The Addition of Frontline Maintenance Avelumab Improves OS in Urothelial Carcinoma

With the addition of avelumab (Bavencio) to best supportive care (BSC) as switch maintenance treatment after platinum-based chemotherapy in patients with locally advanced, unresectable or metastatic urothelial carcinoma, the median overall survival (OS) was improved by 7 months in the phase 3 JAVELIN Bladder 100 study, which was presented during the 2020 American Society of Clinical Oncology (ASCO) Virtual Scientific Meeting.¹

The median OS with avelumab plus BSC was 21.4 versus 14.3 months with BSC alone (HR, 0.69; 95% CI, 0.56-0.86; P <.001). The risk of death was reduced by 31% with the addition of the PD-L1 inhibitor. Overall, the OS benefit was observed across all prespecified subgroups.

The co-primary end points of the study were OS in the overall population and in those with PD-L1–positive tumors. Among the patients with PD-L1–positive tumors, the median OS was not reached with avelumab/BSC versus 17.1 months with BSC alone (HR, 0.56; 95% CI, 0.40-0.79; P = .0003).

Per blinded independent central review, the overall median progression-free survival was 3.7 months with avelumab/BSC versus 2.0 months in the control arm (HR, 0.62; 95% CI, 0.52-0.75; P <.001), and the HR for progression-free survival favored avelumab/BSC in the PD-L1–positive group (HR, 0.56; 95% CI, 0.43-0.73).

Overall, avelumab appeared well tolerated in this study. Adverse events (AEs) of any grade or cause (not only due to avelumab) occurred in 98% of the patients who received avelumab versus 77.7% in the control arm, and any-cause grade 3/4 AEs were observed in 47.4% versus 25.2% of patients, respectively. The most common grade 3 or greater AEs in the avelumab/BSC versus BSC-alone arms, respectively, included urinary tract infection (4.4% vs 2.6%), anemia (3.8% vs 2.9%), hematuria (1.7% vs 1.4%), fatigue (1.7% vs 0.6%), and back pain (1.2% vs 2.3%).

These positive results are practice-changing in the treatment landscape for patients with advanced urothelial cancer and represent a new standard of care in the frontline setting.

In an interview with Targeted Oncology, Petros Grivas, MD, PhD, physician, Seattle Cancer Care Alliance; associate professor, Department of Medicine, Division of Oncology, and clinical director, Genitourinary Cancers Program, University of Washington School of Medicine; and associate member, Clinical Research Division, Fred Hutchinson Cancer Center, discussed the findings from the phase 3 JAVELIN Bladder 100 study, which evaluated the addition of avelumab to best supportive care in patients with locally advanced, unresectable or metastatic urothelial cancer. He also spoke to data from the COVID-19 and Cancer Consortium (#CCC19) on the clinical impact of the coronavirus disease 2019 (COVID-19) on patients with cancer.

TARGETED ONCOLOGY: Could you share some background on the JAVELIN Bladder 100 trial and what the rationale was for evaluating this immunotherapy in this patient population?

Grivas: The JAVELIN Bladder 100 trial was a randomized phase 3 clinical trial trying to answer the following question: when patients in the frontline setting have metastatic urothelial cancer, they get the usual platinum-based chemotherapy, and after completion of this induction chemotherapy, as we call it, they usually get monitored or observed over time to see if there is any progression of the cancer so we can move to the second-line therapy. The question has been, can we maintain (or sustain) the benefit that we see in many patients with the front-line chemotherapy, the induction chemotherapy, in terms of response or stable disease? Since we cannot give chemotherapy forever because of potential AEs, can we sustain or maintain this benefit with immunotherapy in this switch maintenance approach? That's why this was a switch maintenance frontline trial where patients got chemotherapy in the first line, gemcitabine/cisplatin or gemcitabine/carboplatin, and they finished chemotherapy after 4, 5, or 6 cycles. [These] patients were randomized to avelumab, an anti–PD-L1 immunotherapy, plus best supportive care or best supportive care alone. The primary end point of the study was OS (to compare how long these 2 populations live after randomization that occurred 4 to 10 weeks after the end of frontline induction chemotherapy).

TARGETED ONCOLOGY: What were the findings from the trial?

Grivas: The main findings of the study saw that avelumab plus best supportive care significantly prolonged OS compared to best supportive care alone, and this difference was statistically and clinically significant with a prolongation of OS. The median OS exceeded 21 months after randomization in patients with avelumab plus best supportive care. It was a bit more than 14 months in patients with best supportive care alone, which is a huge difference if you think what we usually see in oncology. This met the OS end point based on statistical rigorous evaluation, I would say, with a very impressive hazard ratio of 0.69, suggesting longer life with patients getting avelumab.

This was in all-comers, so we do not need to check any biomarker for the patients. This result was also corroborated in the subset of patients with tumors having high PD-L1 expression—a co-primary endpoint—but because the OS benefit was seen so clearly in all-comers, that's why I say that we do not need to check for PD-L1 or any other biomarker in this maintenance setting.

The toxicity profile and the safety with avelumab was very consistent with what we know about avelumab and other checkpoint inhibitors in urothelial cancer, so there was no difference there compared to what we know. No new safety signals [were seen] whatsoever.

Overall, in my opinion, this is practice-changing because right now instead of finishing chemotherapy frontline and waiting until progression happens, we can actually utilize avelumab based on this study as a switch maintenance frontline approach.

TARGETED ONCOLOGY: Could you elaborate on the toxicity of this regimen?

Grivas: The AEs with avelumab are consistent with what we know from other checkpoint inhibitors and with avelumab in metastatic urothelial cancer. We saw what we call immunotherapy-related AEs, and when you do a clinical trial, you look at what we call treatment-emergent AEs, which is regardless of what caused it, and also treatment-related AEs. In this particular study, there were no new concerns about the safety of avelumab. What we saw in the study was, again, very consistent with what we know about this agent from other studies and what we know about other checkpoint inhibitors in other studies, specifically in urothelial cancer.

I always caution my patients on any immunotherapy to report any particular changes that may happen that could potentially give us a sense of an immunotherapy-related AE, such as fatigue, skin rash, thyroid changes, diarrhea, cough, shortness of breath, changes in the color of the skin, or anything else, because any system/organ could potentially be affected by immunotherapy-related AEs. However, the [chances] of a particularly severe event happening is very low, and this was actually corroborated in this study.

Only a small proportion of patients had to stop avelumab treatment because of toxicity. That proportion was about 12% of patients due to treatment-emergent AEs, of any cause, with avelumab plus BSC.

TARGETED ONCOLOGY: What are the implications of these data?

Grivas: I think the practical implications are for patients who complete frontline platinum-based chemotherapy in advanced urothelial cancer, you do restaging scans, usually CT scans, to restage the patient and see if there is either response or stable disease or progression. After the end of frontline chemotherapy—we usually tend to give 4, 5, or 6 cycles depending on the tolerance and response status—then after you finish chemotherapy and you have a response or stable disease, then you can switch to avelumab before progression in order to maintain this benefit achieved with frontline induction chemotherapy. When I have a discussion with my patients in the frontline setting to discuss options, of course, we still discuss other clinical trials, but I think the standard of care right now for those patients (with no progression on chemotherapy) is pretty much consistent with the results of the JAVELIN Bladder 100 trial.

TARGETED ONCOLOGY: Are there any other next steps planned for this research?

Grivas: I think we would like to show the results in the different subsets of patients. That's an important question, whether all the different subsets/subpopulations benefit with avelumab. That's an important question that we'll plan to present in detail in future analyses and also look at different biomarkers. I think it's a beautiful opportunity to look at biomarkers in this disease and work on very interesting correlative studies. We're also going to look at patient-reported outcomes and quality of life, which is also a very important component. So, stay tuned in the future for subset analyses and subpopulations in terms of outcomes, translational endpoints and correlative studies, biomarkers, and also patient-reported outcomes and quality of life.

TARGETED ONCOLOGY: Overall, how do you see these data impacting the treatment landscape?

Grivas: I think the uptake, in my opinion, is expected to be huge. Of course, we have to wait for FDA approval and for other regulatory agencies to review these data, but after this happens, I have no doubt that this will become a standard of care. It's very difficult to change the standard of care in this disease. We may work for years and do studies that may either be of no benefit at all or of marginal benefit sometimes. I think this study shows pretty clearly that the standard of care is changing. The discussions that we're having during this virtual ASCO meeting are very important and relevant, so we are looking forward to further feedback from colleagues in the community and academia about this practice-changing study and how they view it.

The last point to make is that, as I mentioned before, it's very difficult to have a phase 3 trial that actually significantly prolongs OS, and if I can go back in time, in the last 10 to 15 years, I can think probably of 1 more immunotherapy trial that met the primary end point of OS, the KEYNOTE-045 trial, but this was in the platinum-refractory setting, so second line and beyond. In the frontline setting, this is the first trial with immunotherapy that showed OS benefit, so that's great news for our patients. We're hopeful in the future that more studies will give us positive results.

TARGETED ONCOLOGY: Could you also discuss the methods of design for the analysis from the COVID-19 Cancer Consortium2 on the clinical impacts of COVID-19 in patients with cancer?

Grivas: In the middle of March, many of us started discussing the potential impact of COVID-19 on patients with cancer and vice versa, whether the context of cancer changes the outcome for patients with COVID-19. These important questions may have implications in the discussion with the patient regarding treatment selection, so on and so forth. I think based on this unmet need, especially in those early days, again, this [was in the] middle of March, we developed this consortium with colleagues from other cancer centers, specifically Jeremy Warner, MD, MS, at Vanderbilt University, who has been the ‘orchestrator’ of this approach, and several other highly esteemed colleagues. Dr Warner has worked in the past heavily with surveys and REDCap, which is a HIPAA-compliant platform. We generated this consortium, we have 11 steering committee members, and I'm honored to be 1 of them. The consortium now has grown and has more than 100 institutions from the United States, Canada, and Spain. We are trying to expand and have more of a worldwide presence in order to be able to capture data, and the way we do that [is through] a survey that we developed within the steering committee. This survey is being filled out by providers at each cancer center in order to give us more granular information and specific data in patients with cancer and COVID-19. This is a great resource, using this ‘crowdsourcing’ method, to develop very rapidly granular, high-quality information from different cancer centers to have retrospective data regarding risk factors, baseline factors, demographics, cancer characteristics, history of cancer, treatments of cancer, as well as treatments for COVID-19, and outcomes of those patients. That has been the mission of our consortium.

The main results were published in the Lancet on May 28, 2020.³ At the same time, the ASCO embargo was lifted. Our intent of the main analysis was to look at the 30-day mortality of those patients with cancer and COVID-19 and this number was 13%, which is double or even a bit more than double compared to the mortality we see in other patient populations in the literature. The number is definitely concerning. Then, we looked at particular risk factors that can be associated with higher risk of death within a month from diagnosis, and those included older age, since we know more senior patients have higher risk of death; male sex; former smoking, since we know smoking can be a high risk factor for multiple things in life; poor performance status, eg patients who have ECOG score 2 or higher, so poor functionality has a higher risk of mortality in 30 days; and also the presence of active/measurable cancer in scans as opposed to a cancer in remission; cancer progression was a risk factor as well.

Interestingly, and I have to say up front, we have to take the next finding with a huge grain of salt because of potential confounding factors. The combination of hydroxychloroquine plus azithromycin was associated with higher risk of mortality in 30 days. You can imagine that patients were sicker and in more severe condition they may have had a higher chance to receive this combination. There might be confounding factors of indication and severity that may not allow us to draw definitive conclusions about this combination, so we're very cautious about how we interpret these data, again because of the possible selection and confounding biases.

Overall, I would say that the mortality in 30 days was higher than expected compared to patients historically (with no cancer). At the same time, though, I think that 1 of the take home messages for me, personally, is that if the patient needs a cancer-directed treatment now, I think it's very reasonable to have this dialogue with the patient 1 by 1 and weigh carefully the benefits or risks, and likely proceed with anti-cancer therapy without delay. At least in my practice, I think we usually go ahead and proceed with cancer-directed therapy because the patient may need treatment for cancer. We use extreme precautions, social distancing, strict hygiene measures, masks, and everything that protects our patient, but I think that patients who need urgent treatment for cancer, I think in most practices, they go ahead soon with cancer treatment, even more in places where we may have more control of the pandemic.

TARGETED ONCOLOGY: Are there any plans to continue this research?

Grivas: Absolutely. We don't stop here. This is just the beginning. We already have plans to update our data. The first data analysis was based on 928 patients, so just short off 1000 patients. It's probably the largest COVID-19 and cancer registry to date. This is huge. And the Lancet publication happened about 75 days after we founded the consortium, so this is probably record time. [This shows] what you can achieve as a team when you work together with a time pressure behind you. However, to your point, we don't stop, here we continue. We wish we had 0 cases, but as we all know, this is not the case. We try to capture as much as we can, and right now we have collected many more cases. We're probably going to soon have double or triple the size of this initial sample size. We're going to update our data and look at more specific information, such as specific tumor types, specific treatments, and try to answer questions that many oncologists are asking right now, [such as] “Is it safe to give chemotherapy, immunotherapy in this particular patient with this cancer type?” And to answer this question definitively, [we need] to capture a larger sample size. We need to wait for a higher number of events in order to have more definitive conclusions, always with a caveat of a retrospective study with selection and confounding factors. We're going to continue to try to contribute to this knowledge in the next few months with updated data analyses.

TARGETED ONCOLOGY: Was there any other data from the 2020 ASCO meeting that you found particularly exciting?

Grivas: There's a lot of exciting data for all types, including bladder cancer, which is the area of my expertise. There was another oral presentation by Maha Hussain, MD, [on] the results of a clinical trial with adjuvant atezolizumab (Tecentriq), an anti–PD-L1, versus observation in patients who had radical surgery for bladder cancer or upper track urothelial cancer.⁴ These patients had either received neoadjuvant platinum-based chemotherapy, or if they had not received that, they either could not safely get adjuvant cisplatin (not fit for cisplatin), or refused it. This patient population that I described were randomized to either atezolizumab or observation in this adjuvant trial. The primary end point was disease-free survival, and we also looked at OS as a secondary end point.

This study, despite huge efforts and a lot of work from many individuals, patients, of course, families, investigators, and the sponsor, did not meet the primary end point of disease-free survival. In the adjuvant setting, this did not change practice. We still, for patients who meet the criteria for other studies and could not get (or refuse) adjuvant chemotherapy for the reasons we discussed above (or had received neoadjuvant chemotherapy), continue with other clinical trials, with the standard of care of observation in the absence of a trial.

In that context, I want to say that there are 2 other immune checkpoint inhibitor trials, 1 with pembrolizumab (Keytruda) (which is accruing patients) and the other with nivolumab (Opdivo) that still has not reported results, so we have to wait and see. There also are targeted therapies. For example, there's an ongoing phase 3 trial with infigratinib versus placebo for patients with tumors havingFGFR3 mutation or fusion in the tumor tissue. There is another trial with a different agent in Europe, and these studies are important to answer questions in this adjuvant setting.

TARGETED ONCOLOGY: This year's meeting is a lot different than the previous years, where people are now able to just log in at home and see all of the data at once, but we're also losing that in-person connection. What are your thoughts on the virtual platform?

Grivas: It's a very different experience compared to what we're used to. I think everyone looks forward to ASCO also because of the networking. You can see the content online, but it's different to go there and meet your colleagues, new people, interact, ask and answer questions, and have personal face-to-face, productive, stimulating interactions with colleagues, as well as academic investigators, community oncologists, industry, etc. We work together in different collaborative projects, and we learn from each other, so we missed that this year, no doubt, but I believe that ASCO did the right thing. As always, the ASCO meeting was very productive and thoughtful despite the pandemic, so this was the right thing to do. We're pleased to at least have ASCO virtually. There are all these virtual meetings going on, so it's a virtual world. It is suboptimal but necessary during this pandemic, so I'm glad at least we have had that opportunity to attend that way.

_References

1. _{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. Presented at: 2020 ASCO Virtual Scientific Program; May 29-31, 2020. Abstract LBA1.}
2. _{Warner JL, Rubinstein S, Grivas P, et al. Clinical impact of COVID-19 on patients with cancer: Data from the COVID-19 and Cancer Consortium (CCC19). Presented at: 2020 ASCO Virtual Scientific Program; May 29-31, 2020. Abstract LBA110.}
3. _{Kuderer NM, Choueiri TK, Shah DP, et al. Clinical impact of COVID-19 on patients with cancer (CCC19): a cohort study. Lancet. Published online May 28, 2020. doi:10.1016/S0140-6736(20)31187-9}
4. _{Hussain MHA, Powles T, Albers P, et al. IMvigor010: primary analysis from a phase III randomized study of adjuvant atezolizumab (atezo) versus observation (obs) in high-risk muscle-invasive urothelial carcinoma. Presented at: 2020 ASCO Virtual Scientific Program; May 29-31, 2020. Abstract 5000.}

_{Dr. Grivas' COI/disclosures:}

_{Petros Grivas (all unrelated in the last 3 years): consulting for AstraZeneca, Bayer, Bristol-Myers Squibb, Clovis Oncology, Driver, EMD Serono, Exelixis, Foundation Medicine, GlaxoSmithKline, Genentech, Genzyme, Heron Therapeutics, Janssen, Merck, Mirati Therapeutics, Pfizer, Roche, Seattle Genetics, QED Therapeutics; participation in educational program for Bristol-Myers Squibb; and institutional research funding from AstraZeneca, Bavarian Nordic, Bayer, Bristol-Myers Squibb, Clovis Oncology, Debiopharm, Genentech, Immunomedics, Kure It Cancer Research, Merck, Mirati Therapeutics, Oncogenex, Pfizer, QED Therapeutics.}