Lisa Astor

The FDA has issued a complete response letter (CRL) in regard to the applications for potential accelerated approval of pembrolizumab (Keytruda) in combination with lenvatinib (Lenvima) as treatment of patients with previously untreated, unresectable hepatocellular carcinoma (HCC), according to a press release from Merck and Eisai.

The companies had submitted applications for the potential accelerated approval of the combination regimen based on findings from the single-arm phase 1b KEYNOTE-524/Study 116 trial (NCT03006926). Findings from the study supported an 

FDA breakthrough therapy designation granted to the combination in July 2019

Although clinically meaningful efficacy was achieved in the study, the FDA approved the combination of atezolizumab (Tecentriq) in combination with bevacizumab (Avastin) in May 2020

for the treatment of patients with unresectable or metastatic HCC

 who have not received prior therapy for advanced disease.

 The atezolizumab/bevacizumab combination was approved based on findings from the phase 3 IMbrave150 trial (NCT03434379), which demonstrated an improvement in overall survival (OS) with the combination compared with standard-of-care sorafenib (Nexavar) alone in this patient population.

As a result, the pembrolizumab/lenvatinib did not show evidence of meaningful improvement over available therapies, which now included the atezolizumab/bevacizumab combination, for the treatment of patients with unresectable HCC who have not received prior therapy for advanced disease, and no longer met the criteria for accelerated approval. Earlier FDA-approved indications for the agents are not affected by the CRL though.

The companies plan to continue the evaluation of the combination in this setting to further demonstrate the clinical benefit of pembrolizumab plus lenvatinib. The multicenter, randomized, double-blind phase 3 LEAP-002 trial is continuing to explore the safety and efficacy of the pembrolizumab and lenvatinib combination in comparison with lenvatinib alone as frontline treatment for adult patients with advanced HCC (NCT03713593). The trial is ongoing but no longer enrolling patients.

About 750 patients were enrolled into the study and randomized patients to pembrolizumab/lenvatinib or lenvatinib/placebo. In the investigational arm, patients received 8 or 12 mg of lenvatinib, based on body weight, orally once daily in combination with 200 mg intravenous pembrolizumab on day 1 of each 3-week cycle. Treatment with pembrolizumab continued for up to 35 weeks.

Eligible patients had Barcelona Clinical Liver Cancer (BCLC) stage C disease, or stage B disease that was not amenable to or was refractory to locoregional therapy, a Child-Pugh class A score, an ECOG performance status of 0 or 1, and a life expectancy of more than 3 months. Patients with hepatitis B virus were able to participate in the trial if the virus was well controlled.

Primary end points of the study are progression-free survival (PFS) by RECIST 1.1 criteria and overall survival (OS). Secondary end points include objective response rate (ORR), duration of response (DOR), disease control rate (DCR), time to disease progression (TTP), and adverse events (AEs). The study is also exploring outcome measures by modified RECIST (mRECIST) criteria.

According to findings presented during the 2020 American Society of Clinical Oncology (ASCO) Virtual Scientific Program,

 the ORR by RECIST criteria per independent imaging review was 36% (95% CI, 26.6%-46.2%). By mRECIST criteria, the ORR was 46% (95% CI, 36.0%-56.3%) per independent review and 41% (95% CI, 31.3%-51.3%) per investigator review. The DCR was 88% by both RECIST and mRECIST criteria with independent imaging review. The DCR per investigator review was 86%.

The median DOR was 12.6 months by RECIST criteria and independent review as well as by mRECIST criteria and investigator review. According to mRECIST criteria and independent review, the median DOR was 8.6 months.

Eighty-nine percent out of 93 and 83% of evaluable patients had reduction in tumor size by independent imaging review, which appeared to be durable.

The phase 1b study included an examination of dose-limiting toxicities in 6 patients ineligible for other treatments in part 1 and an expansion phase with 98 unresectable patients in part 2.

Eligible patients had unresectable HCC, BCLC stage B disease that was not amenable to transarterial chemoembolization or stage C disease, Child-Pugh class A score, ECOG performance status of 0 or 1, and at least 1 measurable target lesion by mRECIST criteria.

Primary end points for part 1 were safety and tolerability and for part 2 the primary end points were ORR and DOR by mRECIST and RECIST criteria. Secondary and exploratory end points included PFS, TTP, OS, pharmacokinetics, and antidrug antibodies for pembrolizumab.

Of the 100 patients included in the frontline analysis, the median age was 66.5 years, 81% were male, and 81% had a bodyweight of at least 60 kg at baseline. The majority of patients had an ECOG performance status of 0 (62%), BCLC stage C disease (71%), and a Child-Pugh score of 5 (71%). Additionally, 62% of patients had macroscopic portal vein invasion, extrahepatic spread, or both.

The median PFS by RECIST criteria was 8.6 months (95% CI, 7.1-9.7) and 9.3 months by mRECIST criteria (95% CI, 5.6-9.7). The median OS was 22.0 months (95% CI, 20.4-not evaluable).

The most common treatment-related AEs of any grade observed with the combination were hypertension (36%), diarrhea (35%), fatigue (30%), decreased appetite (28%), and hypothyroidism (25%). Treatment-related AEs led to discontinuation of lenvatinib in 14% of patients, of pembrolizumab in 10%, and of both agents in 6%.

1. Merck and Eisai Receive Complete Response Letter for KEYTRUDA® (pembrolizumab) plus LENVIMA® (lenvatinib) Combination as First-Line Treatment for Unresectable Hepatocellular Carcinoma. News release. Merck and Eisai. July 8, 2020. Accessed July 8, 2020. 

2. FDA Approves Genentech’s Tecentriq in Combination With Avastin for People With the Most Common Form of Liver Cancer. Published May 29, 2020. Accessed July 8, 2020. 

3. Zhu AX, Finn RS, Ikeda M, et al. A phase Ib study of lenvatinib (LEN) plus pembrolizumab (PEMBRO) in unresectable hepatocellular carcinoma (uHCC). 

2020;38(suppl):4519. doi: 10.1200/JCO.2020.38.15_suppl.4519

Articles

The FDA has issued a complete response letter in regard to the applications for potential accelerated approval of pembrolizumab in combination with lenvatinib as treatment of patients with previously untreated, unresectable hepatocellular carcinoma.

FDA Denies Approval of Pembrolizumab/Lenvatinib for Frontline Unresectable HCC

Promising disease control and survival was achieved with the use of liposomal irinotecan (Onivyde) in combination with fluorouracil (5-FU), leucovorin, and oxaliplatin (NALIRIFOX) as a frontline treatment for patients with locally advanced or metastatic pancreatic ductal adenocarcinoma (PDAC), according to the results of a phase 1/2 trial.

Long-term follow-up results from the study were presented in a poster at the virtual 2020 European Society of Medical Oncology (ESMO) World Congress on Gastrointestinal Cancer meeting.

“Pancreatic cancer is aggressive, and we continue to investigate opportunities to improve outcomes for more patients that can extend survival. Unfortunately, current treatments, including immunotherapies that are transforming outcomes for patients with other solid tumors, have not demonstrated similar success in pancreatic cancer,” said lead investigator Zev Wainberg, MD, associate professor of medicine, University of California Los Angeles, in a statement.

 “The initial median progression-free and overall survival data from our phase 1/2 trial are promising and we look forward to seeing how this investigational first-line treatment compares to gemcitabine + nab-paclitaxel in the phase 3 trial now underway.”

The phase 1/2 trial was an open-label, dose-exploration, and dose-expansion study exploring the safety, tolerability, and efficacy of the frontline NALIRIFOX regimen in patients with locally advanced or metastatic PDAC (NCT02551991). Patients had been diagnosed at least 6 weeks before screening and were not previously treated in the metastatic setting, they also had to have an ECOG performance status of 0 or 1, adequate organ function, and a Karnofskyperformance status score of at least 70 for the dose-expansion phase.

In the dose-exploration phase, patients were treated in 1 of 4 cohorts with varying doses of liposomal irinotecan and oxaliplatin: 70 mg/m

(cohort D). In each cohort patients received treatment on days 1 and 15 of each 28-day cycle plus 2400 mg/m2 of 5-FU and 400 mg/m

The primary end point was safety in terms of treatment-emergent adverse events (TEAEs) and dose-limiting toxicities. The primary efficacy end point was progression-free survival (PFS). Secondary end points included overall survival (OS), best overall response, overall response rate (ORR), disease control rate (DCR) at week 16, and duration of response (DOR).

The presentation focused on the pooled population of patients who were treated with 50 mg/m

 of oxaliplatin between the dose-exploration and -expansion phases, as cohort B was selected for expansion (n = 32).

In this pooled population, the median age was 58 years (range, 39-76), and the majority of patients were female (56.2%), white (87.5%), had stage IV disease at diagnosis (87.5%), and had a performance status of 1 (56.3%).

The median PFS was 9.2 months (95% CI, 7.69-11.96), and the median OS was 12.6 months (95% CI, 8.74-18.69). ORR was 34.4% (95% CI, 18.6%-53.2%), consisting of 1 complete response and 10 partial responses. An additional 15 patients had stable disease, resulting in a DCR of 71.9% (95% CI, 53.3%-86.3%) at week 16. The median DOR was 9.4 months (95% CI, 3.52-not estimable).

Investigators also looked to survival according to subtype and of 9 patients with evaluable subtype and tumor response data, 8 had classical subtype and 1 had basal-like subtype. The PFS in the classical group ranged from 7.7 months to 17.8 months and the PFS for the 1 patient with basal-like subtype was 9.6 months.

Dose-limiting toxicities were observed in 2 patients in cohort A, due to neutropenia infection and neutropenia sepsis, 1 case of febrile neutropenia in cohort B, and in cohort C, 2 patients experienced diarrhea, vomiting, anal fissure, anal inflammation, and/or proctalgia. No dose-limiting toxicities were observed in cohort 4.

TEAEs were observed in all patients in the pooled population and grade ≥3 events were seen in 68.8% of patients, with the most common being neutropenia (31.3%), febrile neutropenia (12.5%), and hypokalemia (12.5%). No cases of grade ≥3 peripheral sensory neuropathy or fatigue were observed in the pooled population but were observed in cohort C and A, respectively.

Serious treatment-related TEAEs were observed in 31.3%, which was most frequently due to febrile neutropenia and nausea.

TEAEs led to death in 3 patients—due to malignant gastrointestinal obstruction, upper gastrointestinal hemorrhage, and disease progression—but were not considered treatment related.

These positive findings led to the initiation of an international, open-label, randomized phase 3 trial (NAPOLI-3; NCT04083235) exploring the use of frontline NALIRIFOX compared with gemcitabine and nab-paclitaxel (Abraxane) in patients with metastatic PDAC.

The phase 3 trial is looking to enroll about 750 patients with previously untreated metastatic adenocarcinoma of the pancreas, an ECOG performance status of 0 or 1, and adequate organ function and biological parameters. OS is the primary end point and PFS and ORR are the secondary end points.

FDA granted a fast track designation to the NALIRIFOX regimen

 for the frontline treatment of patients with unresectable, advanced PDAC.3 The combination of liposomal irinotecan and 5-FU/leucovorin are also FDA approved for the treatment of patients with PDAC after disease progression following gemcitabine-based treatment. 

1. Wainberg ZA, Bekaii-Saab T, Boland PM, et al. First-line liposomal irinotecan 5 fluorouracil/leucovorin oxaliplatin in patients with pancreatic ductal adenocarcinoma: Primary analysis from a phase 1/2 study. Presented at: ESMO World Congress on Gastrointestinal Cancer; July 1-4, 2020. Abstract LBA-001.

2. Ipsen presents Phase I/II clinical data evaluating liposomal irinotecan (Onivyde®) as an investigational first-line combination treatment for metastatic pancreatic cancer at the ESMO World Congress on Gastrointestinal Cancer. News release. Ipsen. July 1, 2020. Accessed July 2, 2020. 

3. Ipsen Receives FDA Fast Track Designation for Liposomal Irinotecan (ONIVYDE®) as a First-Line Combination Treatment for Metastatic Pancreatic Cancer. News release. Ipsen. June 17, 2020. Accessed July 2, 2020. 

Long-term follow-up results from the study were presented in a poster at the virtual 2020 European Society of Medical Oncology World Congress on Gastrointestinal Cancer meeting.

Frontline NALIRIFOX Regimen Demonstrates Promising Activity in Advanced PDAC

The FDA has approved pembrolizumab (Keytruda) monotherapy for the frontline treatment of patients with unresectable or metastatic microsatellite instability–high (MSI-H) or mismatch repair deficient (dMMR) colorectal cancer (CRC).

Approval for this indication for pembrolizumab was based on findings from the phase 3 KEYNOTE-177 trial, in which pembrolizumab more than doubled the progression-free survival (PFS) over chemotherapy in patients with MSI-H/dMMR CRC.

The median PFS with pembrolizumab was 16.5 months (95% CI, 5.4-32.4) compared with 8.2 months (95% CI, 6.1-10.2) with chemotherapy, resulting in a 40% reduction in the risk of disease progression or death (HR, 0.60; 95% CI, 0.45-0.80; 

“Patients with unresectable or metastatic MSI-H colorectal cancer have historically faced poor outcomes, and until today, chemotherapy-containing regimens were the only FDA-approved first-line treatment options,” said Luis A. Diaz, MD, head of the division of Solid Tumor Oncology, Memorial Sloan Kettering Cancer Center, in a statement. “In patients who were treated with Keytruda and responded (n = 67) in the KEYNOTE-177 trial, 43% of patients experienced a duration of response lasting 2 years or longer. This approval helps address the unmet need to provide a new monotherapy treatment option for patients.”

KEYNOTE-177 was a multicenter, randomized, open-label, active-controlled trial that enrolled 307 patients with previously untreated unresectable or metastatic MSI-H or dMMR CRC, as determined by polymerase chain reaction for MSI and immunohistochemistry for dMMR status.

Patients were randomized 1:1 to receive 200 mg intravenous pembrolizumab every 3 weeks of investigators choice of: mFOLFOX6 (oxaliplatin, leucovorin, and fluorouracil [5-FU]), mFOLFOX6 plus cetuximab, mFOLFOX6 plus bevacizumab, FOLFIRI (leucovorin, 5-FU, and irinotecan); FOLFIRI plus bevacizumab, or FOLFIRI plus cetuximab.

Treatment in the pembrolizumab arm was continued for up to 35 cycles or until progressive disease, unacceptable toxicity, or patient/physician decision to withdraw. Patients in the chemotherapy arm who progressed were allowed to cross over to the pembrolizumab arm.

According to findings from KEYNOTE-177 presented during the 2020 American Society of Clinical Oncology Virtual Scientific Program, the 1-year PFS rate was 55% with pembrolizumab and 37% with chemotherapy; at 2 years, the PFS rates were 48.3% and 18.6%, respectively.

The objective response rate was 43.8% in the pembrolizumab arm and 33.1% in the chemotherapy arm. Objective responses in the pembrolizumab arm consisted of complete responses in 11.1%, partial responses in 32.7%, and stable disease in 20.9%. In the chemotherapy arm, complete responses were seen in 3.9%, partial responses in 29.2%, and stable disease in 42.2%. About 30% of patients in the immunotherapy arm progressed compared with 12.3% in the chemotherapy arm.

The median duration of response was not reached in the immunotherapy arm compared with 10.6 months with chemotherapy. Responses lasted more than 2 years for 83% of responders in the pembrolizumab arm and for 35% of responders in the chemotherapy arm.

Frequent adverse events (AEs) in the pembrolizumab arm compared with the chemotherapy arm included diarrhea (25% vs 52%, respectively), fatigue (21% vs 44%), nausea (12% vs 55%), decreased appetite (8% vs 34%), stomatitis (5% vs 30%), alopecia (3% vs 20%), vomiting (3% vs 28%), decreased neutrophil count (1% vs 23%), neutropenia (0% vs 21%), and peripheral sensory neuropathy (0% vs 20%).

Grade ≥3 treatment-related AEs, however, were less common in the pembrolizumab arm compared with the chemotherapy arm (22% vs 66%).

“Today’s approval has the potential to change the treatment paradigm for the first-line treatment of patients with MSI-H colorectal cancer, based on the important findings from KEYNOTE-177 that showed Keytruda monotherapy demonstrated superior progression-free survival compared to standard of care chemotherapy,” said Roy Baynes, MD, PhD, senior vice president and head of global clinical development, chief medical officer, Merck Research Laboratories, in a statement. “Our commitment to pursuing biomarker research continues to help us bring new treatments to patients, particularly for those who have few available options.”

The supplemental Biologics License Application for pembrolizumab in this indication was reviewed under the FDA’s Real-Time Oncology Review pilot program within 1 month of submission. The application was also reviewed through the FDA’s Project Orbis in collaboration with the Australian Therapeutic Goods Administration, Health Canada, and Swissmedic.

Pembrolizumab was granted FDA approval for the treatment of adult and pediatric patients with unresectable or metastatic MSI-H/dMMR solid tumors that have progressed after prior treatment and who have no satisfactory alternative treatment options, as well as for patients with MSI-H/dMMR CRC following progression on fluoropyrimidine, oxaliplatin, and irinotecan in 2017.

1. FDA Approves Merck’s KEYTRUDA® (pembrolizumab) for First-Line Treatment of Patients With Unresectable or Metastatic MSI-H or dMMR Colorectal Cancer. News release. Merck. June 29, 2020. Accessed June 29, 2020. 

Andre T. Shiu Kai-Keen, Kim TW, et al. Pembrolizumab versus chemotherapy for microsatellite instability-high/mismatch repair deficient metastatic colorectal cancer: The phase 3 KEYNOTE-177 study. 

. 2020;38(suppl 15):LBA4. doi:10.1200/JCO.2020.38.15_suppl.LBA4

"Patients with unresectable or metastatic MSI-H colorectal cancer have historically faced poor outcomes, and until today, chemotherapy-containing regimens were the only FDA-approved first-line treatment options."

FDA Approves Frontline Pembrolizumab for MSI-H/dMMR CRC

A panel discussion during the American Urological Association’s (AUA) Virtual Experience highlighted ways to treat patients with non–muscle invasive bladder cancer (NMIBC) in the face of a shortage of standard-of-care Bacillus Calmette-Guerin (BCG) treatment.

The panel discussion was moderated by Seth P. Lerner, MD, and the panelists included Stephen A. Boorjian, MD; Ashish M. Kamat, MD, MBBS; James M. McKiernan, MD; and Chad R. Ritch, MD, MBA.

Previously there were 2 manufacturers of BCG, Sanofi Pasteur and Merck. However, Sanofi Pasteur went off line in 2012 and permanently closed in 2017. Merck manufactures Tice BCG from a single plant for distribution to 70 countries. Despite increasing production more than 100%, Merck is operating at full capacity, but the demand has exceeded the supply, and since January 2019, the manufacturer began an allocation distribution, leading to the shortage.

Merck has noted that production of Tice BCG is a top priority for the company, but it is also exploring alternatives to increase production capacity. The FDA and other health authorities have been working with Merck to try to maximize access to BCG and bring new strains to the market.

For example, Kamat, a urologist at Mayo Clinic, noted that BCG is being studied in a SARS-CoV-2, which would hopefully open the drug up for further production in the United States.

In response to the BCG shortage, a joint statement was released from several urology organizations, including the AUA, in February 2019 for strategies to use in the care of patients with NMIBC if BCG is in limited or no supply.

The organizations stated that BCG should not be used for patients with low-risk disease, and intravesical chemotherapy should be the first-line treatment option for patients with intermediate-risk disease, thereby prioritizing the use of BCG for patients with high-risk disease. The statement recommended that patients with high-risk disease received full-strength BCG if available, and if not, they could receive one-half to one-third the standard dose. Additionally, if there is enough BCG supply for maintenance therapy, physicians should aim to give their patients with NMIBC a one-third dose of BCG limited to one year. However, in the event that BCG is not available, induction therapy should be prioritized over maintenance therapy for patients with high-risk disease.

Lerner, the Beth and Dave Swalm Chair in Urologic Oncology, director of Urologic Oncology, director of the Multidisciplinary Bladder Cancer Program, Baylor College of Medicine, explained that urologists can give reduced doses of BCG since an appropriate cytokine response can still be achieved with as little as one-hundredth of a standard dose. He did note, however, that urologists should be careful about billing for split dosing of BCG as coverage may vary by region.

Kamat advised that patient selection for BCG therapy is key even when there is no shortage of the therapy.

Among patients with low-grade, intermediate-risk disease, if they present with 3 or more risk factors—multiple tumors, tumor size >3 cm, early recurrence (<1 year), and/or frequent recurrences (>1 per year)—they should be treated as if they have high-risk disease with transurethral resection of bladder tumor (TURBT) and BCG induction and maintenance therapy.

When giving BCG maintenance therapy, administering on a 6+3 schedule (SWOG protocol) leads to the most benefit without wasting the treatment. Kamat also explained that the duration of treatment with BCG seems to matter more than the dose of the therapy.

In the EORTC 30962 study, which examined the use of full-dose and one-third dosing of BCG maintenance for 1 or 3 years in patients with intermediate- and high-risk NMIBC, those who received 3 years of maintenance therapy at either dosing demonstrated better 5-year disease-free rates than those who only received 1 year of therapy. The patients who received 3 years of the full dose had a 5-year disease-free rate of 64.2% and those who received the one-third dose for 3 years had a 5-year rate of 62.6%. Comparatively, those who received 1 year of maintenance therapy had a 5-year disease-free rate of 58.8% with the full dose and 54.5% with the one-third dose (

Ritch, from the Department of Urology, University of Miami Health Center, explained that the one-third dose can be split up by taking a full dose of 1 vial of 50 mg BCG and reconstitute it to 50 mL and then split that into 3 syringes that are all then reconstituted to 50 mL. These can then be administered to 3 patients within 2 hours.

Kamat recommended that new high-risk patients should receive BCG induction for 6 weeks at one-third of the dose so that more patients can be treated, even though the AUA recommends the full dose at induction. He also recommended that patients with Ta tumors who are at lower risk of progression could hold off maintenance therapy unless they have recurrence at 3 months.

As an alternative to BCG, single-agent intravesical chemotherapy can be used in patients with NMIBC, and Ritch offered that mitomycin C is a readily available option. Although, overall BCG may reduce the time to recurrence compared with mitomycin C (HR, 0.88; 95% CI, 0.71-1.09),

 one review has shown that when no maintenance therapy is given, mitomycin C may delay the time to first recurrence over BCG.

Other single-agent chemotherapy alternatives to BCG include valrubicin, gemcitabine, and taxanes including nab-paclitaxel (Abraxane), which have all shown modest benefit in single-arm studies in patients with NMIBC.

McKiernan, the John K. Lattimer Professor of Urology, chair of the Department of Urology, director of Urologic Oncology, Columbia University Irving Medical Center, focused on patients who have recurred on or following BCG; in this case, additional BCG does not have a high probability of response for these patients. In this setting, gemcitabine has been one of the most studied single-agent chemotherapies showing a disease-free survival rate of approximately 15% to 30%.

In one such study, intravesical gemcitabine was compared with BCG administrated following BCG failure in patients with high-risk NMIBC and gemcitabine showed a 2-year recurrence-free survival (RFS) rate of 19% compared with 3% with BCG (

<.008). Both treatments were considered to be well tolerated.

“You may be surprised to realize that gemcitabine actually worked better than a second induction of BCG,” McKiernan said. “So in the setting of BCG shortage, there’s some pretty strong evidence here to suggest that you should not waste your vital resource of BCG on a patient in that setting if you do get access to single-agent gemcitabine.”

McKiernan added that single-agent gemcitabine is probably the most practical in terms of time in the clinic and ease of use for the practitioner.

Sequential treatment with intravesical gemcitabine followed by docetaxel rescue therapy was found to be beneficial and provide durable response in patients with recurrent NMIBC following BCG. At 1 year, the RFS rate in this patient population was 60% with sequential gemcitabine and docetaxel and 46% at 2 years. The rate of cystectomy-free survival was 84% and only 3.6% of patients progressed on transurethral resection.

“I think this is quietly becoming a standard, non-FDA approved doublet regimen [against] which many other things are being compared,” McKiernan commented.

McKiernan also pointed to a recent phase I study from the Columbia University Medical Center assessing the combination of cabazitaxel (Jevtana) with gemcitabine and cisplatin (CGC) in patients with BCG-unresponsive or recurrent/relapsing NMIBC who were ineligible for or declined cystectomy. Among patients who had received a mean of 3.3 prior courses of induction therapy and had failed at least 2 induction courses, CGC induced an overall complete response (CR) rate of 89% and an RFS rate of 83% at 1 year.

Looking to Newer Treatments for BCG-Unresponsive Patients

Boorjian explained that BCG-unresponsive NMIBC is defined as persistent/recurrent high-grade Ta or T1 urothelial carcinoma within 6 months of completion of an adequate quantity of BCG or persistent/recurrent carcinoma in situ (CIS) (±Ta or T1 disease) within 12 months of completing an adequate course of BCG. Adequate BCG was considered to be 5 of 6 instillations of induction BCG and 2 of 3 maintenance treatments or 2 of 6 courses of the second round of induction. The only exception was patients who presented with high-grade T1 disease at their first evaluation after induction BCG.

He noted that this definition helps frame future treatment decision making for these patients as further BCG shows a lack of significant efficacy in these patients and instead increases their risk of progression.

“This is of particular relevance in the current era that we’re talking about of the BCG shortage where allocation is critical. We don’t want to waste BCG on patients not likely to respond to BCG,” emphasized Boorjian, professor of urology and director of Urologic Oncology Fellowship at The University of Texas MD Anderson Cancer Center.

Guidelines from the AUA and Society of Urologic Oncology (SUO) from 2016 advised that patients with high-risk, BCG-unresponsive should receive radical cystectomy, and Boorjian noted that this is still the gold standard in 2020. For those who are unfit for or unwilling to undergo cystectomy, clinical trials are recommended. If a trial is unavailable, intravesical chemotherapy is suggested, although there is no robust evidence to recommend one treatment over another.

Kamat noted that rates of radical cystectomy increase dramatically in the setting of a BCG shortage; while urologists should not subject their patients to unnecessary surgery, there is a time for cystectomy. He noted that patients with highest-risk features, such as high-grade T1 disease with extensive CIS, prostatic involvement, or variant histology, would benefit from discussions of radical cystectomy.

Checkpoint inhibitor pembrolizumab (Keytruda) was approved by the FDA at the beginning of the year for the treatment of patients with BCG-unresponsive, high-risk NMIBC with CIS with or without papillary tumors who are ineligible for or are unwilling to undergo cystectomy.

 In the single-arm, multicenter, phase 2 KEYNOTE-057 trial, the CR rate with pembrolizumab was 41% (95% CI, 31%-51%) and the median duration of response was 16.2 months.

“I think this is a particularly exciting area of urologic oncology and bladder cancer specifically because we have a number of different clinical trials that are coming in the BCG-unresponsive disease state from a variety of different therapeutic strategies,” Boorjian said. Some of the different emerging strategies include vaccines, interleukin-15 super agonists, immune checkpoint inhibition, small molecule inhibitors of IDO1, viral gene transfer, and oncolytic adenovirus.

Boorjian highlighted an ongoing phase 3 trial (NCT02773849) of a replication-deficient adenoviral vector, rAd-IFN-alpha (nadofaragene firadenovec), in patients with high-grade, BCG-unresponsive NMIBC for which he was an investigator. The adenoviral vector delivers the IFN gene directly to bladder cells and turns the bladder into a “bioreactor.”

The study has enrolled 157 patients and is looking at the CR rate at any time for patients with CIS (n = 103) as a primary end point. Fifty-five patients achieved a CR (53.4%) and 45.5% of patients with an initial CR maintained their CR at 1 year.

Boorjian commented, “we may have a real opportunity here to extrapolate lessons learned from clinical trials in the BCG-unresponsive population to earlier in NMIBC [disease settings].”

1. Lerner SP, Boorjian SA, Kamat AM, McKiernan JM, Ritch CR. what to do during bcg shortage for high-risk nmibc patients? Presented at: AUA Virtual Experience; June 27-28, 2020.

2. Letter Re: BCG Shortage. Bladder Cancer Advocacy Network. February 19, 2019. Accessed June 29, 2020. 

https://bcan.org/wp-content/uploads/2019/05/BCAN-Letter-Re-BCG-Shortage-for-Web.pdf

3. Oddens J, Brausi M, Sylvester R, et al. Final results of an eortc-gu cancers group randomized study of maintenance bacillus calmette-guérin in intermediate- and high-risk ta, t1 papillary carcinoma of the urinary bladder: one-third dose versus full dose and 1 year versus 3 years of maintenance. 

2013;63(3):462-472. doi:10.1016/j.eururo.2012.10.039

4. Schmidt S, Kunath F, Coles B, et al. Intravesical Bacillus Calmette-Guérin versus mitomycin C for Ta and T1 bladder cancer (Review). 

. 2020;1. doi:10.1002/14651858.CD011935.pub2

5. Malmström PU, Sylvester RJ, Crawford DE, et al. An individual patient data meta-analysis of the long-term outcome of randomised studies comparing intravesical mitomycin c versus bacillus calmette-guérin for non-muscle-invasive bladder cancer. 

2009;56(2):247-256. doi:10.1016/j.eururo.2009.04.038Di 

6. Lorenzo G, Perdonà S, Damiano R, et al. Gemcitabine versus bacille calmette-guérin after initial bacille calmette-guérin failure in non-muscle-invasive bladder cancer: a multicenter prospective randomized trial. 

2010;116(8):1893-1900. doi:10.1002/cncr.24914

7. Steinberg RL, Thomas LJ, Brooks N, et al. Multi-institution evaluation of sequential gemcitabine and docetaxel as rescue therapy for nonmuscle invasive bladder cancer. 

2020;203(5):902-909. doi:10.1097/JU.0000000000000688

8. DeCastro GJ, Sui W, Pak JS, et al. A phase i trial of intravesical cabazitaxel, gemcitabine and cisplatin for the treatment of nonmuscle invasive bacillus calmette-guérin unresponsive or recurrent/relapsing urothelial carcinoma of the bladder. 

Published online March 2, 2020. doi:10.1097/JU.0000000000000919

9. Chang SS, Boorjian SA, Chou R, et al. Diagnosis and treatment of non-muscle invasive bladder cancer: aua/suo guideline. 

2016;196(4):1021-1029. doi:10.1016/j.juro.2016.06.049

10. FDA approves pembrolizumab for BCG-unresponsive, high-risk non-muscle invasive bladder cancer. News release. FDA. January 8, 2020. Accessed June 29, 2020. https://bit.ly/2ZiTFoa

Author | Lisa Astor

Articles

FDA Denies Approval of Pembrolizumab/Lenvatinib for Frontline Unresectable HCC

Frontline NALIRIFOX Regimen Demonstrates Promising Activity in Advanced PDAC

FDA Approves Frontline Pembrolizumab for MSI-H/dMMR CRC

Filling the BCG Shortage Hole for Patients With NMIBC