Targeted Oncology
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Molecular Profiling on the Uptake for Increased Targeted Therapies in Bladder Cancer

John Otrompke
Published Online: Nov 03,2016

Sumanta K. Pal, MD

The second revision of the 2016 guidelines on bladder cancer from the National Comprehensive Cancer Network (NCCN) contains substantial changes from past versions, including, for the first time, a reference to molecular profiling as a permissible consideration for treatment decision making. Research has identified tumor mutations in some 236 cancerrelated genes as potential subjects of study in clinical trials, although there are, as of yet, no FDA-approved mutation-specific targeted therapies in bladder cancer.1 The NCCN’s recommendation for molecular testing could make a considerable difference in increasing the amount of trials and targeted therapies in the long run for subtypes of patients with bladder cancer.

NCCN Guidelines Suggest Molecular Testing

“The whole Principles of Imaging section—6 pages worth outlining the appropriate use of imaging and varying modalities one would use across various stages of the disease—is brand new, as are many other supplemental sections,” said Peter Clark, MD, professor of urologic surgery at Vanderbilt University Medical Center, and chair of the NCCN guidelines panel for bladder cancer. While some changes seem to have come quickly, acceptance of molecular profiling, by contrast, has been developing slowly.

The guidelines for metastatic disease now contain a footnote acknowledging that molecular imaging is an option. “That’s new, and from a medical oncology perspective, it represents a substantial change,” explained Sumanta Kumar Pal, MD, assistant professor in genitourinary oncology and medical oncology at the City of Hope Comprehensive Cancer Center, in Duarte, California.

Prior to this there was no consensus regarding whether molecular testing is appropriate, and it had not been referred to in the guidelines. “This particular statement acknowledges the fact that bladder cancer is a very heterogeneous disease, and we might be able to exploit multiple targets,” explained Pal, who also serves on the NCCN panel. However, there are no targeted therapies that are currently approved for use for advanced bladder cancer, Pal said, so they cannot be included in the guidelines.

“As it stands right this second, we really don’t have any of these targeted agents which exist in other diseases, like lung, breast, and kidney cancer, specifically approved in bladder cancer. There is a school of thought that would say for certain patients, if standard therapies started to not work—for example, if the patient developed metastatic bladder cancer—if you’re looking at what to do next, a consideration would be perhaps molecular profiling, and perhaps an off-label use of another agent that targets that pathway,” Clark explained.

Experimental Options for Patients With Advanced Disease

“What we’re really trying to do with molecular testing is to exploit the genetics of patients with advanced bladder cancer,” noted Pal. In a recent Journal of Clinical Oncology article2 in support of molecular testing, Pal, the lead author, noted that researchers have found that 93% of patients with advanced bladder cancer have clinically relevant mutations that make them viable for studies of potential targeted agents.3 Researchers studied 295 cases of relapsed/metastatic urothelial carcinoma to test for frequent genomic alterations, and found 75 individual genes. The most clinically relevant alterations found included TP53 found in 55.6% of patients, CDKN2A (34%), FGFR3 (21%), PIK3CA (20%), and ERBB2 (16%).

“We need to start steering patients toward clinical trials to explore therapies,” he added. “Right now the dilemma is that individuals in the community do not order these tests, so the change in the guidelines gives physicians in the community the opportunity to order profiling in a way that may facilitate patient care,” he said. While molecular profiling may prove important to progress in developing a cure for bladder cancer, as it has in other fields, several concerns have led the NCCN committee to be cautious.

“The single biggest unknown is whether or not its use actually impacts survival,” explained Clark, who added that the cost of the tests is also a factor. “It can be expensive, and I don’t know to what degree insurance covers it; patients may end up having to pay for it themselves,” he noted.

Clinical trials are underway exploring if these mutations can be targeted for a more beneficial treatment for subsets of patients with advanced bladder cancers.

A phase I study of BGJ398, a selective pan-FGFR inhibitor, for example, found antitumor activity in patients with FGFR-mutated solid tumors.4 The trial included 5 patients with urothelial carcinoma with FGFR3 activating mutations, and of these patients, 4 demonstrated a reduction in tumor size of 27% to 48%.

BGJ398 is now being explored in a pilot study for patients with non–muscle invasive urothelial carcinoma (NCT02657486), as well as in a phase II trial for patients with tumors, both solid and hematologic malignancies, with FGFR alterations (NCT02160041). For patients with ERBB3 mutations, afatinib (Gilotrif), an irreversible inhibitor that targets the ErbB family, has shown activity in patients with metastatic urothelial carcinoma.5 Five of 6 patients with HER2/ERBB3 alterations achieved progression-free survival of at least 5 months (range, 5.0-10.3) compared with 15 patients without an alteration (P <.001). The median time to progression in these patients was 6.6 months versus 1.4 months for patients without an alteration.

Afatinib was approved by the FDA in July 2013 as a first-line treatment for patients with non–small cell lung cancer with EGFR exon 19 deletions or exon 21 (L858R) substitution mutations. An ongoing phase II open-label study is exploring afatinib for patients with metastatic urothelial carcinoma following progression on a platinum-based chemotherapy (NCT02780687).

The issue is, however, that none of these treatments have yet been approved for use in bladder cancer by the FDA and are still a long way off from consideration. “I am not in any way trying to advocate the use of non–FDA-approved agents in bladder cancer,” Clark stated. Yet these new agents can target specific oncogenic pathways that already approved treatments cannot.

A Historical Interest in Molecular Profiling

Notwithstanding the fact that it has been slow to adopt principles calling for molecular testing in bladder cancer patients, the NCCN has a history of interest in molecular testing. In 2011, the NCCN published a white paper on the effectiveness of molecular testing, in light of an FDA guidance issued that same year.6 The organization has also compiled a list of available assays, according to oncologist Paul Engstrom, MD, professor of medicine at Temple University Medical Center in Philadelphia, and the lead author on the 2011 white paper.

“It certainly has an effect on what treatment might be utilized in that patient, and in some cases the profile may identify patients with a poor prognosis that need more intensive therapy. The position of NCCN is that molecular testing of tumors can be a valuable way of defining mutations that might contribute to precision treatments that effect only a small part of the metabolism of the tumor, and cause remissions with less toxicity,” said Engstrom, who is currently on the NCCN committee that sets guidelines for colon, rectal, and anal cancer.

The hope of the increased support by the NCCN for molecular profiling is that it may increase the accessibility and frequency of genetic testing. With more cancer-specific genetic information available, patients can be pointed toward clinical trials that could benefit from increased recruitment numbers. Further trials could also lead to more targeted agents for the treatment of patients with advanced bladder cancer eventually being accepted by the FDA and incorporated into future guidelines.

Molecular Analysis for Immunotherapy

One of the other major additions to version 2 of the 2016 NCCN guidelines was the inclusion of atezolizumab (Tecentriq), which also speaks to the importance of molecular analysis, according to Pal. Molecular profiling can also be used to detect mutational load and molecular subtypes of tumors, which may help in predicting a patient’s sensitivity to immunotherapy approaches, such as PD-1/PD-L1 inhibition.

Atezolizumab, a PD-L1 inhibitor, was approved in May as a second- line treatment for patients with advanced bladder disease based on results of the phase II IMvigor 210 trial.7 The drug showed an overall response rate of 14.8% in patients with locally advanced or metastatic urothelial carcinoma regardless of PD-L1 expression, which rose to 26% for patients with PD-L1 expression ≥5%.

“Immunological drugs like atezolizumab are not offered in a mutation-specific context, but it is important to keep in mind that response rates imply that less than a quarter of the patients will respond to therapy. Most responses are partial, yet there is the potential for a complete response, and I think that lends itself to the importance of molecular testing,” he said.

“There is a lot of research taking place trying to look at the role for immune therapy, given the newfound role for atezolizumab for second-line treatment, and trying to make those links between particular genetic mutations,” said Clark, who noted that meetings will soon take place among the members of the NCCN panel to discuss the 2017 guideline revisions. “For example, we need to figure out what to do with non–muscle invasive bladder cancer that has become refractory to treatment.”
 
 
References:
  1. NCCN. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®), Bladder Cancer Version 2.2016. https://www.nccn.org/professionals/physician_gls/pdf/bladder.pdf. Published June 23, 2016. Accessed September 29, 2016.
  2. Pal S, Agarwal N, Boorjian S, et al. National Comprehensive Cancer Network Recommendations on Molecular Profiling of Advanced Bladder Cancer. [Published online July 25, 2016] J Clin Oncol.2016;34(27):3346-3348.
  3. Ross JS, Wang K, Khaira D, et al. Comprehensive genomic profiling of 295 cases of clinically advanced urothelial carcinoma of the urinary bladder reveals a high frequency of clinically relevant genomic alterations. Cancer. 2016;122(5):702-711.
  4. Sequist LV, Cassier P, Varga A, et al. Phase I study of BGJ398, a selective pan-FGFR inhibitor in genetically preselected advanced solid tumors. Presented at: 2014 AACR Annual Meeting; April 5-9, 2014; San Diego, CA.
  5. Choudhury NJ, Campanile A, Antic T, et al. Afatinib Activity in Platinum-Refractory Metastatic Urothelial Carcinoma in Patients With ERBB Alterations. J Clin Oncol. 2016;34(18):2165-2171.
  6. Engstrom P, Bloom M, Demetri G, et al. NCCN Molecular Testing White Paper: Effectiveness, Efficiency, and Reimbursement. J Natl Compr Canc Netw. 2011;9:S1-S16 (suppl 6).
  7. Rosenberg JE, Hoffman-Censits J, Powles T, et al. Atezolizumab in patients with locally advanced and metastatic urothelial carcinoma who have progressed following treatment with platinum-based chemotherapy: a single-arm, multicentre, phase 2 trial. Lancet. 2016;387(10031):1909-1920.



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