rationale that people are using for this, and sacituzumab is currently approved after 2 prior lines of chemotherapy, including 1 in the adjuvant setting.

I think we’ve all had experiences where we might have requested that drug and been able to get it. I think that there were some good points brought up about eribulin, but the question now is how we would sequence things, and I think one of the things that I always think of with our metastatic patients is we need to think about sequencing, but we’re typically not. But I think people had a good rationale for the various approaches. I think that personally, I would have tried to put her on a clinical trial, because obviously, she doesn’t have very chemotherapy-sensitive disease. We recognize that we don’t have trials available for these people, so we don’t always have that as an option, but in terms of other things, I probably would have leaned more toward sacituzumab or eribulin, but I think capecitabine is a very reasonable choice in her as well.

For those of you who chose combination chemotherapy, what were you thinking of in this patient? And let’s turn it back to [when] after 8 months, she progressed, as opposed to now. What combinations are people thinking about?

Well, I didn’t choose that, but the immediate thing is to try to grab for a platinum therapy, right? So carboplatin [in my opinion].

We didn’t have a chance to talk about that there, but the concept, you’re using carboplatin for TNBC.

Or that in fact that she did have paclitaxel, and try to use nanoparticle paclitaxel.

What would your front-line treatment have been between 8 months and 24 months for relapse?

I would probably be keener to use chemotherapy here on a patient that had that 2-year gap between her adjuvant therapy and a relapse. I would probably go toward something like eribulin.

It depends on [the patient’s] goals, and it sounds like she’s active, good performance status, young, and probably, I presume, wants to be very active, so oftentimes, for those patients, I go with oral capecitabine to give them the most latitude for their activities, and to be able to titrate the tolerability. I do restage relatively soon after starting, just to make sure I’m on the right track, because my other go-to for single agent is eribulin. I’ve had a good experience with that, but it does tie patients up, and does have greater intolerability compared with capecitabine.

So let’s think about the patient with rapid recurrence, and the question about why you made these decisions and at this point, [have chosen sacituzumab govitecan]. What is it that’s guiding this recommendation for you?

[The patient in this case] has progressed quite oddly after the initial therapy of 8 months. She has, I would say, an overall poor prognosis. If the clinical trial is not available, I think I will probably go with a combination of carboplatin/gemcitabine, because she had not received carboplatin/platinum and gemcitabine, so that would be 

one option. That could be considered a single-agent treatment, but I will probably go with the doublet to start with and see how she responds, and sacituzumab, I will probably do later.

This is a patient who we chose to give that combination chemotherapy to on her first line as she progressed after 8 months, and now you’re choosing the second-line therapy, and for this question, most of you chose sacituzumab, and about one-fifth of you chose clinical trial or other.

I picked sacituzumab because my thinking was, she is going to have adverse effects [AEs] from other microtubule inhibitors. She may not be able to go through another agent that can worsen neuropathy, so [I would still pick] sacituzumab, I thought I will have a better chance of getting a better response rate, and still maintaining her quality of life.

For example, we don’t know which treatment is the best option, so we try to figure out which would cause less AEs, and not compromise the patient’s quality of life. Other than that, whatever you decide, we have been talking, is just absolutely a personal decision, not based on any clinical trials. That’s my feeling because we don’t know which treatment is the best. There’s no right and wrong answer here, so that’s why I choose sacituzumab. But really, if you ask me, is this the best option for the patient? Well, if you consider AEs it is a good option.…Again, the patient is not curable, so we need to go to sequential therapy and minimize complications from the chemotherapy, but if I knew that one is better than the other, then which is for the best, but we don’t know.

Does anybody else have thoughts or comments about that, or how they made their choice here?

I picked sacituzumab in this situation because my memory of the clinical trial was that sacituzumab was being compared with physician’s choice of single-agent chemotherapy and won out on both progression-free survival [PFS] and overall survival [OS], so we do have a little bit of a hint as to, at least for single-agent chemotherapy, sacituzumab beat out what the physicians chose. I mean, that’s kind of a real-world study in some ways.

Use your best option if you don’t choose sacituzumab, and there was an OS advantage of something like 12 months vs about 7 months. I don’t know how many people in the physician’s choice arm then might have been able to go on to get sacituzumab second line, further line, so it was a question of early vs late, but at least we do have a hint, if you didn’t have that option, that sacituzumab was going to win out. So again, what I would have done otherwise, which again, probably would have been eribulin.

I know there has just been a rush of different drugs out there, and lots of different trials, but there is the ASCENT trial [NCT02574455] that did look at that and found what you said, and my guess is that most patients didn’t go on to get sacituzumab, because it wasn’t available.

 These patients tend to progress quite quickly, so it’s fairly unlikely that they did, although some might have gotten it subsequently after its approval.

Do people want to talk about what they think is the ideal sequence of drugs for a patient who [we have stratified based] on their PD-L1 status? We have one sort of algorithm that we go down if they are PD-L1 positive, and a different one if they are PD-L1 negative. So for PD-L1–negative [patients in the first line] it sounded like people are using a variety of different choices, including eribulin, capecitabine, some carboplatin, and then in the second line, it looked like, from the poll, that many people were choosing sacituzumab. However, for a patient who had had disease progression, her original disease-free interval was longer and there was more variability. Do people have a set algorithm [to look at their PD-L1 status]?

It’s quite individualized to me, for example, if somebody has a large tumor burden, I’d probably try the doublet like you did, carboplatin, the gemcitabine, first-time palliative chemotherapy. After that, I’m not sure the doublet is going to offer any benefits. I will try the single agent, but if the patient has a quick progressive disease, I will probably avoid the capecitabine or the pill form. I’d try the IV drug, and I’d try to switch to sort of a fundamentally different mechanism of action, like sacituzumab, rather than something else. That’s my sort of philosophy.

Does anyone feel differently? Is there any place where you would all put 1 drug? Like, there’s variability, but is your second-line choice always this, or is there anything, or most often, there’s never always in medicine, and I always tell the medical students and residents that there’s no always and nevers in medicine. However, your general go-to in the first line or second line or third line, but variability in some of the other lines, anything that people are thinking about that, and what drives that choice, if that’s what they’re doing?

One of the items is, as somebody mentioned, the disease burden and how aggressive the patient wants to be. I think that the carboplatin/gemcitabine combo is very active, and it does have a higher response rate in my experience, but also more toxicity. You can have very motivated patients who want to have the most aggressive chemotherapy approach, because not only do they have large disease burden, but they do feel that they want to be as aggressive as possible. So that gives you that option, but there are other patients who don’t want as much toxicity, so more customized chemotherapy gives them more flexibility for their lifestyle, and if they haven’t had capecitabine before, then that’s an option.

There are a lot of triple-negative patients who get capecitabine because they got neoadjuvant therapy and then had a partial response, so it’s always a matter of, I think, disease burden is a factor, too, to choosing therapy, and that’s always a consideration.

I was happy about it. I think the earlier you use it, it gives more patients an opportunity to benefit from it, and I think it may eventually be a first-line option, though it isn’t currently approved for that. So I was wondering, do we know what the response rate or PFS is when you use it first line vs second vs third?

I think maybe we’ll get some forest plots coming along that will show, I think, one of the breakdowns, so we can look at that in a second. But if I’m interpreting right, Mayer, what you were also interested in, or what was good about this, was that it was approved earlier on than the conditional approval. It allowed you to give it after just 1 line of therapy, and that was something that you found appealing. Is that right?

I mean, we all know that with each line of therapy, people fall off, and they never get a chance to be exposed to a drug, so the earlier you can give it, potentially the more people can benefit.

It opens more opportunities for the patients to receive this if it is approved in the first-line metastatic setting.…I thought it was…he could use it in the first line, if you had progressed within 6 months to a year after adjuvant, that could be counted as 1 line of treatment, but as the previous colleague has mentioned, of patients from each line of treatment, so the sooner you get it the better it is, given that it has beaten out the standard of care or physician’s choice treatments.

1. Pivot X, Im SA, Guo M, Marmé F. Subgroup analysis of patients with HER2- negative metastatic breast cancer in the second-line setting from a phase 3, open-label, randomized study of eribulin mesilate versus capecitabine. 

. 2018;25(3):370-374. doi:10.1007/s12282-017-0826-4

2. FDA grants regular approval to sacituzumab govitecan for triple-negative breast cancer. FDA. April 8, 2021. Accessed February 17, 2022. https:// bit.ly/3sJiloq

3. Bardia A, Hurvitz SA, Tolaney SM, et al. Sacituzumab govitecan in metastatic triple-negative breast cancer. N Engl J Med. 2021 Apr 22;384(16):1529- 1541. doi:10.1056/NEJMoa2028485

During a Targeted Oncology case-based roundtable event, Claudine Isaacs, MD, discussed treatment options for a patient with triple-negative breast cancer whose condition worsened after first-line gemcitabine plus carboplatin.

Roundtable Discussion: Isaacs Discusses Second- and Third-Line Therapy for Patients with TNBC

A 51-year-old man presented with pallor and worsening fatigue on exertion. His liver and heart function were adequate. A PET/CT scan showed lytic lesions in his ribs and L3 with no increased standard uptake. His ECOG performance score was 1. He received a diagnosis of standard-risk stage II multiple myeloma.

Laboratory results showed a hemoglobin level of 9.2 g/dL, urea nitrogen to creatinine ratio, lactate dehydrogenase, and calcium were within normal limits. The serum β

-microglobulin level was 4.1 mg/L, serum albumin: 3.2 mg/dL, serum M-protein: 1.5 g/dL, λ free light chains: 110 mg/dL. A bone marrow biopsy showed 66% plasma cells. Fluorescence in situ hybridization showed deletion 13q.Urine protein electrophoresis showed a M spike of 400 mg of λ free light chains in 24 hours. An immunoglobin test was positive in urine and serum free light chains.

How do you discuss prognosis with your patients in the modern era?

Who is eligible for transplants in general?

Do you look at the age, fitness, frailty, and performance status of patients?

How much and which organ function do you care about?

Is it important to rule out concomitant cardiac amyloidosis and ask about patients’ preferences?

 I’m a hematologist-oncologist in the Minneapolis area. I work for the University of Minnesota health system in general practice as part of a bigger group. So I see all kind of patients, including [those with multiple] myeloma. The prognosis of multiple myeloma has been improving since I finished my fellowship in 2004.

There are a lot of new drugs, and I tell patients about what I did during my fellowship when we would use VAd [vincristine, doxorubicin, dexamethasone] and others. Now we have so many agents and the prognosis keeps improving. I don’t give them a timeline but often tell them [the survival rate] exceeds 10 years and probably will continue to improve.

Obviously, we all use our training to decide [whether a patient is frail] and…the transplant center dictates what the transplant eligibility is. Over the years I’ve [come to know] what Mayo Clinic or the University of Minnesota prefer.

 Are there any age cutoffs, for example, in your clinic that discourage you from even thinking about referring a patient to any transplant center?

 Usually, for almost everybody [older than] 75 years, I will discuss if I think they are eligible, but I can pretty much say they are not a transplant candidate. But for those [younger than] 75 years, I will discuss at least taking an evaluation.

Fair enough. Those were very good points. I am also a transplant physician at my center and absolutely agree. One of the main points that I try to discuss with patients as well as colleagues is that there’s no rigidly set age cutoff.

I have transplanted patients who were [older than] 75 years, and some of the centers have transplanted patients even older than that. So we look at the so-called physiologic age rather than chronologic age, and if patients are very fit with excellent baseline organ functions and are interested in autologous stem cell transplant [ASCT] for their myeloma or AL [amyloid light-chain] amyloidosis, in particular, there’s perhaps a bigger margin of benefit with the ASCT. Certainly, we have done that and we [consult with colleagues in geriatrics] and use some of the scoring tools for transplant risk stratification in trying to understand if we can identify patients at risk of complications.

 I am from the Medical College of Wisconsin [in Milwaukee]. I was surprised when I [received a referral today for] a 97-year-old patient for transplant. This is the oldest patient who’s been referred to me. We are well-known in the community, and we get referred all the time for patients who are in their early to mid-70s.

I don’t have a cutoff age in my mind, but I’m not really excited about taking someone who’s 80 [years or older] to transplant unless they have high-risk disease based on their cytogenetics or extramedullary disease. For the patient I saw today, I declined transplant.

 I have had a couple of referral [patients] in their 90s. None of them were for transplant, but for how to manage their disease. The center where I trained is where I saw some of these upper cutoff age groups being transplanted, but, truth be told, these were individuals who were running marathons and looked younger than their age. I agree with you, especially if they have high-risk disease. Those are very well-made points.

ASCO [American Society of Clinical Oncology] has general criteria for assessing ASCT eligibility.

 They recommend that patients should be referred to a transplant center to determine transplant eligibility and chronologic age, and [they state that] renal function should not be the sole criteria used to determine ASCT eligibility.

Many of us have transplanted patients on dialysis and, quite frankly, even patients with congestive heart failure who are NYHA [New York Heart Association] class I or II. [Patients who are] stable and controlled on medical management have also been successfully transplanted.

1. Mikhael J, Ismaila N, Cheung MC, et al. Treatment of multiple myeloma: ASCO and CCO joint clinical practice guideline. J Clin Oncol. 2019;37(14):1228-1263. doi:10.1200/JCO.18.02096

During a live virtual event, Muhamed Baljevic, MD, discussed what factors determine whether a patient with stage II multiple myeloma could receive autologous stem cell transplant. 

Part 1: Assessing Transplant Eligibility Following Treatment for Multiple Myeloma

 The RCC [renal cell carminoma] treatment space has rapidly evolved over the last 5 to 10 years. We have multiple regimens that are FDA approved, broadly falling into 1 of 3 categories of drugs: immune checkpoint inhibitors, multitargeted tyrosine kinase inhibitors, and mTOR inhibitors. Historically, we had always used this as monotherapy but more recently we’ve seen the transition to using combination therapy with improved outcomes. What I do expect to see going forward is that we’ll probably become a lot more adept at using these combinations together.

One thing that remains an active question is, what’s the optimal to sequence these patients? The other question is, how do these drugs interact with one another? Is there is some temporal relationship between the 2 medications or the combinations that should be used? Those are studies that probably do need to be done. The other thing is related to monoclonal agents. Most recently, there was the FDA approval of belzutifan, which is an HIF2 inhibitor for patients with VHL [von Hippel–Lindau]disease. As you all know, clear cell kidney cancer has high rates of mutation and loss of VHL, so belzutifan is another drug that may become very interesting for us to understand whether there’s a role for HIF2-directed therapy.

Historically speaking, kidney cancer is also been a malignancy of altered metabolism. Although telaglenastat, which was recently studied in a large randomized phase 3 trial, did not show improved efficacy when using combination with cabozantinib over cabozantinib alone. That doesn’t necessarily mean that there’s not a wolf we’re looking at, metabolic inhibitors in the future. Whether it’s a drug with telaglenastat in a more selected population or if it’s other metabolic inhibitors, it remains to be seen.

Also, when we think about immunotherapies, there are multiple immune checkpoint inhibitors or immune checkpoints available. Targets such as LAG3 and TIM3 and agonists like LT4 all play a significant role in altering immune responses. As we better understand the biology and the attraction of the medications, that will do a lot more in terms of tailoring the specific treatments to the disease state of the patients.

Videos

Next steps investigating novel-based therapies for newly diagnosed metastatic renal cell carcinoma.

Tailoring Therapy for Patients With mRCC

 Nurses play a crucial role in the management of patients with advanced RCC [renal cell carcinoma]. They help connect patients to certain resources, such as social work, nutrition, and sometimes even psychiatry. What’s important for the community of oncology nurses managing patients with advanced renal cell carcinoma is to do a thorough assessment on patients with these treatment regimens, specifically lenvatinib-pembrolizumab, because we’ve seen that these adverse events can affect a patient’s quality of life significantly. It’s very important to fine-tune assessments so that these adverse events are caught in advance, so treatment regimens may not necessarily need to be interrupted or discontinued but rather may just need some modifications.

Patients often express their concerns to the nurses. There’s some hesitance from patients to open up to their physicians because they may be afraid that their treatment may be held or stopped. Establishing a good rapport with your patients. Let them know that if they experience any adverse events, have questions, or feel that something isn’t right, they should reach out. Enforcing good communication with the clinical oncology team and the nurse, and having those open discussions related to adverse events, is really important.

That being said, oncology nurses are also very important in managing patients who have advanced renal cell carcinoma because they’re managing the disease but also helping patients cope with the disease itself. Have referrals placed to support groups, to other communities and community groups that are available to patients, so that they feel that they’re being managed not just for physical symptoms but also for mental health issues that may come up.

The role of the oncology nurses is multifactorial. We are the front line in managing patients because they come to us first with their questions, concerns, and adverse events. We help guide the next steps in conjunction with the physician. It’s very important to have a good rapport and an open patient relationship and to let them know that we’re here for them. We want them to continue this treatment regimen and, of course, have a good quality of life.

Advice to oncology nurses who manage patients with metastatic renal cell carcinoma receiving novel-based therapies, including lenvatinib and pembrolizumab.

mRCC: Role of Oncology Nurses in Managing I/O–TKI Adverse Events

Since the initial presentation of the CLEAR study at ASCO GU [American Society of Clinical Oncology Genitourinary Cancers Symposium] 2021, there have been several subgroup analyses to further understand the regimen. At ASCO GU, looking at the quality-of-life data that were absent from the original CLEAR study, the authors noted that the quality of life on lenvatinib plus pembrolizumab was fairly similar to what was seen with sunitinib. This has waged some of the initial concerns about the absence of the data at the initial presentation. It also fills in some of the knowledge gaps and counters some of the reputation that lenvatinib is a relatively difficult regimen, which it gained during the earlier phase 2 study of lenvatinib plus everolimus. It was reassuring for us to see that when people were treated on lenvatinib plus pembrolizumab, the quality of life was quite similar to sunitinib in that phase 3 study.

Furthermore, there was also a separate analysis looking at depth of response and overall survival. What the authors had seen is that the depth of response did correlate with improved overall survival, meaning people who had deeper responses overall did better. For patients who were treated on the CLEAR study on the sunitinib arm, now that we’ve gone further out, it remains a matter of debate on what they would be necessarily receiving next. A lot of that depends on access to drugs. For patients who are on single-agent TKIs [tyrosine kinase inhibitors], there’s broad access to immune checkpoint inhibitors. Immune checkpoint inhibitors, either as monotherapy or combination, would be very appropriate next choices. However, in certain countries, in which immune checkpoint inhibitors are not yet available, a lot of those patients would be receiving secondary TKIs.

An overview of data demonstrated by other investigational studies of lenvatinib plus pembrolizumab as frontline therapy for metastatic renal cell carcinoma.