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Key Studies in Genitourinary Cancers: Independent Conference Coverage of the 2020 ASCO Virtual Scientific Meeting

Daniel P. Petrylak, MD
Elizabeth R. Plimack, MD, MS
Released: September 1, 2020

Urothelial Carcinoma

JAVELIN Bladder 100: Study Design

Elizabeth R. Plimack, MD, MS:
Next, we turn to studies in UC. The JAVELIN Bladder 100 study was a randomized, open‑label phase III trial of maintenance avelumab plus BSC vs BSC alone in 700 patients with unresectable locally advanced or metastatic UC who achieved a CR, PR, or SD with platinum-based chemotherapy for metastatic disease (Capsule Summary).[14] All patients enrolled on the study had previously responded to standard first-line platinum-based chemotherapy, which is important to keep in mind when interpreting the efficacy data. 

JAVELIN Bladder 100: Subsequent Anticancer Therapy

We should note that some patients in the BSC arm did not receive subsequent therapy, which is likely to have been to their detriment.[14] Almost one third (30.9%) of patients in the BSC arm discontinued with no subsequent therapy, of which 24.7% had discontinued for PD. For patients who received avelumab, 33.4% discontinued with no subsequent therapy and 29.6% had discontinued for PD. 

JAVELIN Bladder 100: Survival

Elizabeth R. Plimack, MD, MS:
The median OS in the overall population was 21.4 months with avelumab plus BSC compared with 14.3 months in the BSC arm—a difference that is statistically significant: HR 0.69 (95% CI: 0.56-0.86); P < .001.[14] The median PFS was also significantly extended with avelumab use: HR 0.62 (95% CI: 0.52-0.75); P < .001.

JAVELIN Bladder 100: OS Subgroup Analysis for Overall Population

Elizabeth R. Plimack, MD, MS:
A subgroup analysis confirmed the OS benefit with avelumab across patient populations.[14]

JAVELIN Bladder 100: Response

Elizabeth R. Plimack, MD, MS:
The ORR was 9.7% with avelumab vs 1.4% in the BSC arm, although this is really not a meaningful metric in this study, because all patients were already in response when they entered the study.[14] In fact, some patients were not evaluable because they had no measurable disease after their platinum-based chemotherapy regimen. 

JAVELIN Bladder 100: Treatment-Emergent Adverse Events

Elizabeth R. Plimack, MD, MS:
TEAEs for avelumab were in line with what we would expect based on the extensive single‑agent data across multiple tumor types.[15] Of note, avelumab is administered every 2 weeks and has a relatively high rate of infusion‑related reactions compared with other ICIs; 10.2% in this study. Overall, 11.9% of patients discontinued avelumab due to TEAEs, and 2 patients receiving avelumab died from causes considered related to study treatment.

JAVELIN Bladder 100: Immune-Related Adverse Events

Elizabeth R. Plimack, MD, MS:
IRAEs were also in line with previous data, and occurred in 29.4% of patients receiving avelumab, with 7.0% reporting grade ≥ 3 IRAEs. There were no grade 4/5 IRAEs.

JAVELIN Bladder 100: Conclusions

Elizabeth R. Plimack, MD, MS:
The median OS of 21.4 months seen in this study is the longest we have seen in any UC study, including frontline chemotherapy combination studies. It seems that platinum‑based therapy provides a really good investment for your patients in terms of maximizing their response to subsequent ICI therapy. However, there are still questions remaining.

The first is, if you have a patient with UC who has responded to previous platinum-based chemotherapy, should you now use an ICI maintenance therapy, or can some patients take a treatment break and initiate an ICI when/if they progress? Progression can be symptomatic, so delaying progression, as was seen with avelumab in this trial, can provide meaningful benefit for patients. That said, some patients may be able to wait until they progress to start an ICI and still achieve the same response. However, we do not know how to identify which patients can wait and which should start an ICI immediately as switch maintenance.

Second, there were some patients in the BSC arm who also did not progress (13% at 12 months). There is a long‑term PFS and OS benefit from platinum-based chemotherapy alone, so by using an ICI as switch maintenance therapy in this setting, we run the risk of overtreating these individuals.

The third caveat is that we do not know how the patients who progress on platinum-based chemotherapy will fare. This trial only included patients who were in response after platinum-based chemotherapy, so patients who do not respond to chemotherapy and receive an ICI in the second‑line setting may be very different. These patients represent approximately 15% of our patients; 85% will achieve at least SD to carboplatin-based or cisplatin‑based chemotherapy, and will be poised to achieve the best long‑term OS we have seen in UC.

Daniel P. Petrylak, MD:
Since these data were reported, avelumab has been approved by the FDA for maintenance treatment of patients with locally advanced and metastatic UC who have not progressed after frontline platinum-based chemotherapy.[15]

As Dr. Plimack mentioned, it is important to note that the JAVELIN Bladder 100 participants are a select group of patients that does not include patients without response to primary chemotherapy. This may explain why we see such an impressive median OS.

It is also not clear from these data whether patients who achieve a CR on platinum-based chemotherapy need maintenance therapy. A subgroup analysis reported OS HRs by best response to first-line chemotherapy, but this analysis included patients with a CR or PR in 1 group, instead of looking at those who achieved a CR vs a PR.

Another concern raised by the OS subgroup analysis is that the HRs were similar regardless of whether the initial chemotherapy was gemcitabine plus cisplatin (HR: 0.69; 95% CI: 0.51-0.94) or gemcitabine plus carboplatin (HR: 0.66; 95% CI: 0.47-0.91). However, other available data, such as the IMvigor130 trial with atezolizumab combined with either cisplatin or carboplatin and gemcitabine, suggest that cisplatin‑based chemotherapy is the better option,[16] so that is surprising. Finally, this and other trials have not included methotrexate plus vinblastine plus doxorubicin plus cisplatin (MVAC) therapy as an option for the initial chemotherapy regimen. Regardless of these caveats, I think these data provide a platform for future clinical trials, where we could add other therapies to the switch maintenance arm.

I do wonder whether avelumab is going to be accepted by the community in this age of COVID-19, where we may be seeking to limit clinic visits. Avelumab is administered every 2 weeks, whereas pembrolizumab is dosed every 6 weeks. If we truly believe that all ICIs are the same, which I am not so sure about, then should we consider giving an every-6‑week treatment with pembrolizumab vs giving avelumab every other week? That is something for which we are going to have to wait to see.

Elizabeth R. Plimack, MD, MS:
My center participated in HCRN GU14-182, a study of maintenance pembrolizumab in the same type of population,[17] so our experience is with that agent. I agree, the every-6‑week infusion schedule for pembrolizumab is appealing in the setting of maintenance therapy.

EV-103 Cohort A: Study Design

Daniel P. Petrylak, MD:
EV‑103 is a phase I/II multi-cohort study of enfortumab vedotin, an antibody–drug conjugate targeting nectin-4, in patients with UC. Our discussion focuses on cohort A, a group of 45 cisplatin-ineligible patients with locally advanced or metastatic UC treated with enfortumab vedotin in combination with pembrolizumab on a dose-escalation and dose-expansion schedule (Capsule Summary).[18]

Enfortumab vedotin was given on Day 1 and Day 8, every 3 weeks (1 dose less than the approved dose when given as a single agent[19]) combined with pembrolizumab given on the 3-weekly schedule. The primary endpoint was AEs and laboratory abnormalities, and key secondary endpoints included ORR, DoR, PFS, and OS. We have seen initial data from this study at previous meetings.[20] This presentation at the ASCO 2020 meeting reported findings about longer‑term responses.

EV-103: Baseline Characteristics

Daniel P. Petrylak, MD:
In EV-103, 91% of patients had visceral disease, which is what we would expect in this population.[18] Approximately one third (31%) of patients have a positive PD-L1 combined positive score (CPS) of ≥ 10, and 27% were not evaluable for PD-L1 expression. The primary tumor site was predominantly in the lower tract (69%).

EV-103: ORR and Tumor Reduction

Daniel P. Petrylak, MD:
Tumor response was impressive, and is probably the best we have seen with a combination regimen in this setting. The ORR in the overall population was 73.3% (95% CI: 58.1-85.4).[18] Of interesting, 53.3% of patients with liver metastases achieved a response. Eleven of 14 (78.6%) patients with high expression of PD-L1 achieved a response vs 12 of 19 (63.2%) with low PD-L1 expression.

Overall, 15.6% of patients had a CR, which compares with the 12% CR rate observed in the EV-201 study of enfortumab vedotin monotherapy in patients with metastatic disease who had been pretreated with platinum chemotherapy and anti–PD-1/L1 therapy.[21] So, there is a question here of whether pembrolizumab is adding to the DoR or to the ORR. 

EV-103: Change in Target Lesions

Daniel P. Petrylak, MD:
The slide shows the change in target lesions on treatment.[18] Most patients (88%) achieved a response by their first assessment, and the median time to response was 2 months.

EV-103: Survival and DoR

Daniel P. Petrylak, MD:
After a median follow-up of 10.4 months, the median DoR had not been reached.[18] The 12‑month DoR rate was 53.7%, with 55% of patients achieving an ongoing response. The median OS has not yet been reached, and the 12‑month OS rate was 81.6% (95% CI: 62.0-91.8). The median PFS was 12.3 months (95% CI: 7.98 to not reached).

EV-103: Safety

Daniel P. Petrylak, MD:
Safety data were similar to previous data on the use of these drugs as single agents; the most common TRAEs being fatigue, alopecia, peripheral neuropathy, diarrhea, and decreased appetite.[18] Grade ≥ 3 TRAEs occurred in 58% of patients. The main clinical concern is how to treat rash in patients receiving enfortumab vedotin, because it may have a different pattern than rash seen with immunotherapy or other agents, and generally requires topical steroids for management.[21]

EV-103: TRAEs of Clinical Interest

Daniel P. Petrylak, MD:
There are a few TRAEs of clinical interest with enfortumab vedotin. Grade ≥ 3 peripheral neuropathy occurred in 4% of patients; grade ≥ 3 rash in 13%; and grade ≥ 3 hyperglycemia in 7%.[18] Immune-mediated AEs requiring systemic steroids were seen in 29% of patients overall, of whom 18% experienced events of grade ≥ 3 severity.

EV-103: Conclusions

Daniel P. Petrylak, MD:
A randomized, phase III trial, EV-302, will assess enfortumab vedotin plus pembrolizumab with or without platinum-based chemotherapy vs platinum-based chemotherapy alone in patients with previously untreated locally advanced or metastatic UC.[22] The question is whether enfortumab vedotin can be used earlier. the response rate seen in studies so far is impressive, particularly in patients with liver and visceral metastases. In EV-103, the ORR in this subgroup was 53.3% compared with 38% in patients with liver metastases in the EV-201 single‑agent trial.[21] Is there true drug synergy when enfortumab vedotin is combined with pembrolizumab? We will need to see the final survival data from this study to assess that.

Elizabeth R. Plimack, MD, MS:
The response rate in this study is the best we have seen in bladder cancer. The EORTC study of high-dose-intensity MVAC in advanced UC reported an ORR of 64% at its 7-year update, with the inclusion of cisplatin,[23] so, in cross-trial comparison, these results are impressive.

Patients in EV-103 were treated with enfortumab vedotin until progression. What do you think about the long‑term tolerability of this agent? Are there any thoughts about stopping therapy for patients who achieve CR?

Daniel P. Petrylak, MD:
That’s a great question. I currently have 4 patients who have achieved CRs on enfortumab vedotin but have varying tolerability issues, including peripheral neuropathy. There is an art to managing neuropathy effectively. We put patients who display symptoms of neuropathy on physical therapy as soon as possible, we use pregabalin, and we reduce or delay dosing to alleviate symptoms.

Overall, patients have tolerated enfortumab vedotin very well but, understandably, are concerned about stopping therapy. I think that we need more data on whether that can be done, not just for enfortumab vedotin but also for ICIs. Now that enfortumab vedotin is approved by the FDA, there is perhaps more scope to consider stopping treatment than there was when patients were being treated on a clinical trial, and may have been concerned about how they would access the drug if they stopped.

Some patients do still progress rapidly on this drug; it is still not a cure at this point, but we are seeing higher numbers of patients achieve a CR, and in my experience, it is a well-tolerated drug. We do need to see data from a randomized trial, but so far, these results are impressive.

Elizabeth R. Plimack, MD, MS:
What might be the scientific basis for potential synergy between enfortumab vedotin and pembrolizumab?

Daniel P. Petrylak, MD:
There was a small preclinical study that did see synergy with this combination in animal models.[24] It could be that cellular damage from the chemotherapeutic agent causes antigen shedding, which is then more visible to the immune system. We have not yet proven that there is true synergy in clinical studies; it appears to be additive.

There are many questions remaining about the biology of enfortumab vedotin, along with other agents that target nectin-4. We do not know, for example, whether the anti-tumor agent monomethyl auristatin E (MMAE), needs to be delivered intracellularly or whether there is a “neighborhood effect.” The mechanism for resistance is also not understood. However, I think the crucial issue from a clinical standpoint is the depth of the response, which is encouraging so far. 

IMvigor010: Study Design

Daniel P. Petrylak, MD:
IMvigor010 is an international, open-label, randomized phase III trial of atezolizumab vs observation in 809 patients with high-risk muscle‑invasive urothelial cancer (MIUC) (Capsule Summary).[25] This is the first fully completed adjuvant study in bladder cancer, which points to the degree of interest in immune therapy in this field.

Patients were eligible if they had undergone radical cystectomy or nephroureterectomy with lymph node dissection within the previous 14 weeks, and had received no radiation or adjuvant chemotherapy following surgery. Patients were stratified based on whether they received neoadjuvant chemotherapy, the number of lymph nodes that were resected, and the stage of disease. The primary endpoint was disease-free survival (DFS) in the ITT population, and the secondary endpoints were OS and safety.

IMvigor010: Baseline Characteristics

Daniel P. Petrylak, MD:
Almost one half (47% to 48%) of patients had received previous neoadjuvant chemotherapy, and 52% were ≤ pT2-4 and pN positive.[25] The distribution of PD-L1 IHC status was as we would expect of this population, with approximately 50% of patients categorized as IC2 or IC3.

IMvigor010: DFS With Adjuvant Atezolizumab vs Observation in High-Risk MIUC (ITT; Primary Endpoint)

Daniel P. Petrylak, MD:
In the primary endpoint analysis, there was no significant difference in DFS between arms.[25] The median DFS was 19.4 months (95% CI: 15.9-24.8) with atezolizumab vs 16.6 months (95% CI: 11.2-24.8) in the observation arm, giving an HR of 0.89 (95% CI: 0.74-1.08; P = .2446). In subgroup analyses, there was no significant difference in any clinical subgroup, including no difference in DFS between the PD-L1 subgroups.

IMvigor010: OS With Adjuvant Atezolizumab vs Observation in High-Risk MIUC (ITT; Secondary Endpoint)

Daniel P. Petrylak, MD:
The OS data are not yet mature, with the median OS not yet reached. However, at this point in follow-up there was no difference in the median OS between arms; HR 0.85 (95% CI: 0.66-1.09).[25]

IMvigor010: Safety Summary

Daniel P. Petrylak, MD:
AEs were typical of those seen with an IO agent.[25] TRAEs occurred in 71% of patients receiving atezolizumab, 16% of these at grade 3/4 severity, and there was 1 (< 1%) grade 5 event. Grade 3/4 IRAEs occurred in 9% of patients receiving atezolizumab, and included rash, hepatitis, colitis, and others.

IMvigor010: Conclusions

Daniel P. Petrylak, MD:
I was surprised by the results of this study, because a significant number of patients from my center were on the trial, and we did not see many patients with progression. There are a few hypotheses on the negative results of this trial. One explanation that has been put forward is that by removing the primary tumor, there is not enough tumor antigen present to elicit an immune response. However, there would still likely be small cellular debris or microscopic disease present following surgery, so I am not sure this is a valid argument.

A second explanation is that it may be the therapy itself. Atezolizumab failed to meet the primary endpoint in the randomized phase III IMvigor211 trial of second‑line therapy for locally advanced or metastatic bladder cancer.[26] Some have speculated that the failure of that trial was due to unusually high response to chemotherapy in the patients with high PD-L1 expression, but one could also argue that there is an inherent difference between PD1 and PD-L1 inhibition. However, the JAVELIN Bladder 100 study of the PD-L1 inhibitor, avelumab, that we have just discussed would argue against that idea.[14]

There are 2 other phase III trials of adjuvant ICIs in metastatic UC: the CheckMate 274 trial of nivolumab, which has completed accrual,[27] and the AMBASSADOR trial of pembrolizumab.[28] I think we will need to see data from these studies to better understand the results of IMvigor010.

Elizabeth R. Plimack, MD, MS:
I agree. Pembrolizumab and atezolizumab have shown differing results in phase III assessment in the second‑line setting, so, as you have said, that could be an explanation here.[26,29] Certainly, these were surprising and disappointing results. 

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