Targeted Oncology Staff

Case Based Peer Perspectives event, Neeraj Agarwal, MD, professor of Medicine, Presidential Endowed Chair of Cancer Research, director, Genitourinary Oncology Program, director, Center of Investigational Therapeutics, co-Leader, Experimental Therapeutic Program at Huntsman Cancer Institute, University of Utah in Salt Lake City, UT, discussed the case of a 57-year-old male patient with nonmetastatic castration resistant prostate cancer.

: Is there a role for germline testing in this patient who has a sister and mother with breast cancer and a brother with pancreatic cancer?

 Personally, I think this is a pretty slam dunk case. The answer is yes. We send these patients to a high-risk genetics clinic.

Would you suggest doing a fluciclovine (Axumin) or prostate-specific membrane antigen (PSMA) PET scan?

In this case, I personally would have done a PSMA or Axumin scan to see if there [was] any local site of disease which can be radiated. My radiation oncology colleagues are very supportive of this approach. But in this case, let’s assume that all these scans were either not done or they were negative.

Is there a role for germline testing in this patient who has a sister and mother with breast cancer and a brother with pancreatic cancer?

PSA is rising in this patient. Would you continue ADT as a monotherapy?

Yes, I would continue, but the question is would you just continue as monotherapy [or do something else]?

Most [responders] said they’d go for a novel hormonal therapy. Somebody said second-generation antiandrogen, which I think is a very reasonable answer.

I think, because PSA’s doubling time is 9 months, it qualifies [for] the eligibility criteria of all these drugs—[with a] PSA doubling time of 10 months or less. But really, what is the real PSA doubling time of the patients who went on the trial? That would be interesting to see. It’s hard to remember what the PSA doubling time of those patients actually was, even though you may have read the 

What are the treatment options available to this patient in terms of antiandrogens to add to ADT?

Enzalutamide [Xtandi] has the highest rate of central nervous system [CNS] penetration among these agents. Apalutamide [Erleada] has less CNS penetration.I think darolutamide [Nubeqa] is best from that perspective. That also translates [into fewer] CNS [adverse] effects with darolutamide, in my view. Does it affect the efficacy of darolutamide? I do not know. There has not been a head-to-head comparison of these agents. But it was given out up front that patients had seizures. So, enzalutamide and apalutamide are out [for this patient], in my view.

Again, there is no real contraindication. Yes, a patient had seizures, but sometimes seizure history is not that confirmatory. This patient was on a medication for seizures, so I would avoid enzalutamide in this case.

Abiraterone [Zytiga] is…not really a category 1 indication, and I would hesitate about using steroids for so long in a young man. So I think darolutamide would be my choice.


What are the recommendations for therapy with these agents?

The updated [National Comprehensive Cancer Network] guidelines on the use of these drugs [show] category 1 indications, because they are [supported by] large phase 3 trials showing overall survival [OS] improvement, which is considered the gold standard for prostate cancer patients.

 The PSA doubling time of more than 10 months—that’s the challenging area.

What is the role of bicalutamide and other first-generation antiandrogens in nonmetastatic CRPC?

I [can] tell you that I [have] used bicalutamide in nonmetastatic CRPC in those patients who have a PSA doubling time of more than 10 months. I think using bicalutamide in this setting is absolutely fine.

These patients eventually start progressing. PSA doubling time usually keeps going down and keeps becoming more rapid. But, I think bicalutamide does have a role in these patients.

What data support the use of these novel antiandrogens in this setting?

The trial designs are very familiar, and very similar, actually. Large trials started almost at the same time with apalutamide, enzalutamide, and darolutamide.

Looking at the SPARTAN trial [NCT01946204] first,2 [there were] 1200 patients with nonmetastatic CRPC, and [patients with] pelvic lymph nodes were included if [these] were less than 2 cm in size below iliac bifurcation. I don’t know how relevant it is, but I need to say that because [these lymph nodes were] a major eligibility criterion, which is different from our many other trials here. PSA doubling time was less than 10 months. Patients were randomized to apalutamide plus continuation of ADT versus placebo plus ADT. Metastasis-free survival [MFS] was the primary end point.

[These were] the baseline characteristics of the patients. 74 years was the median age. The real PSA doubling time on the trial was 4.4 months on the apalutamide arm and 4.5 months on the placebo arm. It basically tells me that even [in the case of] the treating clinicians, like me, who had this trial open in their sites, most of these patients did not get put on the trial for a PSA doubling time of 9 months or 10 months, which was [part of] the eligibility criteria. They really had a fast PSA doubling time in reality. If you look at further subgroups, [there was a] PSA doubling time of less than 6 months; 70% of patients had a PSA doubling time of less than 6 months. So, again, we can see what kind of population it was.

MFS was obviously very remarkably positive [40.5 months vs 16.2 months with placebo], with a hazard ratio [HR] of 0.28. Time to symptomatic progression was also remarkable, favoring apalutamide [HR, 0.45].

OS was recently reported [at the American Society of Clinical Oncology Annual Meeting].3 Again, it supported apalutamide over placebo. [It’s] not surprising, actually, but [consider] the magnitude of OS [73.9 months vs 59.9 months with placebo; HR, 0.78; 

= .0161]. Until I saw this, I was not prescribing apalutamide in my clinic for [patients with] nonmetastatic prostate cancer. But when I saw this 14- or 15-month survival benefit, that really changed my mind.

The most frequent [adverse] effects––all I care [about]…[is] the most common one and the most striking one that affects my patient’s quality of life––fatigue and falls. Fall is important. It’s the reflection of fatigue, in my view. If you look at all-grade fatigue, 33% of patients on the apalutamide arm and 21% of patients on the placebo arm [experienced it]. If you look at grade 3 and 4 fatigue, [there was] not much; 0.9% [with apalutamide] and 0.3% with placebo plus ADT. Then falls; if you look at the falls, grade 3 and 4, [the incidence was 2.7% with apalutamide and 0.8% with] placebo plus ADT. I’m not sure how it is laid down here, but fatigue was higher with apalutamide, not that much higher, but still higher.

Skin rash, we’re looking for the skin rash. It’s not there. It means it was very uncommon. An [issue I get asked about often], especially in the context of metastatic CRPC, is skin rash. It looks like it was not very common, [occurring in less than 15% of patients]. In the TITAN trial [NCT02489318], it was 6% all rash, and grade 3 and 4 [events] were even lower.

The PROSPER trial [NCT02003924] with enzalutamide [was a] very similar trial design. Patients had to have a PSA doubling time of 10 months or less. [Patients received] enzalutamide versus placebo. The primary end point was MFS, and OS was a secondary end point.

The median age was strikingly similar to that in the SPARTAN trial—74 years. PSA doubling time [was] what investigators were [considering] before enrolling these patients in the trial—3.8 months vs 3.6 months. So it looks like they were rapidly progressing. The majority of patients [77%] had a PSA doubling time of less than 6 months.

MFS [was] 22 months longer with enzalutamide versus placebo [36.6 vs 14.7 months; HR, 0.29; 

< .0001]. Median OS was also higher with enzalutamide versus placebo [67.0 vs 56.3 months]. The HR of 0.73 [was] very similar to what we saw with the SPARTAN trial.

Looking at the [adverse] effects now, I think it would be ideal to just compile all [of them] in 1 table, but that [would] be…with a big caveat of cross-trial comparisons. But looking at the fatigue part, 3% versus 1% grade 3 and above adverse events [occurred] in more than 1% of patients receiving enzalutamide. So, fatigue was 3 times higher with enzalutamide; grade 3 fatigue, 3% and 1%. I personally think [enzalutamide is] reasonable in my clinic. I won’t [be dissuaded] much by these differences. Falls were similar, 1% and 1%, and hypertension was 5% versus 2%.

Are any of you concerned about the cardiovascular adverse effects with enzalutamide?

I know when Dr Maha Hussain presented the data, there were a lot of questions about cardiovascular [adverse] effects, but it doesn’t look [as though] they are that different in each of the arms.

What data support the use of the agent that was chosen for this patient?

[Results from]the ARAMIS trial [NCT02200614, were recently] published in the 

[1500] patients with high-risk nonmetastatic CRPC…were randomized to darolutamide versus placebo. Again, [this trial had a] very similar primary end point [to the others], MFS.

It looks like these trials were [almost] copying each other, not only in design but [in terms of the] type of patients that are included…—74 years as a median age. If you look at the PSA doubling time, [it was] 4.4 months or 4.7 months in the placebo arm. Again, the investigators mostly approved those patients on these trials, but they really thought disease was aggressively progressing. And again, 70%, more than two-thirds of patients, had a PSA doubling time of less than 6 months. Otherwise, they were very similar.

[This trial had an] MFS of [40.4 vs 18.4 months]—an 18-month difference, and a 59% risk reduction, with an HR of 0.41, which is remarkable, and consistent with other drugs, other novel agents.

In terms of prespecified and secondary exploratory end points, OS is clearly improved, with an HR of 0.71. Time to pain progression, time to cytotoxic chemotherapy, as expected, …are all better with darolutamide. Time to pain progression [40.3 vs 25.4 months; HR, 0.65] clearly improved, because we are delaying metastatic disease.

OS, [with an] HR of 0.71 [and a] 30% reduction in risk of death, is again very consistent with other novel agents.

I would say [the adverse event profile is] different from apalutamide and enzalutamide, with fatigue, tiredness, and falls. I think this is what is differentiating darolutamide from other drugs, fatigue and falls. Somehow, rash [occurs] more than with placebo [2.9% vs 0.9%], which is intriguing. I always identify rash with apalutamide or associate apalutamide with the rash. But darolutamide seems [to have] 3 times more rash compared with placebo.

Overall, how do you compare these novel agents?

[There is] very consistent improvement in MFS with all these agents, with an HR for MFS of 0.28 with apalutamide, 0.29 with enzalutamide, and 0.41 with darolutamide. [Regarding] OS, again [we see an] HR of 0.78 with apalutamide, 0.73 with enzalutamide, and 0.69 with darolutamide. So, [there is a] consistent reduction in risk of progression and death in the range of 30% to 40%.

Does PSA doubling time affect your choice of therapy?

As we [discussed], in all those trials [it was] pretty much…very consistent that if you look at the patients who were actually recruited on…all 3 trials, SPARTAN, PROSPER, and ARAMIS, …the PSA doubling time was strikingly very similar, around 4 months. So, by the time the PSA doubling time is 4 months, we [tend] to think this is already a disease that is not curable with radiation or surgery.

How do you decide which of these agents to give in the nonmetastatic CRPC setting?

I’m more likely to prescribe one drug over another drug because of drug interactions. Darolutamide has [fewer] drug interactions. I personally have prescribed more enzalutamide for nonmetastatic CRPC, because that was the drug that was in my clinic for the last 6 years. So I didn’t have to change anything. I do have a template on Epic. My nurses are very familiar with enzalutamide, and apalutamide from last year. But I get stuck with drug interactions sometimes, [such as] anticoagulants. [For example,] patients are on…some antiarrhythmic drugs, then …a pharmacist tells me, ‘You cannot prescribe this drug, because it interacts.’ Then I start scratching my head, and I start looking for…the other option. I think, personally, darolutamide has [fewer] drug interactions. That is the most attractive part for me. If I prescribe darolutamide, that is the most common reason for me to do that…because no other drug can be prescribed for that given patient.

Multiple drug interactions [exist] with pretty much all these medications. But somehow, I have learned [about many of them] over the last 10 years of…seeing patients with prostate cancer, and darolutamide has been around for almost 3 years now in different forms, different trials and different forms, basically. Personally, I think it has the least amount of drug interactions. I still go with other medications. Sometimes I have no choice. It is the insurance choice, which I have to follow. If you have not seen a lot of [patients with] nonmetastatic prostate cancer, you will realize that it doesn’t matter what we prefer. I think it’s sometimes easier to go with the formulary of the insurance company.

Having said that, if somebody is having a drug interaction with, say, apalutamide, and there won’t be any drug interactions with darolutamide, it is very easy to have insurance change the drug to darolutamide, and vice versa. So, if you have a patient who has an interaction with darolutamide, but no interaction with enzalutamide, simply ask insurance; I think they’ll change it. That’s what my experience is.

1. NCCN. Clinical Practice Guidelines in Oncology. Prostate cancer, version 2.2020. Accessed August 17, 2020. 

2. Smith MR, Saad F, Chowdhury S, et al; SPARTAN Investigators. Apalutamide treatment and metastasis-free survival in prostate cancer. 

. 2018;378(15):1408-1418. doi:10.1056/NEJMoa1715546

3. Small EJ, Saad F, Chowdhury S, et al. Final survival results from SPARTAN, a phase III study of apalutamide (APA) versus placebo (PBO) in patients (pts) with nonmetastatic castration-resistant prostate cancer (nmCRPC). 

2020;38(suppl 15):5516. doi:10.1200/JCO.2020.38.15_suppl.5516

4. Chi KN, Agarwal N, Bjartell A, et al; TITAN Investigators. Apalutamide for metastatic, castration-sensitive prostate cancer. 

. 2019;381(1):13-24. doi:10.1056/NEJMoa1903307

5. Sternberg CN, Fizazi K, Saad F, et al; PROSPER Investigators. Enzalutamide and survival in nonmetastatic, castration-resistant prostate cancer. 

. 2020;382(23):2197-2206. doi:10.1056/NEJMoa2003892

6. Fizazi K, Shore N, Tammela TL, et al; ARAMIS Investigators. Darolutamide in nonmetastatic, castration-resistant prostate cancer. 

. 2019;380(13):1235-1246. doi:10.1056/NEJMoa1815671

Articles

During a Targeted Oncology Case Based Peer Perspectives event, Neeraj Agarwal, MD, discussed the case of a 57-year-old male patient with nonmetastatic castration resistant prostate cancer.










Agarwal Considers Patient Eligibility Among Novel Antiandrogen Therapies in Nonmetastatic CRPC Setting

 Case Based Peer Perspectives event, Thomas Hutson, DO, PharmD, the director, Urologic Oncology Program cochair, Urologic Cancer Research Center, at Baylor University Medical Center in Dallas, TX, discussed the case of a 66-year old woman with bladder cancer that  presented post chemotherapy.

™: When do you give platinum-based chemotherapy in the frontline setting for patients with bladder cancer? Which regimen do you use?

We generally feel that creatinine clearances above 45 mL/min would be good for platinum chemotherapy. When you start getting below 40 to 45 mL/min, the ability to give cisplatin reliably becomes challenging in that setting. It’s dealer’s choice; it really becomes about your own comfort level.

But looking at the cisplatin-based [regimens in a presentation of cross-trial comparisons from the 2020 American Society of Clinical Oncology (ASCO) Annual Meetin], you see the 2 [regimens]: the dose-dense MVAC [methotrexate, vinblastine, doxorubicin hydrochloride, and cisplatin] and [gemcitabine and cisplatin].

 From the EORTC trials, there was a 72% objective response rate [ORR], a 25% complete response [CR] rate, and a median overall survival [OS] of 15.1 months [with MVAC]. Then gemcitabine and cisplatin [had a lower response], with a 49% ORR, a CR rate of 12%, and a median OS of 14 months.

Another trial compared MVAC versus gemcitabine and cisplatin. It was a noninferiority study, and it showed that gemcitabine and cisplatin was close to dose-dense MVAC in activity. The trial wasn’t completed, so it was underpowered, but that allowed people to feel more comfortable using gemcitabine and cisplatin.

For the median OS, there was about a month difference between the 2 [regimens].

 But when you’re looking at tumor ORR, I feel that dose-dense MVAC gives you a better [response].

So, if I have a younger patient, I would generally lean that way. But those are the regimens we’ve used.

Then, for the patients who were cisplatin ineligible, there was definitely a reduction in benefit [with gemcitabine and carboplatin]. The median OS dropped off by 5 or 6 months, and the CR rate dropped, and the response rate dropped. So that’s clearly an inferior regimen.

What are the drawbacks of comparing trials in this way?

Because we’re [discussing] cross-trial comparisons, if you look at the cisplatin-ineligible population, you’re going to find a greater population that will have more comorbidities, impaired kidney function, and they’re going to have [a greater] volume of cancer. Really, the only way to compare them adequately would be to stratify for those factors in a randomized trial, but we don’t have that. But truly, the response rates are noticeably different, and that’s the bias that’s built into this kind of discussion; there’s a bias there. I think we agree that carboplatin is inferior, but the degree of inferiority could be questioned.

Would you give these regimens as adjuvant or neoadjuvant therapy?

A lot of people think of dose-dense MVAC in the neoadjuvant setting. Everything we use in the neoadjuvant setting is an extrapolation from the metastatic setting. We often think about [the scenario that] if someone was presenting to you with a curative-intent therapy goal, then give them dose-dense MVAC if they’re young and if it makes sense. I think we’re reminding ourselves that there’s a small group of patients who come in with metastatic disease that has spread beyond the lymph nodes or have lymph node metastases, who historically wouldn’t be offered surgery unless they had some type of response or CR to up-front chemotherapy. You would try to use dose-dense MVAC in that situation.

When do you offer surgery to patients in this setting?

At Baylor [University Medical Center], we tend to be a little bit more aggressive than our colleagues down in Houston. My colleagues there will sample anything suspicious, and if they find 

that there’s cancer or lymph node involvement, they will not plan on curative surgery; they will treat with 2 or 3 cycles of a chemotherapy regimen such as dose-dense MVAC or gemcitabine and cisplatin, and then they’ll sample the lymph nodes. If the lymph nodes still have any viable cancer, even if it’s microscopic, they will not proceed with surgery.

At Baylor, we don’t sample the lymph nodes. If we see enlarged lymph nodes, we will give something like 3 cycles of dose-dense MVAC or 3 or 4 cycles of gemcitabine and cisplatin. If we see some type of response there, we don’t sample; we go in and remove it. We cut it all out because we think that’s the only way to give the patient, in our opinion, the best chance of having the best disease control moving forward. I think that we see a difference in practice pattern there.

An example for me would be doing an evaluation before you give neoadjuvant chemotherapy and get scans done. Usually the urologist has only done an abdomen, pelvis, or chest x-ray, and you’re getting a CT chest and a bone scan, and you pick up some [small] nodules in the lung with uncertain significance, maybe some lymph nodes in the pelvis. [I would] move forward with chemotherapy and follow those [patients]. But I’m not going to play games with trying to do biopsies of the lung nodules after chemotherapy or try to base things on any type of response. I go forward [with surgery] if it’s an otherwise fit person. I let them know that [there is a concern with this], but if we don’t go for [it], we’re never going to get them to a good outcome.

If it looks like metastatic spread, then that’s a different story; we would go forward with chemotherapy, and we’re reassessing. If they have a great response or it’s a CR, then [we have to] make some type of decision about how to proceed forward at that point.

How have immunotherapies changed the landscape for bladder cancer?

I think there’s been some thought among the pharmaceutical companies and maybe in practice pattern that because we have immune therapy—because cisplatin can be so difficult to give, and you have drugs like pembrolizumab [Keytruda] and others that are approved for cisplatin-ineligible patients—that everyone is moving away from chemotherapy altogether and not even trying to give chemotherapy. They’re jumping right into immune therapy, but what I’m hearing in the community setting is that that’s not necessarily the case. [They are] still thinking about giving platinum-based chemotherapy up front and thinking about giving cisplatin if they can.

Do you agree with how this patient was treated?

She had 4 cycles. I only give 4; some people like to give 6. I’ve seen people give 8 cycles of therapy, but I think the standard generally is 4 [cycles].

What do you think of the responses to this poll?

Eighty percent are jumping into avelumab [Bavencio] maintenance therapy after 4 cycles of platinum chemotherapy. That’s the new standard of care we want to review. The other 20% said clinical trials, but no one is just doing observation. I think in the past, prior to ASCO this year and the plenary presentation [with] these data, we would have just observed. Unless you had a clinical trial, there was nothing. You would [hope] that your patient would have 4 to 8 months before they would have progression that would warrant more treatment.

Which factors influence your decision to use avelumab maintenance?

Chemotherapy regimens should not influence that....If these patients are platinum refractory, which is going to be a small percentage of patients, that is a negative prognostic sign. You would generally be moving them into second-line therapy, which is checkpoint inhibition. The number of cycles of first-line chemotherapy completed is unlikely an exclusionary component. We don’t test PD-L1 expression levels in bladder cancer. And then, for comorbidities, the only ones that we know about with the checkpoint inhibitors tend to be the autoimmune diseases. You would apply your normal criteria for using checkpoint inhibitors for this patient population.

Please describe the methods for the data presented 

The reason we’re all excited is because that, for the first time, are affecting survival in our patients and [achieving] recurrence free or disease control in our patients. The JAVELIN Bladder 100 trial [NCT02603432] was the avelumab maintenance trial after frontline platinum chemotherapy for patients with advanced 

2 arms from each other to really figure out what the additive benefit of the treatment is.

My first take-home [message] when I look at [the treatment-emergent AE profile] is the high amount of toxicity from being on [best supportive care alone]. A lot of it seems to be grade 1 or 2, things like fatigue, urinary infections, and blood in the urine. It seems like patients who are receiving avelumab are having a greater incidence of grade 1 or 2 toxicities and even greater than or at least grade 3 than they are on best supportive care, so we would attribute an incremental increase of a variety of AEs to immune therapy.

About 12% of patients who were put on maintenance avelumab discontinued it because of treatment-emergent AEs. There was death attributed to 2 patients in the avelumab arm; 1 was due to sepsis at cycle 10, and another was ischemic stroke.

When we look at some of the immune-related AEs, which I know a lot of us focus on, none were grade 4 or 5. High-dose corticosteroids, which [the investigators] defined as greater than or equal to 40 mg of total prednisone daily or equivalent for modulation of an immune-related AE, was 9% of avelumab-treated patients. Avelumab has one of the lowest amounts of immune-related AEs that require steroid use. We know drugs such as pembrolizumab are a bit higher in corticosteroid usage. Avelumab is lower at 9%. And, if we look at the grade 3 AEs that are immune related, it’s pretty low; most of them are grade 1 or 2. There’s the traditional breakdown of thyroid, skin rash, low incidence of pneumonitis, colitis, liver transaminase, and myositis.

Is avelumab approved for use in this patient population?

Based upon this plenary presentation—it was late-breaking abstract number 1, so it was the highest-ranked abstract at ASCO this year—the FDA approved avelumab for urothelial cancer as maintenance on June 30, 2020.

 It was for patients who had unresectable locally advanced or metastatic disease that had not progressed with 4 to 6 cycles of first-line platinum therapy, which could have included carboplatin, based upon this trial. They needed to initiate therapy within 4 to 10 weeks of their last chemotherapy dose, and they were continued on the avelumab therapy until progression or unacceptable toxicity.

[Because of] the FDA approval, there was rapid uptake into the NCCN [National Comprehensive Cancer Network] guidelines.

 We have it listed on our McKesson guidelines now. It is listed as a preferred therapy following platinum-based chemotherapy with category 1. It’s even listed as preferred following dose-dense MVAC with growth factor support. For cisplatin-ineligible patients, they now have gemcitabine and carboplatin listed, followed by avelumab maintenance therapy as an arm that you could use. They also list the immunotherapies that could be utilized by themselves in that situation. This is the current guideline as of June 2020.

Based upon this, we would say that the new standard of care in this setting becomes maintenance therapy with avelumab for what appears to be a 4-to-5-month improvement in survival.

How does this switch maintenance approach compare with other options in bladder cancer, such as second-line treatment?

For the JAVELIN 100 pivotal trial versus KEYNOTE-045 [NCT02256436]…the OS curves showed that there was a 21.4- month median for all-comers [vs median OS of 10.1 months].1 [KEYNOTE-045 looked at] pembrolizumab versus chemotherapy postplatinum therapy after progression.

Looking at a sequence that yields the longest median OS, there are a couple of scenarios that I think will help solidify the benefits of doing maintenance therapy. If you go with your first-line platinum chemotherapy and then have progressive disease, you’re going into the checkpoint second line.

[As seen] from the pembrolizumab trial, patients are getting 10 months with pembrolizumab and 11.1 months for atezolizumab, [according to the IMvigor 211 (NCT02302807) data]. Adding up the estimated median OS is 14 months; if you’re sitting with first-line platinum 4 to 6 cycles, you get randomized then because you’ve had at least stable disease. For maintenance therapy, you’re getting 21.4 months with JAVELIN and 22 months in the pembrolizumab Hoosier Cancer Research Network GU14-182 trial [NCT02500121]. So it’s about a 25-month median OS.

1. Plimack ER. Checkpoint inhibition in metastatic urothelial carcinoma: timing is everything. Plenary session presented at: 2020 American Society of Clinical Oncology Virtual Scientific Program; May 29-June 2, 2020. Accessed August 25, 2020.

2. Powles T, Park SH, Voog E, et al. Maintenance avelumab + best supportive care (BSC) versus BSC alone after platinum-based first-line (1L) chemotherapy in advanced urothelial carcinoma (UC): JAVELIN Bladder 100 phase III interim analysis. 

. 2020;38(suppl 18):LBA1. doi:10.1200/JCO.2020.38.18_suppl.LBA1

3. FDA approves avelumab for urothelial carcinoma maintenance treatment. FDA. Updated July 1, 2020. Accessed August 26, 2020. https://bit.ly/2YENV8t

4. NCCN. Clinical Practice Guidelines in Oncology. Bladder cancer, version 6.2020. Accessed August 26, 2020. https://bit.ly/2EC6Nhw

During a Targeted Oncology Case Based Peer Perspectives event, Thomas Hutson, DO, PharmD, discussed the case of a 66-year old woman with bladder cancer that  presented post chemotherapy.

Hutson Considers Maintenance Treatment for Bladder Cancer Post Chemotherapy

During Case Based Peer Perspectives event, Damian Laber, MD, senior member, Moffitt Cancer Center, Tampa General Hospital in Tampa, FL, discussed the case of a 53-year-old male patient with stage IV colorectal cancer.

™: What factors are most important in the assessment of prognosis and in systemic treatment selection?

One of the things that came [into] discussion a few years ago—[that] is still under discussion, because there are some conflicting results—is the question about right-sided versus left-sided colorectal cancer [CRC]. The distinction is basically right in the middle of the transverse colon. In general, the right-sided CRC is usually the one that [has] more 

mutations. The right-sided colon cancer is the one [where] we use the EGFR receptor inhibitors [such as] cetuximab [Erbitux] or panitumumab [Vectibix] much less.

There is also some research that is trying to differentiate the different genotypes and phenotypes of these colon cancers, hopefully to target the treatment much better, because until now, we were treating colorectal the same way, irrespective of where it came from. But if we look at most of the patients with right-sided colon cancer, the common mutations include the 

mutations. Also, many of them on the right side, they are microsatellite instability [MSI] high, or they are deficient in the mismatch repair [MMR] proteins. And those ones are the ones that we end up using the immune checkpoint inhibitors for. Those will be some of the important take-home messages.

On the left side, the mutations are more in the 

amplification. So that’s why they might respond better to the EGFR inhibitors than the other side. And also, it seems [as though] the prognosis for the patients with CRC is a bit better on [the left side].

What are your impressions of the case at this point?

The patient was started on FOLFOX and cetuximab because it was considered more on the left side, and the therapy was well tolerated. And then after the [treatment], he had a grade 2 rash, which we expect with these agents.

What data support the use of FOLFOX plus cetuximab?

This came from an intergroup study, the SWOG-80405 or CALGB study [NCT03641976].

 What it looked at was FOLFOX or FOLFIRI [leucovorin, 5-FU, and irinotecan] as the backbone chemotherapy. It was not randomized, so the majority of the patients in North America chose FOLFOX. And in some parts of Europe, I think there was more FOLFIRI. Then they randomized the patients. They were all 

wild type. But they randomized the patients to either bevacizumab [Avastin] or cetuximab.

When you look at whether it’s left-sided or right-sided, [for the left-sided tumors], the survival was 38.7 months versus 34.4 [with] the right-sided if they received bevacizumab [adjusted HR, 0.62; 95% CI, 0.32-1.23; log-rank 

cetuximab, with the left-sided tumors, the median survival was 40 months versus 18 months [adjusted HR, 1.68; 95% CI, 0.85-3.34; log-rank 

= .003]. So in these particular cases with the left-sided tumors, when they are wild type, cetuximab is probably more effective. The concern is that on the right side, it’s exactly the opposite, the survival is worse, so we should try to avoid it on the right-sided tumors.

Do other data support the use of cetuximab in this setting?

This [brings] you to the FIRE-3 study [NCT02934529].3 The FIRE-3 study used FOLFIRI as the backbone, and the patients were randomized to cetuximab or bevacizumab. Again, the data on the [patients who were] wild type for the 

mutations [showed an overall survival of 33.1 months with FOLFIRI/cetuximab and 25.6 months with FOLFIRI/bevacizumab (HR, 0.70; 95% CI, 0.53-0.92; 

= .011)]. If you look at the intention-to-treat population at the end of the study, there’s a slight survival advantage for the patients treated with cetuximab versus the patients treated with bevacizumab [28.7 vs 25.0 months; HR, 0.77; 95% CI, 0.62-0.96; 

But, the left-sided tumors are the ones that benefit from cetuximab. [For] the survival advantage, both curves separate. The survival advantage becomes much more, with a hazard ratio of 0.63 [95% CI, 0.48-0.85; 

= .002]. So the median survival will be 28.0 months if you use FOLFIRI/bevacizumab versus 38.3 months by using FOLFIRI with cetuximab.

Now, the opposite holds true on the other side. If you look at the right-sided [tumors], the patients treated with bevacizumab or cetuximab made not much of a difference [18.3 vs 23.0 months, respectively; HR, 1.31; 95% CI, 0.81-2.11; 

= .28]. But it seems [as though] the bevacizumab is better. If you look at where the median survival is, the curves are a bit separated. But then after that, they keep touching points, and they both go down.

How would you manage the cetuximab-mediated rash?

I think this used to be a big probability as soon as cetuximab came about 20 years ago. Now most of us are fairly good at this. The teaching point is that you can use a preemptive approach. Basically, you treat everybody before they develop a bad rash. And most of us, what we will [suggest] is sunscreen and moisturizing lotions, and then we use oral antibiotics, either doxycycline or minocycline. If you do that, then you decrease the incidence of the rash by about half.

 [With] the preemptive [approach], you have much less rash. With the reactive—which is wait until the rash occurs, and then you treat—then you have much more incidence. So you can decide on a patient-by-patient [basis] whether to wait to implement all the preventive therapies or treat them up front just to decrease the incidence of this adverse effect [AE] in the patients that wish to have it.

Now, the other big discussion that I remember we used to repeat, and also we used to tell the patients when they’re having a bad rash, is that patients [who] develop a rash have a better survival [rate] or better outcomes than patients [who] don’t develop a rash [HR, 0.51; 95% CI, 0.40-0.64]. And this comes from a meta-analysis of at least 7 studies.

 Combining all of them, if you go look at the patients [who] develop a rash versus the patients [who] did not develop a rash, then you have a survival advantage.

patient? What other frontline options might you consider for this patient?

So this comes from the latest version of the National Comprehensive Cancer Network [NCCN] guidelines in gastric cancer.6 The guidelines usually list most of the options that are appropriate, and then we can choose. It’s not a pathway that tells us what to do. And remember, this patient was HER2 negative.

So for the first-line treatment, they say that the 2-drug cytotoxic regimens are preferred because of lower toxicity. This comes from the original studies of the DCF [docetaxel, cisplatin, and fluorouracil]. Then the 3-drug cytotoxic regimen should be reserved for medically fit patients with good performance status and access to frequent toxicity evaluations.

They listed the preferred regimens, the fluoropyrimidine, which is either 5-FU or capecitabine and oxaliplatin or another fluoropyrimidine and cisplatin. These [were based on] a 4-arm randomized study that used either 5-FU or capecitabine. They used either oxaliplatin or cisplatin. All the arms show the same responses and the same survival, so you basically can interchange all that.

What treatment options are available for this patient at this point? And based on what data?

For the second-line treatment that is recommended by the NCCN guidelines,

 it really depends on the prior therapy. But if you have received the platinum and the fluoropyrimidine, then the preferred regimens, the category 1 [regimen] is ramucirumab [Cyramza] with paclitaxel, because there was a randomized study. Docetaxel is still listed, paclitaxel and irinotecan also. And then the trifluridine with tipiracil [TAS-102], which is Lonsurf.

That’s usually for third line after the patient fails the first 2 lines. Then 5-FU/irinotecan, something [such as] FOLFIRI, can be used. It doesn’t have a category 1 [recommendation]. Pembrolizumab [Keytruda] is listed for second-line or subsequent line of therapies, and anybody that has MSI-high or deficient MMR tumors; that’s for all tumor types, but also for third-line or subsequent therapy for gastric adenocarcinoma with a CPS of more than 1. You can still use it at third line just by having that, even if a patient doesn’t express MSI or MMRs.

Would the treatment choice be different if this were a gastroesophageal junction (GEJ) versus a gastric tumor?

Yeah, I do the same. Most of us would treat the same.

The RAINBOW study [NCT01170663] was published more than 5 years ago.

 This is the study that established ramucirumab as a category 1 therapy. It was a randomized study of patients with metastatic or locally advanced or unresectable gastric or GEJ adenocarcinoma—so it was the same—who had progressed after a firstline of therapy with a platinum and a fluoropyrimidine-based therapy. Half of the patients receive a placebo, instead of ramucirumab, and the standard, which was single-agent paclitaxel. They used a weekly regimen on days 1, 8, and 15. The other half received the drug, which is the ramucirumab, at 8 mg/kg. This was given every 2 weeks, so day 1 and day 15. And then the paclitaxel weekly, exactly the same as the other arm.

This was a quite large study for this population, [more than] 300 patients per arm. They were all treated until progression or toxicity. And the end point was survival, and safety and follow-up were measured.

The median progression-free survival was 4.4 months for the combination of ramucirumab and paclitaxel versus 2.9 months for the paclitaxel alone. The hazard ratio and the 

value all were statistically positive [HR, 0.635; 95% CI, 0.536-0.752; 

The median overall survival for the combination, which was the best arm, was 9.6 months versus 7.4 months, again, with a positive hazard ratio and 

Based on this, the FDA granted the approval for ramucirumab with paclitaxel for second-line treatment of gastric or GEJ adenocarcinoma. And that’s why it has the category 1 [recommendation].

Now, if you look at the responses—again, this is in second line— the complete responses [CRs] are rare [less than 1%]. The partial responses [PRs] happen—that’s where the big difference was, about 27% for the combination versus 16% for the single arm. That’s basically what we expect. With single-arm, active chemotherapy, it’s usually around a 15% response rate, and when we combine it, usually we do another 10%, or we double those responses.

And the stable disease [SD] [rate is] about half of the patients. The disease control rate [DCR], which adds the CR, PR, and SD rates, which is basically when you consent the patient, that’s roughly how we practice. We tell the patient that we’re going to treat as long as they don’t progress. If we see progression, that’s when we stop, or we change therapy, unless there is toxicity. But that would be the 80% of the patients [who], most likely, if you do restaging quite often, at the first one, you might be happy, and then after the second or third restaging, that’s when you would expect the progressions in these patients.

What are your thoughts on this poll? Do you consider DCR to be a clinically meaningful end point?

The majority of the people say yes. It’s not something that we will likely use on a clinical trial as the final end point, because it could be subjective how we read the scans and how we measure them, and so forth. But in the day-to-day practice, I strongly believe that’s roughly how we practice oncology. The only thing we don’t want to see is the cancer growing, because that’s basically how the patients die.

What is the safety profile like with this combination?

When you add a second medication, you increase the AEs. 

Ramucirumab is an EGFR2 receptor inhibitor. So the AEs are basically the vascular AEs, which include the hypertension, the proteinuria, the concern for bleeding, and the concern for blood clots. We’ve been using these drugs for so many years that we’re accustomed. We know when to use it, and we also know when not to use them.

And then sometimes we also see more laboratory changes. So we might see a bit more neutropenia and anemia. But it’s rare that you will see an increased risk of the complications from that. So it’s rare that you’re going to see neutropenic fevers and infections.

What are the available treatment options for when the patient develops further disease progression?

There are several studies that [relate to further treatment options], because now that we follow these patients so closely, we are getting into third-line therapies for [them]. TAS-102 is now called Lonsurf, and this came from the study that led to the indication.

 These were patients with measurable metastatic gastric or GEJ cancer. They had received more than 2 prior regimens—it would be exactly like our patient. To be on the study, they still [had to] have adequate organ function. They were able to take oral medications, [had] good performance status, no serious comorbidities from before, no prior TAS-102, which is the Lonsurf, and no unresolved toxicity.

This was a 2:1 randomization, because they didn’t have a control arm because we didn’t have any established control at that time. So by doing a 2:1, they made sure most of the patients received the drug, versus the ones [who] received placebo.

The progression-free survival [curves] favor TAS-102 or the trifluridine/tipiracil [HR, 0.57; 95% CI, 0.47-0.70; 2-sided 

< .0001]. The overall survival [curves] separate, and they favor the treatment arm [HR, 0.69; 95% CI, 0.56-0.85; 2-sided 

= .00058]. And that’s what led to the approval and the indication of Lonsurf in the third-line treatment for patients with gastric or GE junction adenocarcinoma.

For all who have experience with Lonsurf, that’s not a big deal. But for the ones who don’t have too much experience, we give it usually day 1 to 5, so we usually take it Monday to Friday; we skip the weekends. We give it for 2 weeks on, and then 2 weeks off. So every 4 weeks, we repeat that. And it is an analogue of the fluoropyrimidine, but it’s considered to have much less or no cross-reactivity with 

prior 5-FU, and that’s why you get responses.

The KEYNOTE-059 study [NCT02335411] was looking at pembrolizumab monotherapy in advanced gastric or GEJ cancer following progression on 2 or more therapies.

 This was an open-label and a multicohort phase 2 study. This is not a randomized study, don’t get fooled by the 3 different cohorts. There were 3 different populations. Cohort number 1, they were all patients [who] progressed after 2 prior lines of therapy—so, like our patient—and all of them received single-agent pembrolizumab at the standard dose, 200 mg every 3 weeks. And they were monitored as a phase 2 study for responses, progression, and survival, but in a noncontrolled study.

Cohort number 2 were patients with no prior therapy, so first-line, and it was adding pembrolizumab to the combination of cisplatin and either 5-FU or capecitabine—similar approach that we do for lung cancer or other tumors. And cohort number 3, there were also patients with no prior therapies, but they tested positive for PD-L1. Same idea—high expressers, you avoid chemotherapy.

So each one of these cohorts will be presented as a different study. It’s not a randomized study. So the one that was published 2 years ago in 

is in the ones that have more than 2 prior therapies, so basically it’s cohort number 1.

These patients were treated for about 2 years. If [a patient was] still responding, [they] keep going. Nobody knows what to do after that. If [the patient has] a CR, and nothing happened after 2 years, maybe [the patient could] take a break. But honestly, we don’t know what to do in those.

paper, in the cohort of patients [who] have received 2 or more therapies are the objective responses, which is the CR and the PR, in 30 patients, which is about 11.6% of the patients. About 27% of the patients basically end up benefiting from the DCR. Basically, you can expect somewhere around 27% of patients will respond in the third line to pembrolizumab.

What other potential treatment regimens are emerging in this space?

Nivolumab [Opdivo] and paclitaxel plus ramucirumab—using the backbone of paclitaxel and ramucirumab and seeing whether we can add the PD-L1/PD-1 inhibitors. On this particular study, 43 patients were treated, and then the DCR was 83.7%, with the overall response rate of 37.2% and SD in 46.5%.

 So these data are starting to appear in abstract forms, and we need to wait for the final studies.

Are there ramucirumab studies in the first line in gastric cancer?

They haven’t been completed or published, so they were mostly [based] on phase 2 studies.

Would you consider using pembrolizumab monotherapy for CPS 1 or higher as frontline therapy based on KEYNOTE-062 (NCT02494583)?

I think, so far, not yet. But once the study gets published, then we will be looking at that very closely, because most of us like to use that as first line if we expect a high response rate at least.

References: 
1. Baran B, Ozupek NM, Tetik NY, Acar E, Bekcioglu O, Baskin Y. Difference between left-sided and right-sided colorectal cancer: a focused review of literature. 

2. Venook AP, Niedzwiecki D, Innocenti F, et al. Impact of primary (1º) tumor location on overall survival (OS) and progression-free survival (PFS) in patients (pts) with metastatic colorectal cancer (mCRC): analysis of CALGB/SWOG 80405 (Alliance). 

2016;34(suppl 15):3504. doi:10.1200/JCO.2016.34.15_suppl.3504

3. Heinemann V, von Weikersthal LF, Decker T, et al. FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab as first-line treatment for patients with metastatic colorectal cancer (FIRE-3): a randomised, open-label, phase 3 trial. 

2014;15(10):1065-1075. doi:10.1016/S1470-2045(14)70330-4

During Case Based Peer Perspectives event, Damian Laber, MD, discussed the case of a 53-year-old male patient with stage IV colorectal cancer.

Author | Targeted Oncology Staff

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