Immunotherapy Added to CT Might Just Work in Bladder Cancer

Alexander M. Castellino, PhD

September 30, 2019

Dr Enrique Grande

BARCELONA, Spain — Immunotherapy added to chemotherapy might just work in advanced bladder cancer: results so far from IMvigor130 show an improvement in progression-free survival (PFS), but the data for overall survival (OS) are immature.

Immunotherapy with atezolizumab (Tecentriq, Roche/Genentech) in combination with chemotherapy (CT) achieved a statistically longer median PFS of 8.2 months compared with 6.3 months for those receiving CT alone. With a hazard ratio (HR) of 0.82 (P = .007), patients receiving the combination were at an 18% reduced risk for progression.

This is the largest trial in advanced bladder cancer so far, involving 1213 patients, noted study leader Enrique Grande, MD, of the MD Anderson Cancer Center Madrid, Spain.

Speaking here during a press briefing at the European Society of Medical Oncology (ESMO) 2019 annual meeting, he suggested that these results could be practice changing.

However, the OS data from the trial are immature. An interim analysis shows a trend but did not reach statistical significance: median OS was 16.0 months for the combination of atezolizumab and CT and 13.4 months for CT alone (HR, 0.82; 95% CI, 0.70, 0.96).

ESMO expert Ignacio Durán, MD, PhD, Hospital Universitario Marqués de Valdecilla, IDIVAL, Santander, Spain, suggested it is too early to be excited, but added the study is asking an important question: Does adding immunotherapy to conventional CT improve outcomes in a devastating disease?

This is the first signal that adding immunotherapy to CT might work better than CT alone in bladder cancer, Durán noted. Statistical significance does not always translate to clinical significance or relevance, he told Medscape Medical News.

However, he added that he will "not be going back to my clinic and changing my practice. These data need a longer follow-up...we need confirmation that the signal is real," he observed. One way this can be achieved is to wait and see if the separation of the OS curves is maintained over time and whether it achieves significance, he noted.

"Overall survival data are needed before we can consider this a new standard of care," Durán said.

Understanding Cisplatin Status in Bladder Cancer

Most trials in bladder cancer have been done in either cisplatin-eligible or cisplatin-ineligible patients, Grande said. "IMvigor130 is the first trial to include all patients," he added.

Durán explained that the first study to show bladder cancer was sensitive to cisplatin-based therapy was reported in 1989, he noted. The regimen used was MVAC (methotrexate, vinblastine, adriamycin, and cisplatin). Approximately 12 years later, a simpler combination of cisplatin and gemcitabine was shown to be as effective as MVAC and less toxic.

"These are the tools we have been using to treat patients with bladder cancer for a few decades," Durán said. But he also pointed out that the toxicities associated with cisplatin-based therapies are significant.

Not all patients with bladder cancer can receive cisplatin-based therapy, Durán said. Patients who are "ineligible" would meet one any one of the following: Eastern Cooperative Oncology Group performance status ≥ 2; creatinine clearance < 60 mL/min; grade ≥ 2 hearing loss; grade ≥ 2 neuropathy; New York Heart Association Class III heart failure.

"This would exclude approximately 50% of patients with bladder cancer," Durán said. It was only recently that the combination of carboplatin and gemcitabine was shown to be less toxic than cisplatin-containing regimens.

With the advent of immuno-oncology, immunotherapy agents have been approved as monotherapy for the first-line treatment of bladder cancer, but these therapies have been approved only for cisplatin-ineligible patients and those with high program death ligand 1 (PD-L1) expression, Durán pointed out.

That is why it is important to find regimens that can improve upon outcomes seen with chemotherapy, he noted.

Details of IMvigor130 Results

IMvigor130 was a Phase 3 study that randomized 1213 patients with advanced bladder cancer to one of three arms: atezolizumab and platinum-based CT (gemcitabine with cisplatin or carboplatin); atezolizumab monotherapy; or platinum-based CT (gemcitabine with cisplatin or carboplatin).  

In addition to the main results reported above, Grande also presented data based on tumor PD-L1 expression, which showed better responses in patients with high expression.

For patients with low PD-L1 expression, median OS was 13.5 months for atezolizumab monotherapy and 12.9 months with CT (P = 1.07). But for patients with high PD-L1 expression, median OS was not reached for patients receiving atezolizumab monotherapy and was 17.8 months for CT alone (HR, 0.68; 95% CI, 0.43 - 1.08).

Objective response rates were 47%, 23%, and 44% for combination atezolizumab, atezolizumab monotherapy, and chemotherapy, respectively. Correspondingly, complete responses were reported in 13%, 6%, and 7% of patients.

In an ESMO press statement, Durán noted that the so-called "complete responses" — understood as relevant shrinkage or disappearance of cancer metastases — were around twice as likely with the combination compared to CT or immunotherapy alone.

"This is remarkable. We are now eager to see if patients receiving the two therapies together live longer, and with a similar quality of life, than those receiving chemotherapy and immunotherapy alone or sequentially," he said.  

Grande reports relationships with Pfizer, Bristol-Myers Squibb, Ipsen, Roche, Eisai, EUSA Pharma, MSD, Sanofi Genzyme, Adacap, Novartis, Pierre Fabre, Lexicon, Celgene, Astellas, Janssen, Bayer, AstraZeneca, and Molecular Templates. Durán reports relationships with Roche-Genentech, BMS, MSD, Janssen, AstraZeneca, Seattle Genetics, Pharmacyclics, Bayer, Novartis, DebioPharm, Astellas, Ipsen, Eisai, and Clovis.

ESMO 2019 Annual Meeting. Presented September 30, 2019. Abstract LBA14. 

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