(UroToday.com) The 2024 American Society of Clinical Oncology (ASCO) annual meeting featured a session on optimizing treatment for your patient with urothelial cancer, and a presentation by Dr. Pooja Ghatalia discussing the optimal treatment intensity for frontline therapy for advanced urothelial cancer. Prior to ESMO 2023, chemotherapy followed by maintenance immunotherapy was the standard front line treatment for metastatic urothelial carcinoma. This was based on trials completed back in the 2000s whereby gemcitabine + cisplatin and dose dense MVAC led to overall responses rates of ~50% to 70% in the cisplatin eligible patients, and gemcitabine + carboplatin having a response rate of 36% in the cisplatin ineligible patients:
Following chemotherapy, standard of care became maintenance avelumab based on the JAVELIN Bladder 100 trial that showed a median overall survival of 21.4 months versus 14.3 months for best standard of care:1
More recently, several trials have compared chemotherapy + immunotherapy in the front line setting, including IMvigor130,2 KEYNOTE-361,3 DANUBE,4 and CheckMate-901,5 with the aforementioned first three trials negative, but with CheckMate-901 being a positive trial:
In CheckMate 901, 608 cisplatin-eligible patients underwent 1:1 randomization to either:
- Nivolumab 360 mg on D1 + gemcitabine (1,000 mg/m2) on D1/8 + cisplatin (70 mg/m2) on D1 in 3-week cycles, up to a total of 6 cycles
- Nivolumab maintenance at 480 mg every 4 weeks was continued as maintenance therapy in responders until progression, unacceptable toxicity, withdrawal, or up to 24 months
- Gemcitabine + cisplatin at same doses/schedule/cycles
The trial design for CheckMate 901 is as follows:
The co-primary endpoint of progression free survival per blinded independent central review was significant with improvement in median progression free survival from 7.6 to 7.9 months (HR: 0.72, 95% CI: 0.59 – 0.88, p = 0.0012):
Similarly, overall survival showed a median improvement in the experimental arm of nearly 3 months (21.7 versus 18.9 months; HR: 0.78, 95% CI: 0.63 – 0.96, p = 0.017). The objective response rate was higher in the experimental arm (58% versus 43%), with a higher proportion of patients achieving a complete response with nivolumab + gemcitabine/cisplatin (22% versus 12%):
Based on these results, on March 6, 2024, the FDA approved nivolumab in combination with cisplatin and gemcitabine for first-line treatment of adult patients with unresectable or metastatic urothelial carcinoma. Could the use of cisplatin-based chemotherapy have led to the positive results in CheckMate-901? Dr. Ghatalia states that potentially, yes. Additional work from the IMvigor130 trial showed that patients receiving cisplatin-based chemotherapy had an improved overall survival when combined with atezolizumab:
More recently, enfortumab vedotin has been approved in the bladder cancer space. Enfortumab vedotin is an antibody drug conjugate that targets nectin-4 and releases its MMAE payload in cancer cells. The objective response rates from monotherapy trials ranges from 40-50% in the second and third line setting, and in combination with pembrolizumab in early studies demonstrated objective response rates of 73% (EV 103-A, cisplatin ineligible) and 64.5% (EV 103-K, cisplatin ineligible). These results led to the trial design of EV-302, with the objective of comparing the combination of enfortumab vedotin + pembrolizumab to platinum-based chemotherapy in previously untreated locally advanced/metastatic urothelial carcinoma patients, regardless of cisplatin eligibility and PD-L1 expression status.6 Patients in this trial were randomized 1:1 to either enfortumab vedotin + pembrolizumab (n = 442) or gemcitabine + cisplatin/carboplatin (n = 444) for a maximum of 6 cycles. Notably, there were no maximum treatment cycles for enfortumab vedotin (i.e., continued until clinical/disease progression or unacceptable toxicity), whereas pembrolizumab was administered for a maximum of 35 cycles. The dual primary endpoints were progression-free survival, assessed via blinded independent central review, and overall survival. The study design is as follows:
The median patient age was 69 years, and the vast majority (97.5% had an excellent performance status, ECOG: 0 – 1). Notably, ~25% of patients had upper tract disease. Overall, 46% of patients were cisplatin-ineligible, and 58% had tumors with a high PD-L1 expression. Liver metastases, a known adverse prognostic factor, was present in 22% of patients:
Compared to platinum-based chemotherapy, enfortumab vedotin + pembrolizumab prolonged progression-free survival from a median of 6.3 months to 12.5 months (HR: 0.45, 95% CI: 0.38 – 0.45, p < 0.001):
Overall survival was nearly doubled in the enfortumab vedotin + pembrolizumab arm, with median survivals of 31.5 and 16.1 months, respectively (HR: 0.47, 95% CI: 0.38 – 0.58, p < 0.00001). These survival benefits were observed despite a higher proportion of patients in the chemotherapy arm receiving a subsequent systemic therapy (66.2% versus 28.9%):
Significantly, clinically meaningful benefits for enfortumab vedotin + pembrolizumab were observed irrespective of cisplatin eligibility:
A complete response was observed in 29% of patients in the enfortumab vedotin + pembrolizumab arm, compared to 12.5% for platinum-based chemotherapy. The objective response rates were 68% and 44%, respectively:
On December 15, 2023, the FDA approved enfortumab vedotin in combination with pembrolizumab for patients with locally advanced or metastatic urothelial cancer. However, enfortumab vedotin + pembrolizumab is associated with significant toxicity. Serious treatment related adverse events occurred in 27.7% of patients in the enfortumab vedotin + pembrolizumab arm, compared to 19.6% with chemotherapy. Treatment related adverse events leading to death occurred in 4 patients (0.9%) in each arm. Overall, grade 3+ adverse events occurred in 56% and 70% of patients in the enfortumab vedotin + pembrolizumab and chemotherapy arms, respectively. The most common enfortumab vedotin treatment related adverse events were skin reactions, peripheral neuropathy, ocular disorders, and hyperglycemia:
The median onset of peripheral neuropathy from enfortumab vedotin + pembrolizumab is ~3 months:
Although the skin reactions and hyperglycemia tend to resolve in the majority of patients, only ~23% of patients have resolution of their peripheral neuropathy at 7 months. Toxicity related to enfortumab vedotin tends to be secondary to deconjugation of the MMAE payload before the drug reaches the target site, targeted mediated endocytosis, and release of the payload from targeted/non-targeted cells after apoptosis occurs:
Cutaneous toxicity from enfortumab vedotin + pembrolizumab is quite common given that nectin-4 tends to be expressed in hair follicles and sweat glands. These rashes are often erythematous and scaly, have pruritic papules, and occur in the intertriginous, flexural, acral, and truncal regions. Up to 10% of these lesions are grade 3-4 bullous or a desquamative rash. Prophylaxis includes zinc-containing moisturizers and sunscreen, while treatment of mild to moderate symptoms includes topical steroids and/or antibiotic cream. Patients experiencing these symptoms should have a brief treatment break and resume enfortumab vedotin + pembrolizumab at the same or lower dose. For grade 3 adverse events, treatment may include oral steroids (0.5 mg/kg/day x 14 days), and grade 3+ or recurrent adverse events should include stopping the treatment and a dermatology referral:
With regards to neurologic toxicity from enfortumab vedotin + pembrolizumab, this includes sensory, motor, and autonomic dysfunction in a symmetric “stocking-glove” distribution, which can be progressive and rapid. Management of grade 1 toxicity is no dose adjustment, but for grade 2 toxicity includes holding treatment till toxicity decreases to <= grade 1, then treating with a reduced dose. Grade 3 or 4 toxicity should lead to treatment discontinuation:
An under-reported toxicity from enfortumab vedotin + pembrolizumab is pneumonitis, presenting as shortness of breath, fever and/or cough. The median onset is ~3 months after starting treatment, with organizing pneumonia as the most common pattern of toxicity. Steroids may be needed for treatment and this can also occur in an overlapping fashion with pembrolizumab pneumonitis. Hyperglycemia occurs in ~10% of patients that receive enfortumab vedotin + pembrolizumab, occurring via an unknown mechanism but likely related to insulin resistance. Risk factors include a high BMI and base-line hemoglobin A1c of > 6.5%. Treatment should be to hold enfortumab vedotin + pembrolizumab if the glucose is > 250. Dry eyes/blurry vision occurs in 36%/14% of patients treated with enfortumab vedotin + pembrolizumab, and treatment includes artificial tears and topical steroids in more severe cases. Generally, patients should have a baseline eye examination prior to starting enfortumab vedotin + pembrolizumab treatment.
Dr. Ghatalia notes that in this fast moving disease space of front-line treatment for metastatic urothelial carcinoma, the preferred initial therapy is enfortumab vedotin + pembrolizumab. If patients are unable to access enfortumab vedotin + pembrolizumab, the next step is determining cisplatin eligibility:
There are several unanswered questions for the front-line treatment of metastatic urothelial carcinoma. This includes understanding the optimal duration of treatment and response to enfortumab vedotin re-challenge after holding for toxicity. Dr. Ghatalia is the PI on a trial looking at reducing treatment burden among patients responding to enfortumab vedotin + pembrolizumab over time:
There is also a planned phase II trial of enfortumab vedotin + pembrolizumab induction therapy followed by maintenance pembrolizumab:
Another important unanswered question is sequencing of therapies. The ECOG-ACRIN 8231 is assessing sacituzumab + pembrolizumab versus sacituzumab among patients that have previously received adjuvant anti-PD(L)1 therapy:
Another trial is answering the question of what is the role of chemotherapy among patients that progress after enfortumab vedotin + pembrolizumab?
Dr. Ghatalia concluded her presentation by discussing the optimal treatment intensity for frontline therapy for advanced urothelial cancer with the following take home messages:
- Enfortumab vedotin + pembrolizumab has become the preferred front-line treatment option for patients with metastatic urothelial carcinoma
- Gemcitabine + cisplatin + nivolumab followed by maintenance immunotherapy is another front-line therapy options for patients who cannot receive enfortumab vedotin + pembrolizumab
- Clinicians should closely monitor treatment related adverse events such as peripheral neuropathy, cutaneous toxicity, and pneumonitis
- Induction enfortumab vedotin + pembrolizumab followed by maintenance pembrolizumab is of growing interest
Presented by: Pooja Ghatalia, MD, Fox Chase Cancer Center, Philadelphia, PA
Written by: Zachary Klaassen, MD, MSc – Urologic Oncologist, Associate Professor of Urology, Georgia Cancer Center, Wellstar MCG Health, @zklaassen_md on Twitter during the 2024 American Society of Clinical Oncology (ASCO) Annual Meeting, Chicago, IL, Fri, May 31 – Tues, June 4, 2024.
References:
- 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.
- 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.
- 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.
- Powles T, van der Heijden MS, Castellano D, et al. Durvalumab alone and durvalumab plus tremelimumab versus chemotherapy in previously untreated patients with unresectable, locally advanced urothelial carcinoma (DANUBE): A randomized, open-label, multicentre, phase 3 trial. Lancet Oncol. 2020;21(12):1574-1588.
- Van der Heijden MS, Sonpavde G, Powles T, et al. Nivolumab plus Gemcitabine-Cisplatin in Advanced Urothelial Carcinoma. N Engl J Med. 2023 Nov 9;389(19):1778-1789.
- Powles T, Valderrama BP, Gupta S, et al. Enfortumab Vedotin and Pembrolizumab in Untreated Advanced Urothelial Cancer. N Engl J Med. 2024 Mar 7;390(10)875-888.