CE / CME
Physician Assistants/Physician Associates: 1.50 AAPA Category 1 CME credits
Nurses: 1.50 Nursing contact hours
Physicians: maximum of 1.50 AMA PRA Category 1 Credits™
Pharmacists: 1.50 contact hours (0.15 CEUs)
Released: March 25, 2024
Expiration: March 24, 2025
EV‑302/KEYNOTE‑A39: First-line Enfortumab Vedotin-ejfv + Pembrolizumab vs Chemotherapy in Advanced UC
Terence Friedlander, MD:
The next abstract I would like to review is the EV‑302/KEYNOTE‑A39 study, which was a randomized, open-label phase III trial of enfortumab vedotin-ejfv (EV) with pembrolizumab for locally advanced and metastatic urothelial cancer.20,21 This is a follow-up to the data presented at the European Society for Medical Oncology (ESMO) Congress 2023, where the trial results were first released.22 In this study, 886 patients were randomized to receive either EV plus pembrolizumab or gemcitabine with either cisplatin or carboplatin as first-line therapy. The primary endpoints were OS and PFS, and key secondary endpoints included ORR, duration of response, disease control rate, and safety.
EV-302/KEYNOTE-A39: PFS and OS in ITT
Terence Friedlander, MD:
The median PFS and OS in the ITT population was previously reported.21,22 Of importance, the median PFS was doubled for patients who received EV with pembrolizumab vs patients who received chemotherapy, with a HR of 0.45 (95% CI: 0.38-0.54). Likewise, the median OS was almost doubled in the EV plus pembrolizumab arm vs the chemotherapy arm at 31.5 months vs 16.1 months, respectively. This was highly significant with an HR of 0.47 (95% CI: 0.38-0.58) and a P value <.00001.
EV-302/KEYNOTE-A39: PFS by BICR Subgroup Analyses of Stratification Factors
Terence Friedlander, MD:
At ASCO GU, a number of efficacy subgroup analyses were presented. With respect to median PFS, it is notable that almost all of the subgroups benefited from treatment with EV and pembrolizumab.20 The HR values were all 0.5 or less, implying that regardless of cisplatin eligibility, level of PD‑L1 expression, or presence or absence of liver metastases, all subgroups benefited from EV plus pembrolizumab vs patients who received standard platinum‑based chemotherapy.
EV-302/KEYNOTE-A39: PFS by BICR Subgroup Analyses of Other Factors
Terence Friedlander, MD:
The PFS benefit was consistent in additional subgroups.20 Regardless of age, race, geographic region, sex, ECOG PS, upper or lower tract primary disease, presence or absence of visceral metastases, and renal function, the majority of the HR values were impressive at approximately 0.5 or less. Of particular interest, there is a clear benefit for EV plus pembrolizumab among patients with visceral metastases (HR: 0.45, 95% CI: 0.37-0.55), as well as for patients with upper tract urothelial cancer (HR: 0.50, 95% CI: 0.35-0.71). These data indicate that irrespective of the cancer origin site, EV plus pembrolizumab is a better regimen compared with cisplatin or carboplatin and gemcitabine.
EV-302/KEYNOTE-A39: OS Subgroup Analyses of Stratification Factors
Terence Friedlander, MD:
With regard to median OS, investigators reported a similar benefit with EV plus pembrolizumab among subgroups.20 HR values greatly favored treatment with EV and pembrolizumab whether patients were cisplatin eligible, regardless of PD-L1 expression, or whether or not they had liver metastases.
EV-302/KEYNOTE-A39: OS Subgroup Analyses of Other Factors
Terence Friedlander, MD:
EV plus pembrolizumab was associated with improved median OS regardless of age, race, geographic region, sex, ECOG PS, disease origin site, metastatic disease site, or renal function.20
Of note, patients with visceral metastatic disease had a median OS of over 2 years with EV plus pembrolizumab, vs 13.6 months with chemotherapy. These are particularly compelling data for a high‑risk patient population.
It is also reassuring to know that EV plus pembrolizumab seemed to benefit patients with moderate or severe renal dysfunction as well. These data should give HCPs some confidence that this regimen will be effective in real‑world populations.
EV-302/KEYNOTE-A39: ORR by BICR Subgroup Analyses of Stratification Factors and Site of Metastases
Terence Friedlander, MD:
Analysis of ORR also clearly shows the benefit of treatment with EV plus pembrolizumab vs standard chemotherapy with an ORR of 67.6% vs 44.4% for platinum‑based chemotherapy—an absolute difference of 23.3%.20 EV plus pembrolizumab was favored regardless of cisplatin eligibility, PD‑L1 expression, presence or absence of liver metastases, and site of metastasis. These data further illustrate the strong anti-tumor activity of EV plus pembrolizumab.
EV-302/KEYNOTE-A39: Overall Safety
Terence Friedlander, MD:
With regard to safety, the key takeaway was that there were no new safety signals associated with EV plus pembrolizumab compared with previously presented data.20-22
There are specific AEs related to this regimen. Peripheral sensory neuropathy was much higher in the EV plus pembrolizumab group—50% of patients experienced grade 1 or 2 peripheral sensory neuropathy, and 3.6% experienced a grade ≥3 event, compared with only 9.9% (grade 1/2) of patients in the chemotherapy arm. Skin problems like pruritus, alopecia, and maculopapular rash, were also more commonly observed with EV plus pembrolizumab vs chemotherapy.
Conversely, myelosuppression—which is a feature of chemotherapy but not a common feature of EV plus pembrolizumab—was observed at much lower rates in the EV and pembrolizumab arm vs the chemotherapy arm. In addition, the rates of anemia, neutropenia, and thrombocytopenia were very low in patients who received EV plus pembrolizumab vs patients who received chemotherapy. So there are trade‑offs in terms of tolerability when using EV plus pembrolizumab compared with chemotherapy.
EV-302/KEYNOTE-A39: Clinical Implications
Terence Friedlander, MD:
This study is certainly the most practice changing study in urothelial cancer in the last year, perhaps in the last 5 years.21 The data show that EV plus pembrolizumab is a very active regimen and outperforms the standard of care chemotherapy across all subgroups analyzed.20
It was reported at ESMO Congress that more than 30% of patients received maintenance immunotherapy in the control arm, which is considered standard of care in the United States, and almost 60% of patients total received a checkpoint inhibitor in the second‑line space or later on in their treatment course.22 The proportion of patients getting a checkpoint inhibitor at some point in their treatment course is reflective of real world practices. Thus, I do not think that the difference in OS results is due to the underperformance of the control arm.
The data are so compelling across OS, PFS, and ORR that I think EV plus pembrolizumab should be the standard of care instead of platinum‑based chemotherapy followed by avelumab.
I think an ongoing question is what to do for patients who may have received adjuvant immunotherapy after surgery. Is EV plus pembrolizumab still the right treatment for first‑line metastatic disease? I think if there is synergy between EV and pembrolizumab, it makes sense to give EV and pembrolizumab even after a checkpoint inhibitor. But there are no data yet on the use of EV plus pembrolizumab after a checkpoint inhibitor, so additional trials are needed.
Unfortunately, the toxicity associated with this regimen is real. There are patients who experience serious peripheral neuropathy or serious skin reactions to EV plus pembrolizumab. I think it is important that providers are aware of these toxicities before they use this regimen, so they can counsel patients about dose reductions, dose delays, or dose holds.
Some patients already have grade 1 or even grade 2 neuropathy. I think EV should not be used if the neuropathy is grade 2 or higher, as the payload monomethyl auristatin E (MMAE) is a microtubule stabilizer and can cause serious neuropathy.23,24 For patients with grade 1 neuropathy, I might consider using EV after an informed discussion, and might start the patient at a lower dose with close monitoring. Obviously if patients cannot receive immunotherapy, then giving standard platinum‑based chemotherapy would make sense.
An alternative is gemcitabine, cisplatin, and nivolumab, which improved outcomes vs gemcitabine plus cisplatin in the CheckMate 901 trial.25 Although cross‑trial comparisons should be viewed cautiously, the benefits of EV plus pembrolizumab stand out more to me, compared with the CheckMate 901 regimen. Further, many of the toxicities of EV, especially neuropathy and hyperglycemia, are also associated with cisplatin.26 In addition, the steroids used to control nausea associated with either regimen may cause significant hyperglycemia. Thus, HCPs must be thoughtful about using either one of these regimens in patients with uncontrolled diabetes or preexisting neuropathy. But I think once providers are comfortable using EV plus pembrolizumab, it really should be the preferred regimen for patients who have locally advanced or metastatic urothelial cancer and have not had previous treatment.
Rana R. McKay, MD
This regimen has absolutely changed the landscape of how HCPs treat urothelial cancers with metastatic disease. Frontline chemotherapy is no longer the standard. I think that for patients who are candidates to receive EV plus pembrolizumab, this has now become the new standard of care. It is certainly going to change how we sequence treatments and how we strategize therapy for patients.
I find it very exciting to have this option for my patients and to see OS for urothelial cancer approaching 3 years, which was never heard of 5 years ago. In that sense, this trial is really striking.
AMBASSADOR: Adjuvant Pembrolizumab vs Observation in High-Risk Muscle-Invasive Urothelial Carcinoma
Terence Friedlander, MD:
The next study I want to discuss is the phase III AMBASSADOR trial. This randomized trial was designed to determine the value of adjuvant pembrolizumab after cystectomy in patients who have pathologic T2 or higher or node‑positive disease and received neoadjuvant chemotherapy, or those with pathologic T3 or node‑positive disease who were either cisplatin ineligible or declined chemotherapy.27 Pembrolizumab was given for up to 18 cycles, approximately 1 year of therapy. The coprimary endpoints of this study were OS and disease‑free survival (DFS), and secondary endpoints included OS and DFS in the PD‑L1–positive vs PD‑L1–negative populations, as well as safety. I think it is important to keep in mind that this study utilized observation instead of a placebo in the comparator arm, since the patients knew what treatment they received.
AMBASSADOR: Baseline Characteristics
Terence Friedlander, MD:
In terms of baseline characteristics, the groups were well-balanced and the majority of the patients in this trial were male and White.27 These are important factors to keep in mind as these results are applied to other racial, ethnic, and gender populations. Most of the patients in both arms received neoadjuvant chemotherapy. Approximately 50% of patients enrolled in the study had node-positive bladder cancer at the time of surgery, and 40% had T2 or T3, node-negative bladder cancer. These percentages were balanced between the 2 arms. More than half of patients in each arm were PD‑L1 positive using the 22C3 assay. The majority of patients had bladder as their primary tumor site, although approximately 20% in each arm had disease in the upper tract, either the ureter or the renal pelvis. Approximately 15% of patients in each arm had some variant histology, excluding neuroendocrine disease.
AMBASSADOR: Disease‑Free Survival in ITT Patient Population and by Patient Age and ECOG PS
Terence Friedlander, MD:
With respect to efficacy, there is a clear benefit to giving pembrolizumab in the adjuvant setting.27 The median DFS with pembrolizumab more than doubled vs observation (29.0 months vs 14.0 months) with an HR of 0.69 (95% CI: 0.54-0.87, P = .001). It is exciting to see an improvement in DFS with pembrolizumab compared with close surveillance or watchful waiting in patients who have bladder cancer with a high risk of metastasis.
Across the different subgroups of age and ECOG PS, pembrolizumab therapy resulted in better DFS. Among patients with an ECOG PS of 2, there was a much wider confidence interval, but this may be attributed to the limited number of patients (n = 31), so it is difficult to make definitive conclusions regarding that population.
AMBASSADOR: Disease‑Free Survival by Neoadjuvant Treatment and Disease Stage, Site, and PD‑L1 Status
Terence Friedlander, MD:
When we examine subgroups based on neoadjuvant treatment, disease stage, site, and PD‑L1 status, the data still show a benefit with pembrolizumab for the majority of these subgroups.27 This included the subgroup of patients who did and those who did not receive neoadjuvant therapy; and among patients who were either T2/3N0 or NX and patients who were node positive. There are 2 subgroups—patients with positive surgical margins and patients who were T4N0 or NX—that are too small to produce conclusive data with wide confidence intervals.
What was quite interesting to me was that patients with lower tract disease clearly benefited, but the HR for patients with upper tract disease crossed 1 (HR: 1.05, 95%CI: 0.61-1.82). Other trials of immune checkpoint therapy also found that patients with upper tract primary tumor sites may not benefit as much from immune checkpoint therapy.28 This phenomenon calls into question the biology of upper tract disease, which may be different from lower tract disease. One of the challenges is that a fairly small number of patients with upper tract disease were enrolled in each arm. Additional data are needed to determine conclusively whether patients with upper tract disease have less benefit from adjuvant pembrolizumab.
Finally, both patients with PD‑L1–positive tumors and those with PD-L1–negative tumors derived a benefit with adjuvant pembrolizumab. This presents a bit of a contradiction with what is known about the biology of checkpoint inhibitors in urothelial cancer.29 I am not sure that there is a very convincing explanation as to why the PD-L1–negative subgroup seemed to benefit more from adjuvant pembrolizumab than the PD-L1–positive group, except that perhaps this difference is not statistically significant. Of note, the assays used to determine PD‑L1 positivity differ from study to study, so one must be careful about extrapolating conclusions from one study to another.
AMBASSADOR: Interim OS in the Total Patient Population and by Patient Age and ECOG PS
Terence Friedlander, MD:
In contrast to DFS, the interim OS data do not demonstrate any benefit associated with pembrolizumab vs observation.27 In the observation arm, 22% of patients went on to receive a checkpoint inhibitor in the post-DFS setting, which may affect these data. Although OS was negative at this interim analysis, it is important to recall that investigators still saw a strong PFS benefit. Additional follow-up data are still needed to draw conclusions regarding OS in this study.
The subgroup analyses by age and PS are a bit difficult to interpret. Patients older than age 75 appeared to derive the most benefit (HR: 0.62, 95% CI: 0.39-0.99) in contrast to younger patients where the HR was approximately 1. With respect to ECOG PS, HR values were close to 1 with the ECOG PS 1 group experiencing moderate improvement in OS, but the HR of 0.89 (95% CI: 0.63-1.27) does not suggest a significant benefit. I think interpretation of these data is confounded by the subsequent therapy these patients received.
AMBASSADOR: Interim OS by Neoadjuvant Treatment and Disease Stage, Site, and PD‑L1 Status
Terence Friedlander, MD:
In terms of OS in other prespecified subgroups, no difference was observed between patients who did or did not receive neoadjuvant chemotherapy.27 Patients who had T2/T3N0 or NX disease appeared to benefit a little more than the other subgroups, noting again that the subgroup of patients with positive surgical margins was small.
Of interest, the patients with upper tract disease experienced worse OS when treated with adjuvant pembrolizumab than patients with lower tract disease. However, due to the small number of patients in this group, the small number of total events observed, and the 95% CI crossing 1, I do not think that these data should be taken conclusively.
Similar to DFS, patients with PD‑L1–negative tumors seemed to demonstrate improved OS vs those with PD‑L1–positive tumors. This again calls into question the precision and reproducibility of PD‑L1 assays, as this result was very unexpected. In prior studies with immune checkpoint inhibitors such as nivolumab, the PD‑L1–positive group seemed to benefit much more than the PD‑L1–negative group.30 However, the differences in assays and therapies used in these studies require caution when comparing and interpreting these results.
AMBASSADOR: Other Systemic Therapy
Terence Friedlander, MD:
As I alluded to earlier, patients in this study may have received other systemic therapy in addition to pembrolizumab or observation.27 I applaud the investigators for separating the data by subsequent therapy either before or after patients met the primary endpoint of DFS. In the observation arm, 5% of patients (n = 18) received a checkpoint inhibitor before the primary endpoint of DFS. Presumably, this could obscure some of the differences between the 2 arms. Then, after a DFS event, 30% of patients in the observation arm received other therapy, including 22% who received checkpoint inhibitors. It is hard to say whether this magnitude of crossover to a checkpoint inhibitor completely eliminated the survival benefit of pembrolizumab, but it might have made the data harder to interpret.
AMBASSADOR: Adverse Events
Terence Friedlander, MD:
With regard to AEs, there were no new safety signals observed with adjuvant pembrolizumab.27 The rates of hematologic and nonhematologic AEs were similar in both treatment arms. The rate of grade 3/4 AEs was higher with pembrolizumab vs observation (43.5% vs 27.1%).
AMBASSADOR: Most Common Treatment-Related Adverse Events
Terence Friedlander, MD:
Specifically considering treatment-related AEs in the pembrolizumab arm, most were grade 1 and 2, and a small number were grade 3.27 These were common AEs that are frequently seen with checkpoint inhibitors.
AMBASSADOR: Clinical Implications
Terence Friedlander, MD:
What are the implications of this study? To date, there have only been 3 studies of adjuvant immunotherapy in urothelial cancer. IMvigor010 was a study of atezolizumab that was considered a negative study; it did not meet its primary endpoint.31 CheckMate 274, a study of nivolumab, showed a DFS benefit for nivolumab compared with placebo, though the OS data are still pending.30 Thus AMBASSADOR is viewed as a decider study because 1 study produced negative results, and 1 produced positive results. It is interesting that the results presented here are split down the middle.27 AMBASSADOR is positive for DFS, but not for OS which are coprimary endpoints.
Given that both nivolumab and pembrolizumab are approved already for advanced urothelial carcinoma, I think it makes sense that pembrolizumab demonstrates some activity in this context, but it is hard to understand a few things about this study. One is the magnitude of benefit in OS. There was not much receipt of immunotherapy in the control arm at later time points, yet pembrolizumab did not provide an OS benefit. The differences in OS among patients with PD-L1–positive vs PD-L1–negative tumors also seem contradictory to what is known about PD-L1 as a biomarker.
To put these results in context, I believe that thinking about adjuvant therapy in bladder cancer as one-size-fits-all is not the correct way to interpret this study. There are other biomarkers that may prove useful for patient selection for therapy. In the IMvigor010 study, cell-free DNA detectable after removal of the bladder predicted a high risk of relapse.31 The phase III IMvigor011 trial (NCT04660344) is enrolling patients based on the presence of cell-free DNA after cystectomy, and I think that is a more informed way to think about the use of checkpoint inhibitors. There is a lot more to be done with biomarkers to understand the determinants of efficacy.
Assuming pembrolizumab is FDA approved for adjuvant use, I think it would be reasonable to use pembrolizumab for treatment, based on this DFS data, even though there is no OS difference. Longer-term follow-up is still necessary to make these decisions.
Rana R. McKay, MD:
I think these data are very important and have clinical implications, especially in the context of the adjuvant nivolumab data in urothelial cancer. I think the big story here is the lack of impact on OS. Additional OS data with further follow-up and curation of the data are still needed, but I just want to commend the cooperative groups for being able to execute this very large, practice-informing study. Hopefully we will see additional data at future congresses.
PemCab: Pembrolizumab and Cabozantinib for Patients With Untreated Advanced/Metastatic Urothelial Carcinoma
Terence Friedlander, MD:
PemCab was an open-label phase II trial examining the activity of pembrolizumab plus cabozantinib in previously untreated, locally advanced or metastatic urothelial cancer in patients deemed cisplatin ineligible with tumor PD-L1 CPS ≥10, or patients who were platinum ineligible regardless of PD-L1 status, or who refused cisplatin-based chemotherapy.32 Patients were required to have an ECOG PS of 0 to 2. This trial enrolled 36 patients, with the goal of establishing a platinum-free treatment option. The primary endpoint was ORR by investigator and secondary endpoints included 6-month PFS, OS, duration of response, disease control rate, and safety.
PemCab: Baseline Characteristics
Terence Friedlander, MD:
The baseline characteristics of this patient population are as expected from patients with locally advanced or metastatic urothelial cancer.32 Approximately 75% of patients had visceral metastases and approximately 70% had some evidence of renal dysfunction.
PemCab: Patient Disposition
Terence Friedlander, MD:
The patient disposition shows that most of the patients have already finished treatment or are off study treatment due to various factors, so the study data are fairly mature.32
PemCab: ORR and OS
Terence Friedlander, MD:
The ORR was 45%, with 16 patients responding to pembrolizumab plus cabozantinib; 14% of patients had complete responses and 31% had partial responses.32 The median duration of response was fairly long, at 14.7 months. The median PFS was 7.6 months, and the median OS was 17.1 months. Altogether, I think this therapy demonstrated reasonable efficacy, though it is hard to know how to interpret these data in the setting of multiple new therapies that are active in the frontline space.
PemCab: Treatment-Emergent Adverse Events in ≥20% of Patients
Terence Friedlander, MD:
In terms of AEs, there were no new safety signals, but it is apparent that this regimen is not the easiest to tolerate.32 Fatigue, diarrhea, palmoplantar erythrodysesthesia, and other skin issues were fairly common, and there were some grade 3 events observed in those categories. These AEs are on target for cabozantinib, which is an active and approved therapy in renal cell carcinoma (RCC) and liver cancer.7 Overall, 50% of patients experienced grade ≥3 treatment-emergent AEs. Grade 4 events associated with cabozantinib occurred in 2 patients, including colonic perforation and GI bleeding. Approximately half of patients required dose interruptions with cabozantinib.
Immune-related AEs associated with pembrolizumab were also common (83%), with 11% of patients requiring high-dose steroids. The median number of doses was 7.5 cycles for cabozantinib and 10 cycles for pembrolizumab.
Despite the proportion of patients requiring dose interruptions or reductions, I think this regimen could be tolerable for a fit patient.
PemCab: Clinical Implications
Terence Friedlander, MD:
I applaud the authors for devising a treatment regimen that is platinum-free, because so many patients are not able to tolerate platinum chemotherapy. But is there a role for a tyrosine kinase inhibitor (TKI) like cabozantinib in urothelial cancer? TKIs have multiple effects, including on VEGF, MET and other pathways that may be important in urothelial cancer. Combinations of a TKI with immunotherapy is effective for treatment of RCC.33,34
In this study the ORR is 45%; however, 40% response rates have been observed in studies of single agent cabozantinib in prostate cancer.10 There have also been studies of single agent TKIs, such as pazopanib, in the past, that did not show much efficacy for treatment of urothelial cancer.35 So, it is not clear to me how each of the components of this regimen are contributing to the anti-tumor activity observed. Future studies should endeavor to tease out the individual effects of each treatment component.
I think with the introduction of EV plus pembrolizumab into the frontline, and the addition of other ADCs and targeted therapies in the second line, I am unsure where this regimen fits into the treatment landscape for urothelial carcinoma. It will be interesting to see these data in a larger cohort.
ANTICIPATE: Neoadjuvant APL-1202 Plus Tislelizumab for Muscle-Invasive Bladder Cancer
Terence Friedlander, MD:
The phase I/II ANTICIPATE trial is assessing a combination of oral APL-1202 and tislelizumab in patients with cisplatin-ineligible localized bladder cancer planning to undergo cystectomy.36 APL-1202 is a MET AP2 inhibitor with both antiangiogenic and antitumor properties also known as nitroxoline,37 and tislelizumab is an anti–PD-1 checkpoint inhibitor. The study consisted of a phase I dose escalation of APL-1202 plus tislelizumab and a phase II study comparing APL-1202 plus tislelizumab vs tislelizumab alone. The primary endpoint was pathologic complete response rate, and a key secondary endpoint was safety.
ANTICIPATE: Interim Analysis of the Pathologic Complete Response Rate
Terence Friedlander, MD:
Results presented at ASCO GU were an interim analysis of the phase II study that enrolled 42 patients—32 were evaluable for this analysis.36 In the combination therapy arm, 39% (n/N = 7/18) of patients exhibited a pathologic complete response, defined as pathologic T0 or N0, compared with 21% (n/N = 3/14) in patients who only received tislelizumab. This endpoint is particularly meaningful in this setting because patients who achieve T0 or N0 rarely relapse from bladder cancer. Disease in 1 additional patient was down staged to less than T2.
ANTICIPATE: Adverse Events
Terence Friedlander, MD:
In terms of safety, the most common treatment emergent grade ≥3 AEs in the combination arm were anemia and decreased lymphocyte counts.36 One patient experienced intestinal obstruction vs 3 patients with single-agent tislelizumab.
Treatment-related AEs with the combination were observed in more than 60% of patients, including 22% that were grade ≥3. Of note, this is a small trial with only 18 patients receiving combination therapy, so the absolute numbers of these events are quite small. In addition, some of these grade 3 AEs are easily treated, such as anemia and diarrhea.
Of importance, there was 1 death from septic shock post radical cystectomy in the combination arm. Although the investigators determined this death was not related to the study drugs, I think HCPs should continue to monitor the development of this drug to make sure that there are no other issues related to sepsis.
ANTICIPATE: Clinical Implications
Terence Friedlander, MD:
As with the previously discussed study, I applaud the investigators for developing a platinum-free neoadjuvant regimen. The data suggest that this combination of drugs has some increased activity compared with a PD-1 checkpoint inhibitor alone.36 I think this is very exciting, since in the neoadjuvant space, cisplatin/gemcitabine is currently the only regimen that is guideline recommended.38,39
In the future, I would love to see whether there are any predictive biomarkers for response to this drug, such as cell-free DNA. In all, I look forward to seeing the final analysis of these data and learning how this regimen performs in a larger study.
Sequencing Erdafitinib and Enfortumab Vedotin in Advanced Urothelial Carcinoma: Retrospective Analysis From the UNITE Database
Terence Friedlander, MD:
The last study I want to discuss investigates the sequencing of erdafitinib and EV in patients with advanced urothelial cancer with FGFR2/3 alterations.40 This was a retrospective study from the UNITE database, which is a consortium of academic centers that provides data on treatment patterns, particularly in treatment of urothelial cancer with novel agents. In total, there are over 600 patients in the database. Of these patients, 94 had an FGFR2/3 alteration.
In this study, the investigators performed a retrospective analysis to address the optimal sequence of therapy for patients with an FGFR2/3 alteration—either an FGFR inhibitor like erdafitinib first followed by the ADC EV or vice versa. Both EV and erdafitinib are FDA approved for treatment of urothelial cancer, but there has never been a head to head study investigating which drugs should be given or in what order.41,42 The study endpoints included OS and PFS.
Sequencing Erdafitinib and Enfortumab Vedotin in Advanced Urothelial Carcinoma: Baseline Characteristics
Terence Friedlander, MD:
There were 24 patients who started with erdafitinib and subsequently received EV, and 15 patients who started with EV and subsequently received erdafitinib. A group of patients who received EV monotherapy without erdafitinib served as a control arm.40
Although there were only a small number of patients in each group, there was not a dramatic difference in terms of the baseline characteristics between either group.
Sequencing Erdafitinib and Enfortumab Vedotin in Advanced Urothelial Carcinoma: OS, PFS, and ORR
Terence Friedlander, MD:
In terms of OS, the group that started with erdafitinib and transitioned to EV demonstrated a similar median OS compared with the patients who started with EV and transitioned to erdafitinib (21 months and 19 months, respectively).40 In comparison, patients who received EV monotherapy had a lower median OS of 12 months.
The median PFS was similar for all 3 groups at 5 to 6 months.
The ORR to EV was 67% when EV was the first drug given vs 32% when erdafitinib was administered first. The ORR to erdafitinib was essentially the same regardless of the sequence of therapy. Despite the limited number of individuals in this analysis, the data modestly favors giving EV first.
Sequencing Erdafitinib and Enfortumab Vedotin in Advanced Urothelial Carcinoma: Clinical Implications
Terence Friedlander, MD:
I think this is an important study to try and better understand how HCPs should be sequencing therapies in advanced urothelial cancer. HCPs now have a plethora of options, including EV and erdafitinib.39 Until now it was quite unclear which of these therapies to use as first- or second-line therapy for patients with FGFR mutations. Now, I think this study suggests that the OS and PFS of these drugs is comparable regardless of sequencing, although patients who are treated with EV first seem to have a higher response rate to that drug.
In my practice, I typically start with EV and switch to erdafitinib if the disease progresses, based on informed discussion of the risk–benefit profiles of each drug and considering patient preference. In the future, if a study incorporated a programmed switch between these 2 drugs, it would be great to see patient reported outcomes on tolerability, as that perspective could help determine when to use these drugs in the absence of a dramatic difference in efficacy.
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