ESMO 2023: Discussant: EV-302/KEYNOTE-A39 & CheckMate 901: Welcoming a New Standard of Care in the First-Line Treatment of Urothelial Carcinoma

(UroToday.com) The 2023 European Society of Medical Oncology (ESMO) Annual Congress held in Madrid, Spain between October 20^th and 24^th, 2023 was host to a presidential session. Dr. Andrea Apolo delivered the discussant for the preceding two late-breaking oral abstract presentations:

• EV-302/KEYNOTE-A39: Open-Label, Randomized Phase 3 Study of Enfortumab Vedotin in Combination with Pembrolizumab (EV+P) Vs Chemotherapy (Chemo) in Previously Untreated Locally Advanced Metastatic Urothelial Carcinoma (la/mUC)
• Nivolumab plus gemcitabine-cisplatin versus gemcitabine-cisplatin alone for previously untreated unresectable or metastatic urothelial carcinoma: results from the phase 3 CheckMate 901 trial

The standard of care management of advanced/metastatic urothelial carcinoma pre-ESMO 2023 consisted of 1^st line cisplatin + gemcitabine in eligible patients (carboplatin + gemcitabine in cisplatin ineligible) followed by maintenance avelumab in those who achieve response to platinum-based chemotherapy. Immune checkpoint inhibitors are reserved for platinum-ineligible patients (pembrolizumab) or in the 2^nd line following chemotherapy (pembrolizumab, nivolumab, or avelumab).

Enfortumab vedotin is an antibody-drug conjugate consisting of three parts:

• The antibody: Anti-nectin-4
• The payload: Monomethyl auristatin E (MMAE)
• The linker (stable in circulation, but releases the cytotoxic agent in the target cell)

Nectin-4 is highly expressed in metastatic urothelial cancer patients, thus not necessitating tumor screening. The payload MMAE (plus linker) is vedotin, a microtubule-disrupting agent (200x more potent than vinblastine). In December 2019, the FDA accelerated the approval of EV for 2 indications:

1. Platinum and PD-1/L- refractory metastatic urothelial carcinoma
2. Cisplatin-ineligible and have previously received PD-1/PD-L1 therapy

EV-302/KEYNOTE-A39 and CheckMate-901 are the first two phase 3 trials of checkpoint inhibitor combinations versus platinum-based chemotherapy to demonstrate an overall survival benefit in the 1^st line metastatic urothelial carcinoma disease space. Two previous trials (IMvigor130:¹ Chemotherapy + atezolizumab; KEYNOTE-361:² chemotherapy + pembrolizumab) have failed to show an OS benefit in this setting, with an additional trial (NILE: Chemo +/- durvalumab +/- tremelimumab) currently ongoing.

The goals of treatment in the 1^st line setting in metastatic urothelial carcinoma are:

• Early tumor shrinkage
• Durable responses
• Longer overall survival
• Minimal treatment toxicity

One potential criticism of the control arm in EV-302 is that almost half of patients received carboplatin due to cisplatin ineligibility. However, it appears that the objective response rate (ORR) with carboplatin in 1^st line phase 3 trials is comparable to that seen in cisplatin/gemcitabine or any platinum/gemcitabine treated patients at 41 – 42%, as summarized below:

The combination of EV + pembrolizumab has the highest ORR observed to date. The ORR was 68% with almost 30% of patients having a complete response. While cross-trial comparisons are fraught with limitations, these figures trump those observed in CheckMate-901 with nivolumab + gem/cis (58% and 22%, respectively) or other platinum-based chemotherapy combinations.

In addition to an improved ORR, the duration of response was also longest with EV + pembrolizumab, with the median duration not yet reached with this combination, compared to a median of 9.5 months with nivo + gem/cis.

Most importantly, there are clear OS benefits with both nivo + gem/cis (CheckMate-901) and EV + pembrolizumab (EV-302). CheckMate-901 is the 1^st study of combination chemotherapy + immune checkpoint inhibitors to demonstrate a significant OS benefit in this setting (21.7 versus 18.9 months).

Why was this CheckMate-901 positive and the other trials of chemotherapy + checkpoint inhibitors (IMVigor130 and KEYNOTE-361) negative? This may be related to the eligibility criteria, which included cisplatin ineligible patients in these two latter trials. A subgroup analysis of these trials clearly demonstrates an improvement when analysis is limited to those who received gem/cis. Potential reasons for this preferential improvement with cisplatin, as opposed to carboplatin, maybe that cisplatin has been associated with immunomodulatory effects, potentially through the induction of immunogenic cell death. Correlative studies in IMvigor130 have shown that:

1. Cisplatin, versus carboplatin, improved outcomes in patients with pre-treatment tumors exhibiting restrained adaptive immunity and
2. Cisplatin induced transcriptional changes in circulating immune cells, including upregulation of antigen presentation and T-cell activation

As such, it appears that cisplatin does not induce, but actually ‘reboots’ a pre-existing immune response leading to a dramatic response in a small subset of patients.

It is important to note that both sequential (JAVELIN 100:³ avelumab maintenance) and combination chemotherapy + checkpoint inhibitors have efficacy in this disease space. We, however, cannot directly compare these studies with different patient populations, with JAVELIN-100 specifically including those patients responding to 1^st line chemotherapy.

However, what is clear is that the combination of enfortumab vedotin + pembrolizumab far outperforms any other available combination for the 1^st line treatment of unresectable or metastatic urothelial carcinoma. The median OS of 31.5 months in the experimental arm of EV-302 outperforms all other combinations.

Dr. Apolo noted that more patients in the control arm of EV-302 received maintenance checkpoint inhibition before progressive disease (32% versus 20% in CHeckMate-901), and 59% received any subsequent checkpoint inhibitors (versus 40%). Given that approximately 30% of patients currently receive avelumab maintenance in clinical practice, these patterns are likely reflective of real-world practice.

Clearly, the results presented today are transformative and EV + pembrolizumab has emerged as the 1^st line treatment option for the 1^st line treatment of metastatic urothelial carcinoma. The ORR was 68% with almost 30% having a complete response. Subgroup analyses consistently favored the experimental arm in this cohort of ‘all comer’ 1^st line patients, with high activity irrespective of PD-L1 status, presence/absence of liver metastases, and cisplatin eligibility.

With the emergence of enfortumab vedotin + pembrolizumab as a 1^st line therapy, what does the best 2^nd line therapy become? Dr. Apolo suggested the following novel treatment paradigm in light of these novel data:

We also need to consider the EV + pembrolizumab-associated toxicities. Grade 3+ events occurred in 56% of patients, compared to 70% with chemotherapy. EV has a unique toxicity profile, which includes peripheral neuropathy (can be treatment-limiting), skin reactions, ocular disorders, and hyperglycemia. Can we give EV for 6 months and then continue pembrolizumab for maintenance? Can we dose-reduce EV in responders? It will be crucial to assess the efficacy of dose de-escalation strategies for this combination.

Why were the results of this combination so uniquely impressive? Why does MMAE combine so well with checkpoint inhibitors? Microtubule-destabilizing drugs such as dolastatin 10 or MMAE are highly potent cytotoxics that inhibit polymerization of tubulin to form microtubules. MMAE is an analog of dolastatin 10, with human dendritic cells exposed to MMAE upregulating costimulatory molecules and displaying enhanced T cell-stimulatory capacity. Preclinical studies have shown that EV induces early hallmarks of immunogenic cell death in vitro, immunomodulatory changes in mouse xenografts, and gene expression patterns associated with immunogenic cell death.

Another antibody drug conjugate with an MMAE payload is disitamab vedotin, which targets HER2. In September 2020, this drug was granted US FDA breakthrough therapy designation for urothelial carcinoma in the 2^nd or 3^rd line settings.

Similar to EV + pembrolizumab, it appears that the combination of disitamab vedotin + toripalimab (anti-PD-1) is associated with promising efficacy outcomes in HER2+ metastatic urothelial carcinoma patients.

As seen in other disease spaces, with the impressive results for EV + pembrolizumab, there are ongoing efforts to introduce this combination (along with EV + durvalumab +/- tremelimumab) in earlier disease settings (neoadjuvant and adjuvant), summarized in the slide below:

Dr. Apolo concluded her presentation as follows:

Two phase 3 trials in the first-line treatment of advanced/metastatic urothelial carcinoma have demonstrated an improvement in overall survival:

• Nivolumab + gemcitabine/cisplatin and enfortumab vedotin + pembrolizumab
• Nivolumab + gemcitabine/cisplatin is the first chemo/immunotherapy combination to show a survival benefit with a median OS of 21.7 months; however, the combination of enfortumab vedotin + pembrolizumab almost doubled the median OS versus chemotherapy (OS: 31.5 months), making it the new standard of care for patients in this setting.

Many challenges and questions arise when "Welcoming enfortumab vedotin + pembrolizumab as a new standard of care", including:

1. What treatment then becomes the best second-line therapy?
2. Can we dose de-escalate enfortumab vedotin, in enfortumab vedotin + pembrolizumab?
3. What is the underlying biology leading to the great response and OS and how do we build on this?
4. What is the efficacy of enfortumab vedotin + pembrolizumab in earlier states of disease (MIBC and NMIBC)?
5. Enfortumab vedotin + pembrolizumab is expensive; will patients, insurance, and public systems be able to afford this treatment?

Presented by: Andrea B. Apolo, MD, Chief, Bladder Cancer Section Genitourinary Malignancies Branch Center for Cancer Research, National Cancer Institute, Bethesda, MD

Written by: Rashid K. Sayyid, MD, MSc – Society of Urologic Oncology (SUO) Clinical Fellow at The University of Toronto, @rksayyid on Twitter during the 2023 European Society of Medical Oncology (ESMO) Annual Meeting, Madrid, Spain, Fri, Oct 20 – Tues, Oct 24, 2023. 

References:

1. Galsky MD, Arranz Arija JA, Bamias A, et al. Atezolizumab with or without chemotherapy in metastatic urothelial cancer (IMvigor130): A multicentre, randomized, placebo-controlled phase 3 trial. Lancet. 2020 May 16;395(10236):1547-1557.
2. Powles T, Csoszi T, Ozguroglu M, et al. Pembrolizumab alone or combined with chemotherapy versus chemotherapy as first-line therapy for advanced urothelial carcinoma (KEYNOTE-361): A randomized, open-label, phase 3 trial. Lancet Oncol. 2021 May 26;S1470-2045(21)00152-2.
3. Powles T, Park SH, Voog E, et al. Avelumab Maintenance Therapy for Advanced or Metastatic Urothelial Carcinoma. N Engl J Med 2020 Sept 24;383(13):1218-1230.