Cora N. Sternberg, MD, discusses the case of a 66-year-old woman with bladder cancer.
Cora N. Sternberg, MD, professor of Medicine, clinical director, Englander Institute for Precision Medicine, Weill Cornell Medicine, Meyer Cancer Center in a NewYork-Presbyterian, discusses the case of a 66-year-old woman with bladder cancer.
Targeted OncologyTM: What is your experience around dose-dense (DD) MVAC (methotrexate, vinblastine, doxorubicin, cisplatin) and cisplatin/gemcitabine?
STERNBERG: Patients who get DD MVAC have a tail in their outcomes curve, which is not enough to show the overall survival [OS] but is statistically significant.1 There are patients who do better with DD MVAC. It is usually given in 50-year-old patients. Most patients with urothelial cancer are in their 70s or even 80s. Gemcitabine and cisplatin doesn’t have a tail in its outcomes curve unlike [DD MVAC] but it is probably the most often used. The overall response rates [ORRs] are not as high with the DD MVAC or MVAC, but it’s the most popular.2
The EORTC [European Organisation for Research and Treatment of Cancer] study [NCT00014274] by Maria De Santis, MD, et al3 compared gemcitabine and carboplatin [gem-carbo] with M-CAVI [methotrexate, carboplatin, vinblastine]. It was a very toxic regimen and patients did better on gem-carbo than on M-CAVI, which is not used anymore. The ORR was 36% in patients on gemcitabine and carboplatin, 72% in those on DD MVAC, and 49% on those on gemcitabine and cisplatin. Median OS [mOS] in the cisplatin-ineligible patients was 9.3 months, which is less than the cisplatin-eligible patients that was 15.1 months for DD MVAC and 14 months for gem-cis. It’s always impossible to compare trials because it’s different patient populations.
What is the rationale for considering avelumab (Bavencio) for maintenance therapy?
In the year 2020, there was a failure of 3 phase 3 trials on immunotherapy combined with chemotherapy in bladder cancer. The KEYNOTE-361 study [NCT02853305], which was presented at ESMO [European Society for Medical Oncology] 2020, added pembrolizumab [Keytruda] to chemotherapy with either gemcitabine/carboplatin or gemcitabine/cisplatin. With the negative results from the trial, I think pembrolizumab lost its halo a little bit in urothelial cancer. People were quite disappointed because they thought that adding pembrolizumab would really make a difference, but it didn’t.4,5
The DANUBE trial [NCT02516241], a large trial with a long follow-up, had 3 different arms. One of them was [combination therapy with] durvalumab [Imfinzi] and tremelimumab [CP-675,206], [another one was monotherapy with durvalumab, and the third was standard-of-care therapy with gem-cis or gem-carbo based on cisplatin eligibility].6 Tremelimumab is a CTLA-4 inhibitor and durvalumab a PD-L1 inhibitor. In this trial, we learned how important statistics are, because the 2 end points that they looked at were both negative. However, the end point of durvalumab and tremelimumab combination, which was not a primary end point in the patients who were PD-L1 positive, was positive.6 So, how you design a trial from the very beginning can make a huge difference. The DANUBE trial, which had the longest follow-up, failed and durvalumab has been pulled off the United States market as a second-line therapy, probably because of the statistics and the way it was designed.
The IMvigor130 trial [NCT02807636], which was a first-line trial that added atezolizumab [Tecentriq] to either gem-carbo or gem-cis also failed. Although the progression-free survival [PFS] presented at the ESMO meeting in 2019 was promising, the OS data were held up for years and was finally presented at the AACR [American Association for Cancer Research annual meeting], but there was no difference in OS either. Atezolizumab was also pulled off the United States market as a second-line therapy.7 It is a shame this happened because of these trials.
The Hoosier Cancer Research Network [HCRN] GU14-182 is a phase 2 trial [NCT02500121], which does not really show an OS difference. There were 108 patients on chemotherapy who were randomized 1:1 and switched to maintenance with either intravenous [IV] pembrolizumab 200 mg every 3 weeks or IV placebo every 3 weeks for up to 24 months. They had a crossover built into the study and [patients on the placebo arm] all received pembrolizumab. The ORR in the pembrolizumab arm was twice as high as that of the placebo arm. The PFS was 5.4 months vs 3 months, and the difference in OS was not statistically significant.8 This was [a small study with] only about 50 patients in each arm. It was a precursor to [the results of the] JAVELIN Bladder 100 trial [NCT02603432], which was a much larger trial. There was no significant interaction between the PD-L1 status and the treatment arm, either for PFS or OS, in the HCRN trial.
So there is a rationale for using immunotherapy maintenance after frontline chemotherapy. We saw before that immunotherapy with chemotherapy does not seem to work. A Spanish trial presented at ESMO 2020 used avelumab up front and then gave chemotherapy and that didn’t work either.9
It seems that by giving chemotherapy and killing tumor cells and causing DNA damage, new antigens, which are immunogenic, are formed. So, the anti–PD-L1 and anti– PD-1 immunotherapy that works to make the patient’s own T cells kill the tumor cells as many more new antigens are formed. That’s just one of the mechanisms of action. It’s thought that by giving chemotherapy first you knock out as many cells as you can, cause DNA damage, and increase the number of neoantigens. There are other potential mechanisms of action that would explain why this would work in this order.10
Do the cisplatin eligibility, PD-L1 status, and eGFR of a patient influence the decision to use avelumab?
In this case study, the patient was PD-L1 positive, but I think that is irrelevant at this point because the patient was cisplatin ineligible. Atezolizumab and pembrolizumab are approved for cisplatin-ineligible patients who are PD-L1 positive. In the United States, you can give it even to patients who are not PD-L1 positive, but in the rest of the world it is only for patients who are PD-L1 positive. These are patients who can get any chemotherapy but can’t get the carboplatin.
The JAVELIN Bladder 100 study of avelumab maintenance after first-line therapy had patients who had a complete response [CR], partial response [PR], or stable disease [SD] with standard first-line chemotherapy. They got 4 to 6 cycles of either gem-cis or gem-carbo.11 MVAC and other regimens were not included in this trial and even in the NCCN [National Comprehensive Cancer Network] guidelines.
Patients had unresectable, locally advanced, or metastatic urothelial cancer. They had a treatment-free interval between 4 weeks and 10 weeks, and we scanned them in the study to make sure that they had maintained the initial response. The 700 patients were randomized 1:1 to IV avelumab 10 mg/kg every 2 weeks and best supportive care, or best supportive care alone. They weren’t given IV placebo in this trial. The primary end point was OS and we analyzed populations of all the patients and the PD-L1– positive patients. There was no crossover that was built in as a part of this study, unlike the HCRN trial.11
The results of the JAVELIN Bladder 100 trial were presented at the American Society of Clinical Oncology 2020 and published in the New England Journal of Medicine. The OS rate at 12 months was 71% in the avelumab and best supportive care [BSC] arm vs 58% for the BSC arm. At 18 months, the OS rate was 61% for avelumab plus BSC compared with 44% for BSC alone. The mOS was 21 months vs 14 months, with a [stratified] hazard ratio of 0.69 [95% CI, 0.56-0.86; P < .001]. The PD-L1–positive population was even more positive than this.11
The ORR in the PD-L1–positive population was 13.8% and 9.7% in the overall population. The disease control rate [for the overall population] including CR, PR, and stable disease was 41% in the avelumab plus BSC arm [and 27.4% for BSC alone arm]. For the PD-L1–positive population, disease control was 43.9% in the avelumab plus BSC arm compared with 27.8% for the BSC alone arm.11
The hazard ratios for practically every subgroup that was looked at favored the avelumab plus BSC arm. This was independent of age, ECOG performance status, and whether they got [carboplatin or cisplatin as first-line chemotherapy]. [Other subgroups looked at included best response to first-line chemotherapy (CR, PR, or stable disease)], whether they had visceral or nonvisceral disease and whether their creatinine clearance was more or less than 60 mL/min, and the PD-L1 status. The patients with PD-L1–positive status really benefited quite a lot and those with negative status crossed the hazard ratio of 1 but still showed a benefit for avelumab and BSC.11
The mPFS in the PD-L1–positive population was 2.1 months in the BSC arm vs 5.7 months in the avelumab arm [HR, 0.56; 95% CI, 0.43-0.73]. The OS had not been reached yet in the avelumab arm compared with the BSC arm that was 17.1 months [HR, 0.56; 95% CI, 0.40- 0.79; P < .001]. So patients with PD-L1 status and all other patients in this study benefited from the avelumab maintenance.11 Most patients benefited [from avelumab maintenance based on site of metastases]. The OS and PFS showed a benefit based on best response. The patients with CR, for example, had an OS with a hazard ratio of 0.81 [95% CI, 0.47-1.38], whereas those with PR had an OS with a hazard ratio of 0.62 [95% CI, 0.46-0.83].
In the BSC arm, nearly half of the patients went on to receive an immune checkpoint inhibitor, either PD-L1 or PD-1 inhibitor.11 This shows that waiting and treating a patient when they progress is not as good as treating patients immediately. Even when they have a good response to chemotherapy with a CR, PR, or stable disease, treating them right away with avelumab is a better way to go. Even though half of the patients crossed over, the OS is much better when they are treated earlier.
Treatment-emergent adverse events [TEAEs] led to discontinuation of avelumab in 11.9% of patients. Death was attributed by the investigator to study treatment toxicity in 2 patients [0.6%] in the avelumab plus BSC arm. One was due to sepsis in cycle 10 of avelumab and the other one due to an ischemic stroke 100 days after a single dose of avelumab.11
The immune-related AEs [irAEs] often seen with immunotherapy included hypothyroidism, rash, and hyperthyroidism. There were no grade 4 or 5 irAEs. High-dose corticosteroids (> 40 mg of prednisone or equivalent) were administered in only 9% of patients treated with avelumab.11 The FDA approved avelumab for urothelial cancer maintenance treatment in June 2020.12
In the NCCN guidelines and the ESMO guidelines, [category 1 recommendations for] patients who are cisplatin eligible include gem-cis with avelumab maintenance and DD MVAC and growth factor support with avelumab maintenance. For cisplatin-ineligible patients, the preferred regimens are gem-carbo followed by avelumab maintenance. You can give atezolizumab or pembrolizumab for patients who are PD-L1 positive or are ineligible for any platinum-containing regimen.13
[Considering the outcomes based on duration of first-line chemotherapy using either quartiles or number of cycles showed that] no matter how long the patients got treated, they all benefited from the avelumab treatment. This was true whether they had a CR, PR, or stable disease. I think they had a little bit more benefit if they had 6 cycles of chemotherapy, but there was a benefit even in those who had 4 cycles or 5 cycles of first-line chemotherapy.14
1. Sternberg CN, de Mulder P, Schornagel JH, et al. Seven year update of an EORTC phase III trial of high-dose intensity M-VAC chemotherapy and G-CSF versus classic M-VAC in advanced urothelial tract tumours. Eur J Cancer. 2006;42(1):50-54. doi:10.1016/j.ejca.2005.08.032
2. von der Maase H, Sengelov L, Roberts JT, et al. Long-term survival results of a randomized trial comparing gemcitabine plus cisplatin, with methotrexate, vinblastine, doxorubicin, plus cisplatin in patients with bladder cancer. J Clin Oncol. 2005;23(21):4602-4608. doi:10.1200/JCO.2005.07.757
3. De Santis M, Bellmunt J, Mead G, et al. Randomized phase II/III trial assessing gemcitabine/carboplatin and methotrexate/carboplatin/vinblastine in patients with advanced urothelial cancer who are unfit for cisplatin-based chemotherapy: EORTC study 30986. J Clin Oncol. 2012;30(2):191-199. doi:10.1200/JCO.2011.37.3571
4. Merck provides update on phase 3 trial evaluating Keytruda as monotherapy and in combination with chemotherapy in patients with advanced or metastatic urothelial carcinoma. News release. Merck. June 9, 2020. Accessed July 27, 2021. https://bit.ly/3x5o8op
5. Powles T, Csőszi T, Özgüroğlu M, et al; KEYNOTE-361 Investigators. Pembrolizumab alone or combined with chemotherapy vs chemotherapy as first-line therapy for advanced urothelial carcinoma (KEYNOTE-361): a randomised, open-label, phase 3 trial. Lancet Oncol. 2021;22(7):931-945. doi:10.1016/S1470-2045(21)00152-2
6. Powles T, van der Heijden MS, Castellano D, et al; DANUBE Study Investigators. Durvalumab alone and durvalumab plus tremelimumab versus chemotherapy in previously untreated patients with unresectable, locally advanced or metastatic urothelial carcinoma (DANUBE): a randomised, open-label, multicentre, phase 3 trial [published correction appears in Lancet Oncol. 2021;22(1):e5]. Lancet Oncol. 2020;21(12):1574-1588. doi:10.1016/S1470-2045(20)30541-6
7. Galsky MD, Arija JÁA, Bamias A, et al; IMvigor130 Study Group. Atezolizumab with or without chemotherapy in metastatic urothelial cancer (IMvigor130): a multicentre, randomised, placebo-controlled phase 3 trial. Lancet. 2020;395(10236):1547-1557. doi:10.1016/S0140-6736(20)30230-0
8. Galsky MD, Mortazavi A, Milowsky MI, et al. Randomized double-blind phase II study of maintenance pembrolizumab versus placebo after first-line chemotherapy in patients with metastatic urothelial cancer. J Clin Oncol. 2020;38(16):1797-1806. doi:10.1200/JCO.19.03091
9. Perez Valderrama B, Castellano Gauna D, Pinto Marin A, et al. LBA27 phase II multicenter, randomized study to evaluate efficacy and safety of avelumab with gemcitabine/carboplatin (CG) vs CG alone in patients with unresectable or metastatic urothelial carcinoma (mUC) who are ineligible to receive cisplatin-based therapy. Ann Oncol. 2020;31(suppl 4):S1158-S1159. doi:10.1016/j.annonc.2020.08.2256
10. Grivas P, Agarwal N, Pal S, et al. Avelumab first-line maintenance in locally advanced or metastatic urothelial carcinoma: applying clinical trial findings to clinical practice. Cancer Treat Rev. 2021;97:102187. doi:10.1016/j.ctrv.2021.102187
11. Powles T, Park SH, Voog E, et al. Avelumab maintenance therapy for advanced or metastatic urothelial carcinoma. N Engl J Med. 2020;383(13):1218-1230. doi:10.1056/NEJMoa2002788
12. FDA approves avelumab for urothelial carcinoma maintenance treatment. FDA. Updated July 1, 2020. Accessed July 27, 2021. https://bit.ly/3jaforD
13. NCCN. Clinical Practice Guidelines in Oncology. Bladder cancer, version 4.2021. Accessed July 27, 2021. https://bit.ly/3ilwynx
14. Loriot Y, Powles T, Durán MÁC, et al. Avelumab (Ave) first-line (1L) maintenance plus best supportive care (BSC) vs BSC alone for advanced urothelial carcinoma (UC): JAVELIN Bladder 100 subgroup analysis based on duration and cycles of 1L chemotherapy. J Clin Oncol. 2021;39(suppl 6):438. doi:10.1200/JCO.2021.39.6_suppl.438