Cases were analyzed from the National Cancer Database, in which 1,185,763 patients with CRC were identified. Over the study period, the pro- portion of patients who received diagnoses at <50 years increased from 11.5% in 2004 to 14.3% in 2015 (P <.0001), and these patients presented with more advanced stages of their disease (

Patients who received diagnoses at <45 years were more likely to have poorly differentiated disease, which tends to be more aggressive. Despite this, survival in this population is higher than in the &ge;50 years group (

Diagnoses in men <50 years rose in non-Hispanic whites but in no other demographic group (P <.0001). Conversely, women of all racial and ethnic subgroups saw an increase in diagnoses at younger ages over time (P <.01).

Patients from all income brackets experienced an increase in CRC diagnoses; however, those in the highest income quartile (&ge;$63,000) saw the greatest rise.

Interestingly, in 2005, patients <50 years with private insurance typically received diagnoses at lower rates compared with patients without insurance or Medicaid. By 2015, the gap had closed and patients in all subgroups were receiving diagnoses with similar frequency. In addition, the incidence of younger-onset CRC rose in urban areas (P <.001) but not in rural areas.

The investigators thought these changes were due to factors such as better access to healthcare or an increased risk from healthcare exposure, such as antibiotic use.

Investigators stated that the United States Preventive Services Task Force should update its recommendations to start screening at an age earlier than 50 years. The American Cancer Society has already revised its guidelines to advise screening at 45 years.

Goodgame BW, Virostko J, Capasso A, Yankeelov T. Recent trends in age at diagnosis of colon cancer in the United States, 2004-2015, a National Can- cer Database study. Poster presented at: 2019 American Society of Clinical Oncology Gastrointestinal Cancers Symposium; January 17-19, 2019; San Francisco, CA. Abstract 490. bit.ly/2U5A1HB.

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Clinical Articles

A retrospective study revealed an increase in the incidence of colorectal cancer in patients &lt;50 years across all income brackets and demographic groups, according to investigators from The University of Texas at Austin Dell Medical School. The findings were presented at the 2019 Gastrointestinal Cancers Symposium.

Higher Rates of Advanced CRC Are Being Diagnosed in Patients <50 Years Compared With Older Populations

A discussion between regulators and special interest groups has cooled some of the excitement generated by the emergence of chimeric antigen receptor (CAR) T-cell therapy for treating hematologic cancers. The Centers for Medicare & Medicaid Services (CMS) issued a proposed National Coverage Determination (NCD) memo for CAR T-cell therapy in February 2019.

In a response letter addressed to Seema Verma, administrator of the Centers for Medicare & Medicaid Services, the Community Oncology Alliance (COA) voiced significant concerns regarding the memo&rsquo;s specific language.

COA&rsquo;s concerns focus on the site of care that treatment is delivered (inpatient vs outpatient and hospital vs community setting), the strict eligibility requirements that limit use to patients with recurrent or relapsed disease, and restrictive and onerous language regarding off-label coverage, data collection, and CMS&rsquo; flexibility in covering future CAR T-cell therapies.

&ldquo;The current NCD seems to restrict the therapy to a hospital environment,&rdquo; said Frederick M. Schnell, MD, COA&rsquo;S medical officer, in an interview with

. &ldquo;Nonetheless, COAas is the entire oncology community&mdash;is very supportive of these new kinds of potentially lifesaving interventions.&rdquo;

According to the NCD, CMS recommends that CAR T-cell therapy be covered in the hospital setting or in hospitals that are participating in clinical trials involving CAR T-cell therapy.

COA contends that although CAR T-cell therapy was initially delivered exclusively in the inpatient setting, at least 26% of adult patients in clinical trials were infused in the outpatient setting.

Juno Therapeutics showed decreased resource use for patients who received the therapy in the outpatient setting, with an approximate 40% reduction in hospital days, compared with patients in the inpatient setting. Further, 88% (7 of 8) of patients remained outpatient for at least 3 days post CAR T-cell administration.

&ldquo;There are some data in the CAR T-cell space that show higher costs associated in the hospital setting, but that&rsquo;s typical of high-intensity care,&rdquo; Schnell said. The response letter pointed out that hospitals are not the only settings of care that meet the necessary qualifications.

State-of-the-art oncology practices that have experience delivering high-intensity care can provide the care needed for patients who are candidates for CAR T-cell therapy, according to COA. Stem cell transplants, which are similar in complexity to CAR T-cell therapy, are performed successfully in the community oncology practice setting. Such procedures often require the same infrastructure that CAR T-cell therapy requires, with a designated care area that protects patients from transmission of infectious agents and allows for appropriate evaluation and treatment. In some cases, community oncology practices conduct these complex procedures on their own or in partnership with local hospitals. For practices that would need to partner with hospitals to administer the therapy, those relationships and capabilities are already in place, COA said.

&ldquo;[Although] autologous stem cell therapy was initially launched in the inpatient setting, through the dedication of a strong coalition of community-based oncologists, it evolved to the outpatient setting and moved away from the solitary academic medical center,&rdquo; Schnell said.

Before CAR T-cell therapy clinics start popping up on every street corner, however, Schnell emphasized that because of the extensive training and excellent support staff needed, he foresees medium-size oncology practices in metropolitan areas taking on this new venture. &ldquo;The practice needs a dedicated staff to care for the patients, to handle products, and to deliver the drugs in a controlled way,&rdquo; he said.

Practices that are familiar with allograft stem cell transplants will be at an advantage if they are considering offering CAR T-cell therapies, Schnell said. &ldquo;All the infrastructure is in place. As clinicians become more comfortable, it&rsquo;s the natural progression to bring this into state-of-the-art phy- sician practices,&rdquo; he added. &ldquo;This will be a gearshift for them, but given a learning curve, they will need to retrain their staff and retrofit their clinics as CAR T-cell therapy becomes more prevalent.&rdquo;

The COA response pointed out that some community oncology practices already have or currently participate in studies on CAR T-cell therapy, which provides for geographic diversity that will improve patient access to the treatment.

Other challenges COA foresees with the NCD include patient eligibility, off-label use, and restrictive data collection procedures. The NCD also limits eligibility to recurrent or relapsed patients but does not encompass future CAR T-cell therapies, which are undergoing investigation in clinical trials. COA emphasized that these trials target patients in earlier stage disease, so these patients would not be eligible for coverage, according to the NCD.

COA&rsquo;s response states that the draft&rsquo;s off-label language establishes a negative precedent for cancer treatment. The organization contends that off-label use of CAR T-cell treatment will be permitted only when indicated for use in the National Comprehensive Cancer Network Drugs & Biologics Compen- dium with a grade of 2 or 1, and that the patient must be enrolled in a CMS-approved clinical trial and followed for at least 2 years to access off-label uses. COA is concerned that the additional requirements envisioned in the proposed decision memo represent a departure from CMS&rsquo; prior treatment of permissible off-label use of oncology drugs.

COA&rsquo;s last objection involves funding for future CAR T-cell treatments. The NCD suggests that studies would not be funded by CMS, with pro- viders shouldering additional costs to administer the therapy. This could adversely affect patients&rsquo; access. If CMS decides to follow through on this proposal, COA recommends using an observational study format that remains flexible and evolves with newly approved indications and new CAR T-cell products. &ldquo;COA contends that CMS should be more circumspect and more accommodating when new products become available,&rdquo; Schnell said.

The group looks forward to working with CMS as CAR-T cell therapy become part of the ongoing and developing oncology armamentarium.

CMS proposes coverage with evidence development for chimeric antigen receptor (CAR) T-cell therapy [press release]. Baltimore, MD: Centers for Medicare & Medicaid Services; February 15, 2019. go.cms.gov/ 2SXbV52. Accessed March 27, 2019.

COA comments: CMS CAR-T cell therapy proposed coverage determination [press release]. Washington, DC: Community Oncology Alliance; March 15, 2019. bit.ly/2WN3Q1g. Accessed March 27, 2019.

Primary analysis results from Novartis pivotal JULIET trial show Kymriah (tisagenlecleucel) sustained complete responses at six months in adults with r/r DLBCL, a difficult-to-treat cancer [press release]. Basel, Switzerland: Novartis; December 10, 2017. bit.ly/2pBzNur. Accessed March 27, 2019.

Juno Therapeutics highlights data and presentations supporting best- in-class strategy for JCAR017 at ASH [press release]. Seattle, WA: Juno Therapeutics, Inc; December 12, 2017. bit.ly/2G3Si4d. Accessed March 27, 2018.

A discussion between&nbsp;regulators and special interest groups has cooled some of the excitement generated by the emergence of chimeric antigen receptor T-cell therapy for treating hematologic cancers.

Coverage Concerns Temper Enthusiasm Surrounding CAR T-Cell Treatment

A recent retrospective cohort study found that site of care may be a significant factor associated with racial and ethnic differences in the receipt of palliative care, according to results published in

In terms of race, 22.5% of patients in the analysis who identified as non-Hispanic white received palliative care versus 20% of black patients and 15.9% of Hispanic patients (P <.001). After adjusting for site of care and covariates, the difference between white and black patients was no longer statistically significant (OR, 1.02; 95% CI, 0.99-1.04). Furthermore, Hispanic patients were more likely to receive palliative care compared with white patients when considering the same variables (OR, 1.06; 95% CI, 1.01-1.10).

&ldquo;If you look at non-Hispanic white patients treated at minority-serving hospitals [MSHs], their adjusted odds of receiving palliative care were not significantly different [from] black patients at these hospitals,&rdquo; said lead investigator Alexander P. Cole, MD, in an interview with

. &ldquo;Conversely, for black patients at non-MSHs, [the] adjusted odds of receiving palliative care were similar to white patients.&rdquo;

The site of care was the facility reporting the patient case to the National Cancer Database, from which the study data were abstracted, and was defined as either an MSH or a non-MSH. MSHs were determined first by defining the proportion of minority patients (black or Hispanic); the hospitals in the top decile were considered MSHs.

The main outcome measure was any receipt of palliative care, including pain control and symptom relief, in which the goal of treatment was explicitly mentioned in the medical records. For instance, pain control following a routine surgical procedure was not considered palliative. Baseline sociodemographic covariates included age at and year of diagnosis, sex, and ethnicity. Variables such as insurance carrier, education level, and household income also were included.

The study cohort consisted of 601,680 men and women &ge;40 years with 4 main cancer typesmetastatic prostate, nonsmall cell lung, colon, and breast&mdash;over a 12-year period. In total, 21.7% of patients received palliative care for their disease, with all patients treated at MSHs least likely to receive it, regardless of ethnicity. Based on an adjusted logistic regression model, patients who received their care at MSHs had two-thirds the odds of receiving palliative care compared with those who received care at non- MSHs (OR, 0.67; 95% CI, 0.53-0.84).

&ldquo;The data seem to be showing us that it really comes down to differences in care at different hospitals,&rdquo; said Cole, a resident in the Division of Urological Surgery at Brigham and Women&rsquo;s Hospital and Harvard Medical School in Boston, Massachusetts. &ldquo;Because 90% of minorities receive care at about 20% of hospitals, this means that we can make a huge difference by focusing on these hospitals that are not [delivering] as much palliative care.&rdquo;

Factors that increased a patient&rsquo;s likelihood of receiving care were treatment in a later study year and insurance status; patients insured by Medicaid or uninsured were most likely to receive palliative care. Study investigators hypothesized that this could be due to the absence of a strong fee-for-service incentive; additionally, patients in this population may have initial clinical presen- tation at a later stage of disease, when palliative care is the only option.

Further analysis focused on the association between cancer type and MSH status with the receipt of palliative care. Odds of receiving palliative care at MSHs compared with non-MSHs were 33% lower in the prostate cancer subgroup (OR, 0.67; 95% CI, 0.55-0.82), 27% lower in both lung cancer (OR, 0.73; 95% CI, 0.57-0.93) and breast cancer (OR, 0.73; 95% CI, 0.59-0.89), and not significantly lower in colon cancer (OR, 0.86; 95% CI, 0.67-1.09). As in the overall cohort, adjustments for MSH status offset the association between race and ethnicity and the odds of receiving palliative care.

These data suggest that the site of care may be a significant factor associated with observed differences in palliative care in racial and ethnic minorities in the United States. This is especially important because care for minorities is concentrated in a small number of hospitals, and addressing just these facilities may help improve access to care. Supporting these findings are previous study results that found that MSHs had higher readmission rates and worse performance in nononcologic clinical scenarios, as well as high inpatient mortality rates and poorer outcomes from emergency general sur- gery.

Systemic differences, such as experience of hospital chairpersons, may also contribute to quality of care at MSHs.

&ldquo;The next steps are really 2-fold. First, we need to drill down on the specific hospital characteristics [that] are associated with these differences,&rdquo; Cole said.

The second step involves partnering with important stakeholders. &ldquo;Here in Massachusetts, we are working with the Department of Public Health to identify and address where these disparities are occurring in the health system at the [regional, county, and hospital level] and think holistically about interventions to help us deliver better care in these lower-performing areas,&rdquo; he said.

Cole AP, Nguyen D-D, Meirkhanov A, et al. Association of care at minority-serving vs non-minority-serving hospitals with use of palliative care among racial/ethnic minorities with metastatic cancer in the United States. JAMA Netw Open. 2019;2(2):e187633. doi: 10.1001/ jamanetworkopen.2018.7633.

Jha AK, Orav EJ, Li Z, Epstein AM. Concentration and quality of hospitals that care for elderly black patients [erratum in Arch Intern Med. 2007;167(14):1532]. Arch Intern Med. 2007;167(11):1177-1182. doi: 10.1001/archinte.167.11.1177.

Zogg CK, Jiang W, Chaudhary MA, et al. Racial disparities in emergen- cy general surgery: do differences in outcomes persist among universally insured military patients? J Trauma Acute Care Surg. 2016;80(5):764-775. doi: 10.1097/TA.0000000000001004.

A recent retrospective cohort study found that site of care may be a significant factor associated with racial and ethnic differences in the receipt of palliative care, according to results published in <em>JAMA Network Open.</em>

Data Suggest Site of Facility Plays Significant Role in Racial Differences in Quality of Care

Since the approval of sipuleucel-T (Provenge) for the treatment of minimally symptomatic metastatic castration-resistant prostate cancer in 2010, barriers to administration and the approval of competing drugs has tampered wide adoption of its use. Despite it being the first FDA-approved personalized cancer vaccine with positive efficacy and safety data, its use has not been widely adopted.

Although the trajectory of this groundbreaking therapy has been different from that of checkpoint blockade immunotherapy, advocates for sipuleucel-T point out that the public has become more aware of and interested in cancer vaccines now, and they believe the product has the potential to benefit a larger group of patients. Dendreon Pharmaceuticals, the manufacturer of sipuleucel-T, last year began a new effort to expand its market by launching ProVent (NCT03686683), a phase III randomized trial testing the effectiveness of sipuleucel-T versus active surveillance in decreasing histologic progression of low-grade prostate cancer (

ProVent &ldquo;has a lot of potential, depending on how quickly it can accrue. Obviously, that is a very, very big space. There&rsquo;s lots of interest in patients with newly diagnosed, low-grade prostate cancer on active surveillance,&rdquo; said Raoul S. Concepcion, MD, director of The Comprehensive Prostate Center and clinical associate professor at Vanderbilt University School of Medicine, both in Nashville, Tennessee. He has served as a physician adviser to Dendreon.

Several other trials are testing combinations or sequencing of sipuleucel-T with radiotherapy, checkpoint inhibitors, and other therapies. &ldquo;It will maintain itself as a go-to medication for metastatic castration-resistant prostate cancer, but the future is in combination therapylearning how to mix it not only with chemotherapy, but with androgen-receptor pathway blockers or with other immunotherapeutic agents that might enhance the overall response to sipuleucel-T,&rdquo; said Leonard G. Gomella, MD, director of the Kimmel Cancer Center Network at Thomas Jefferson University Hospital in Philadelphia.

Sipuleucel-T treatment begins with leukapheresis, typically at a physician&rsquo;s office or blood-collection center. The harvested white blood cells, most importantly dendritic antigen-presenting cells, are sent to a manufacturing facility. They are incubated with a recombinant fusion protein consisting of prostatic acid phosphatase (PAP), an antigen that is highly expressed in most prostate cancer cells, and granulocyte-macrophage colony-stimulating factor.

Three or 4 days after the initial blood draw, the activated cells are reinfused into the patient, activating an immune system response against PAP-expressing prostate cancer cells. The procedure is conducted 3 times over a period of 6 weeks.

Attitudes toward sipuleucel-T have been heavily shaped by the fact that the therapy has not demonstrated significant impacts on lowering prostate-specific antigen (PSA) levels and on slowing disease progression in radiographic imaging studies. The first phase III trial, D9901 (N = 127), did not achieve a statistically significant improvement in the primary endpoint of median time to progression; PSA progression was not included in the primary endpoint.

The study was not powered for overall survival (OS), but investigators were surprised to find the sipuleucel-T group had a median survival advantage of 4.5 months over the placebo group (25.9 vs 21.4 months; log-rank P = .01). The estimated survival rate at 36 months was 34% for sipuleucel-T and 11% for placebo (P = .005).

The data were pooled with findings from another phase III trial, D9902A, and the integrated results showed a similar median survival benefit of 4.3 months (HR, 1.50; 95% CI, 1.10- 2.05; log rank P = .011).

Yet the failure to meet the original endpoint and the lack of evidence of direct antitumor effect, along with other concerns, sowed skepticism among some members of the FDA advisory committee reviewing the data.

In 2007, the agency issued a complete response letter to Dendreon and asked for more data.

Gomella said immunotherapy was still new and the FDA wanted more robust evidence that it was effective. At the time, &ldquo;immunotherapy in prostate cancer was heresy,&rdquo; he said. &ldquo;Whoever thought that prostate cancer would respond to an immune agent? There was a lot of hesitation.&rdquo;

Dendreon followed up with the pivotal IMPACT trial, in which 512 patients were assigned in a 2:1 ratio to receive either sipuleucel-T (n = 341) or placebo (n = 171), with a primary endpoint of OS.6 In the sipuleucel-T group, there was a relative reduction of 22% in the risk of death as compared with the placebo group (HR, 0.78; 95% CI, 0.61-0.98;

= .03). This represented a 4.1-month improvement in median survival (25.8 vs 21.7 months), confirming the findings of the previous studies.

The 36-month survival probability in IMPACT was 31.7% in the sipuleucel-T group versus 23.0% in the placebo group. The median time to objective disease progression did not differ significantly between the study groups (14.6 vs 14.4 weeks, respectively).

Among patients with PSA assessments after baseline, reductions of at least 50% on 2 visits at least 4 weeks apart were observed in 8 of 311 patients (2.6%) in the sipuleucel-T group, compared with 2 of 153 patients (1.3%) in the placebo group. Adverse events (AEs), all-grade and grades &ge;3, were comparable between the 2 treatment groups; all-grade AEs more frequently reported in the sipuleucel-T patients included chills, fever, and headache.

The decision to approve sipuleucel-T was hailed by patients and advocacy groups, but the new therapy did not fare well in the marketplace, earning Dendreon a little more than half of the expected product revenues in 2011. It did not become available in other countries. Physicians at some US medical centers declined to use sipuleucel-T because of doubts that it worked, while fearing angry responses from patients who demanded it.

At the same time, other patients who would benefit from sipuleucel-T could not always be convinced to take the therapy. &ldquo;The hard part was, we didn&rsquo;t know if it worked in patients or not because there was no objective decrease in PSA and there was no objective decrease in lymph nodes. Bone scans are always tough to evaluate in patients. So there was nothing objective from a patient [or] a provider point of view to tell us if this drug worked or not,&rdquo; said Sandy Srinivas, MD, a professor of medicine (oncology) at Stanford University Medical Center and member of the National Comprehensive Cancer Network guidelines panel for prostate cancer.

It is possible that sipuleucel-T would eventually have an observable effect on tumor progression, but trial investigators may have felt compelled to switch therapies before that point because their patients&rsquo; PSA levels were rising, Gomella said. &ldquo;The patient gets nervous, the doctor gets nervous, and they might not have given the drug enough of a chance to really have an impact before they moved to the next treatment,&rdquo; he said.

Uncertainty about the therapy&rsquo;s mechanism stoked an unusual controversy. In 2012, a paper in the Journal of the National Cancer Insti- tute hypothesized that sipuleucel-T appeared to extend survival only because older men (aged &ge;65 years) in the control group had worse OS outcomes versus younger participants, due perhaps to differences in the harvested cells used in the placebo group (two-thirds of cells were frozen and not reinfused).

Dendreon and the IMPACT investigators rejected the claims.

Another obstacle to adoption has been what Concepcion called the &ldquo;cost density&rdquo; of sipuleucel-T, which runs about $100,000. That adminis- tration is also complex, which put some doctors off the therapy, said Gurkamal Chatta, MD, clinical chief of genitourinary medicine at Roswell Park Comprehensive Cancer Center in Buffalo, New York.

&ldquo;There are multiple layers to coordinating everything. You have to arrange for the leukapheresis, then you have to get the patient to come in to receive the product. It&rsquo;s really 6 trips rather than 3 trips,&rdquo; he said.

Sipuleucel-T&rsquo;s surprising OS benefit was both the key to its eventual approval and a complicating factor in the trial designs. One of the &ldquo;major sell- ing points&rdquo; for trial patients was the availability of sipuleucel-T as a salvage therapy for those in the control arm, Gomella said. When those patients&rsquo; cancer progressed, they had the option of having their cryopreserved blood cells activated with the fusion protein and reinfused, extending their survival but muddying the trial results.

&ldquo;The IMPACT trial was its own worst enemy, in a way, and actually probably underrepresented the survival advantage from sipuleucel-T,&rdquo; said Gomella, who coauthored an analysis of the salvage therapy. &ldquo;This was not the cleanest trial in the world, because the placebo arm was not a pure placebo arm. If you started to look at the net benefit, if you took the sipuleucel-T salvage arm out, you actually saw much, much better survival in the treatment arm.&rdquo;

About two-thirds (165 of 249) of the control patients received the frozen product, APC8015F. After adjusting for independent predictors of postprogression survival, a statistical analysis showed them trending toward improved survival (HR, 0.78; 95% CI, 0.54-1.11; P = .17).9 Estimated median OS benefit for sipuleucel-T versus control adjusted for APC8015F treatment was 8.1 months, if APC8015F was equally effective as sipuleucel-T.

&ldquo;Theoretically, it was a doubling of the survival, which is pretty impressive,&rdquo; Gomella said.

Another posthoc analysis of the IMPACT data showed greater survival benefit in patients who had lower PSA when they received sipuleucel-T.

When the trial results were subdivided by baseline PSA into quartiles, patients in the lowest baseline PSA quartile (&le;22.1 ng/mL) showed an estimated median survival time of 41.3 months, versus 18.4 months in the highest quartile (>134.1 ng/mL). In the control arm, the estimated median survival times were 28.3 months versus 15.6 months for patients in the lowest versus highest baseline PSA quartile.

&ldquo;You need to treat people who have maybe intermediate- to low-risk disease, where the PSA is not taking off but is gradually going up, where essentially you give the immune system a chance to &lsquo;harness&rsquo; the cancer,&rdquo; Chatta said. &ldquo;If somebody doesn&rsquo;t have super-aggressive disease...you can buy some time before you commit them to essentially lifelong therapy on a daily basis either with abiraterone [Zytiga] or enzalutamide [Xtandi].&rdquo; The other therapies available for these patients are docetaxel and radium-223 (Xofigo).

Further data have come from PROCEED, a phase IV registry study that Dendreon set up. A signif- icant finding was the greater benefit for African American men with mCRPC. A multivariate analysis matching 420 Caucasian patients with 210 African American patients by baseline PSA found OS was 39.5 months for the latter group versus 28.1 months for the former (P <.001; HR, 0.665; 95% CI, 0.530-0.835).

Younger age, lower PSA or alkaline phosphatase, and higher hemoglobin levels were independently associated with longer OS, as was no prior chemotherapy

The ProVent trial that launched last year takes a different tack, using standard needle biopsies to measure histopathologic disease progression in men on active surveillance. The phase III trial will be conducted at approximately 50 sites across the United States with a targeted enrollment of 450 participants. They are being randomized 2:1 to receive sipuleucel-T or placebo.

Immunotherapy combinations are also beginning to get attention. In a recent, small phase I trial, 9 men with mCRPC received sipuleucel-T followed by escalating doses of ipilimumab (Yervoy).

The combination was well tolerated. Statistically significant increases in serum immunoglobulin G (IgG) and IgG-IgM levels specific for PAP and PA2024 were observed after administration of sipuleucel-T, and levels increased further with use of ipilimumab. A phase II trial combining sipuleucel-T with immediate versus delayed ipilimumab remains active (NCT01804465).

Other current trials combine sipuleucel-T with atezolizumab (Tecentriq) in patients with asymptomatic or minimally symptomatic mCRPC (NCT03024216) and with stereotactic ablative body radiation (NCT01818986).

Fitzhugh M. Dendreon seeks expanded role for Provenge in new early stage prostate cancer trial. Dendreon website [reprinted from BioWorld. 2018;29(98)]. dendreon.com/Portals/12/dendreon-pharmaceuticals-bioworld-reprint.pdf. Accessed January 8, 2019.

Questions and answersProvenge. US FDA website. www.fda.gov/biologicsbloodvaccines/cellulargenetherapyproducts/approvedproducts/ucm210037.htm. Updated March 16, 2018. Accessed January 25, 2019.

Small EJ, Schellhammer PF, Higano CS, et al. Placebo-controlled phase III trial of immunologic therapy with sipuleucel-T (APC8015) in patients with metastatic, asymptomatic hormone refractory prostate cancer. J Clin Oncol. 2006;24(19):3089-3094. doi: 10.1200/JCO.2005.04.5252.

Higano CS, Schellhammer PF, Small EJ, et al. Integrated data from 2 randomized double-blind, placebo-controlled, phase 3 trials of active cellular immunotherapy with sipuleucel-T in advanced prostate cancer. Cancer. 2009;115(16):3670-3679. doi: 10.1002/cncr.24429.

Dendreon receives complete response letter from FDA for Provenge BLA [news release]. Seattle, WA: Dendreon Corporation; May 9, 2007. fiercebiotech.com/biotech/press-release-dendreon-receives-complete-response-letter-from-fda-for-provenge-bla. Accessed January 25, 2019.

Kantoff PW, Higano CS, Shore ND, et al; IMPACT Study Investigators. Sipuleucel-T immunotherapy for castration-resistant prostate cancer. N Engl J Med. 2010;363(5):411-422. doi: 10.1056/NEJMoa1001294.

Begley S. Insight: new doubts about prostate-cancer vaccine Provenge. Reuters website. reuters.com/article/us-provenge/insight-new-doubts-about-prostate-cancer-vaccine-provenge-idUSBRE82T07420120330. Published March 30, 2012. Accessed January 8, 2019.

Huber ML, Haynes L, Parker C, Iversen P. Interdisciplinary critique of sipuleucel-T as immunotherapy in castration-resistant prostate cancer. J Natl Cancer Inst. 2012;104(4):273-279. doi: 10.1093/jnci/djr514.

George DJ, Nabhan C, DeVries T, et al. Survival outcomes of sipuleucel-T phase III studies: impact of control-arm cross-over to salvage immunotherapy. Cancer Immunol Res. 2015;3(9):1063-1069. doi: 10.1158/2326-6066.CIR-15-0006.

Schellhammer PF, Chodak G, Whitmore JB, et al. Lower baseline prostate-specific antigen is associated with a great overall survival benefit from sipuleucel-T in the Immunotherapy for Prostate Adenocarcinoma Treatment (IMPACT) trial. Urology. 2013;81(6):1297-1302. doi: 10.1016/j.urology.2013.01.061.

Sartor AO, Armstrong A, Ahaghotu C, et al. PD24-12 Overall survival analysis of African American and Caucasian patients receiving sipuleucel-T: preliminary data from the PROCEED registry. J Urol. 2017;197(4S):e456-e457. doi: 10.1016/j.juro.2017.02.1089.

Scholz M, Yep S, Chancey M, et al. Phase I clinical trial of sipuleucel-T combined with escalating doses of ipilimumab in progressive metastatic castrate-resistant prostate cancer. Immunotargets Ther. 2017;6:11-16. doi: 10.2147/ITT.S122497.

Since the approval of sipuleucel-T for the treatment of minimally symptomatic metastatic castration-resistant prostate cancer in 2010, barriers to administration and the approval of competing drugs has tampered wide adoption of its use.

Sipuleucel-T Shows Potential With New Trial Data, But Questions Regarding Clinical Relevance Remain

The immune checkpoint inhibitor pembrolizumab (Keytruda) continued to demonstrate encouraging antitumor activity in an interim analysis of KEYNOTE-057, which involved a subset of 102 patients with nonmuscle-invasive bladder cancer (NMIBC).

Specifically, at month 3, 40.2% of patients demonstrated a complete response (CR; 95% CI, 30.6%-50.4%), with a median duration of CR of 12.7 months (0.0+ to 20.5+ months), with 53% of patients exhibiting a CR lasting &ge;9.

Patients with high-risk disease who had previously received bacille Calmette-Guérin (BCG), an intravesical immunotherapy, and became unresponsive to the treatment or were ineligible for cystectomy received pembrolizumab 200 mg every 3 weeks for 24 months or until recurrence, progression, or unacceptable toxicity.

Although up to 70% of patients with high-grade disease will respond to BCG, &ldquo;the challenge is that many of these patients do not maintain a response. Durability of response is a major clinical issue,&rdquo; said Arjun V. Balar, MD, assistant professor of medicine, and director of the Genitourinary Medical Oncology Program, at NYU Langone&rsquo;s Perlmutter Cancer Center in New York, New York. Balar presented the findings during the 2019 Genitourinary Cancers Symposium in San Francisco, California.

Traditionally, these patients undergo radical cystectomy once they become unresponsive to BCGthe disease naturally progresses toward muscle-invasive and, eventually, metastatic disease. Balar noted, however, that surgery carries a great deal of morbidity and also a mortality risk. Many patients either decline to undergo or are ineligible for cystectomy. This represents a significant unmet medical need. The hope is that pembrolizumab could ultimately preserve a patient&rsquo;s bladder.

Balar highlighted patients in cohort A of the study who were characterized with carcinoma in situ with or without papillary disease (high-grade Ta or T1). Patients were evaluated using cystoscopy, urine cytology, and biopsy if abnormalities were detected, on an every-12-week interval, and also with CT urograms on an every-24-week schedule. For this cohort, the primary endpoint was CR.

At data cutoff, 102 patients had received pembrolizumab with a median follow-up of 15.8 months (range, 4.6-28.2 months) and 23 patients continued on treatment (22.5%). Seventy-eight patients discontinued therapy because of persistent disease (n = 43), recurrent disease or stage progression (n = 22), and 8 patients discontinued treatment because of treatment-related adverse effects (AEs). Other reasons for discontinuation included CR, physician decision, protocol violation, and patient withdrawal.

When the CR rate (CRR) at month 3 was stratified by subgroup factors, Balar noted, ethnicity and geographic location may have had an effect. The investigators reported that Caucasians had a CRR of 31.9% (22 of 69; 95% CI, 21.2%- 44.24%) compared with non-Caucasians, who had a CRR of 55.6% (15 of 27; 95% CI, 35.3%-74.5%). Patients in the United States had a CRR of 27.8% (10 of 36; 95% CI, 14.2%-45.2%), and patients outside the United States had a CRR of 47% (31 of 66; 95% CI, 34.6%-59.7%).

Similarly, the investigators reported the effects of PD-L1 status. Patients who were PD-L1 positive (combined positive score &ge;10) had a 30.8% CRR (95% CI, 17.0%-47.6%), and patients who were PD-L1 negative (combined positive score <10) had a 47% CRR (95% CI, 34.6%-59.7%).

&ldquo;However, we do not want to make too many inferences about these subgroups,&rdquo; Balar said.

Overall, the pembrolizumab AE profile was consistent with that of previous studies, Balar noted. The investigators reported that 98 patients (96.1%) had &ge;1 AE, 66 patients (64.7%) reported treatment-related AEs, 29 patients (28.4%) reported grade &ge;3 AEs, and 13 patients (12.7%) reported grade ---3/4 treatment- related AEs. The most commonly reported treatment-related AEs of any grade were pruritus (n = 11), diarrhea (n = 11), fatigue (n = 10), and hypothyroidism (n = 6). Among grade 3/4 treatment-related AEs, the most commonly reported included hyponatremia (n = 3) and arthralgia (n = 2), with adrenal insufficiency, cholestatic hepatitis, and hypophosphatemia each with 1 case reported.

Balar said that the data reported in this interim analysis need to be tested in a randomized setting, pointing out KEYNOTE-676, a phase III study evaluating the safety and efficacy of pembrolizumab in high-risk NMIBC that is persistent or recurrent after BCG induction, which is currently enrolling patients (NCT03711032).

The immune checkpoint inhibitor pembrolizumab continued to demonstrate encouraging antitumor activity in an interim analysis of KEYNOTE-057, which involved a subset of 102 patients with nonmuscle-invasive bladder cancer.

Interim Analysis of KEYNOTE-057 Shows Encouraging Antitumor Activity in NMIBC

Findings from a study of tumor samples collected from patients with pancreatic ductal adenocarcinoma (PDAC) revealed that 17% of tumors harbored a known genomic alteration for which targeted therapies have already been developed, conferring feasibility to implementing precision medicine in a disease that has seen little progress in the development of effective therapeutic agents.

Genomic mutations in KRAS, TP53, CDKN2A, and SMAD4 are most frequently observed in PDAC, yet no currently available targeted agents are directed at these alterations. Adding to this is the heterogeneous characterization of PDAC because of numerous mutations present at low levels (<5%), contributing to the slow evolution of systemic therapies.

&ldquo;The complex genomic heterogeneity in otherwise histologically similar PDACs suggests a one-size-fits-all approach to treating patients will not be successful,&rdquo; said Aatur D. Singhi, MD, PhD, and colleagues in their report published in Gastroenterology. &ldquo;Targeted genomic profiling of known genomic alterations across multiple tumor types highlights potentially targetable and predictive biomarkers for treatment in a significant subset of PDACs.&rdquo;

Targeted genomic profile analysis was performed using 3594 PDAC samples from an international cohort of patients. In addition, investigators assessed for tumor mutation burden (TMB) in 1021 samples (28%) and microsatellite instability (MSI) status in 2563 (71%).

Investigators categorized genomic alterations based on signaling pathways using published literature as follows: receptor tyrosine kinase/ Ras/mitogen-activated protein kinase (RTK/Ras/ MAPK) activation, DNA damage repair, cell cycle regulatory, transforming growth factor (TGF)&beta; signaling, histone modification, switching/sucrose nonfermenting (SWI/SNF) complex, PI3K/mTOR signaling, Wnt/&beta;-catenin pathway, Notch signaling, angiogenesis, and Hedgehog signaling (

Alterations were further divided into clinically relevant genomic alterations for which there are available anticancer drugs on the market or in clinical trials. Those identified in the PDAC samples (17%) were classified by Singhi et al as either targetable mutations in RTK/Ras/MAPK signaling or predictive biomarkers for treatment in the DNA damage repair pathways.

In total, 19,120 genomic alterations were identified in 317 genes, with KRAS alterations occurring with the highest frequency. Contrary to established data, about 12% of samples were

wild-type; previous studies showed an absence of KRAS mutations in <5% of PDACs. Investigators hypothesized that the discordance may be due to differences in the tumor samples collected. Prior reports often used specimens from pancreatic surgical resections, whereas the clinical cohort in the study included both resectable and unresectable disease samples.

The identification of a significant number of

wild-type PDACs creates the opportunity to detect alternative drivers of targeted therapy within the RTK/Ras/MAPK pathway. Kinase fusion genes, such as ALK, BRAF, RET, and NTRK1, were the most commonly reported puta- tive driver alterations in this group.

Limited data regarding the use of available targeted therapies in PDAC exist; however, a presentation from the 2018 Gastrointestinal Cancers Symposium showed that the investigational pan-ALK/TRK/ROS1 inhibitor entrectinib produced partial responses in all 3 patents, 2 with

fusionpositive 2 pancreatic cancer. Other mutations include BRAF deletions, which may be targetable with the MEK1/2 inhibitor trametinib (Mekinist); ALK fusions, for which 1 of the FDA-approved ALK inhibitors may show activity; and other amplifications and missense mutations in genes involved in the RTK/Ras/MAPK pathway.

Although individual mutations in genes involved in the DNA damage repair pathway typically presented at frequencies <5%, they collectively affected 81% of PDACs in the cohort. The investigators said that germline alterations with the greatest implication for treatment are those present in the BRCA-FANC family (14%) and may serve as predictive biomarkers for sensitivity to therapies such as PARP inhibitors and platinum-based cytotoxic regimens.

No clinical trials are comparing the efficacy of platinum-based chemotherapy against other agents in patients with PDAC, but several ret- rospective analyses suggest that patients with

-mutated disease see benefit in overall survival (OS) rates with these chemotherapy options compared with nonplatinum-based chemotherapy.

Early clinical trials of PARP inhibitors in

-mutated PDAC demonstrated positive responses. In a phase II trial evaluating olaparib (Lynparza) in patients with different tumor types who harbored a germline

1/2 mutation, the response rate in 23 patients with pancreatic cancer who had received an average of 2 prior lines of chemotherapy for metastatic disease was 22% (95% CI, 7.5%-43.7%).

Of those patients, there was 1 complete response and 4 partial responses; 8 patients had stable disease and 40.9% were alive at 12 months.

Promising data from olaparib trials led to the phase III randomized POLO trial (NCT02184195) of maintenance olaparib monotherapy versus placebo in patients with germline

-mutated metastatic pancreatic cancer whose disease has not progressed on frontline platinum-based chemotherapy. In October 2018, the FDA granted the PARP inhibitor orphan drug designation in the treatment of pancreatic cancer.

Then, in February 2019, Myriad Genetics announced that, based on the trial results, it would submit a supplementary premarket approval application to authorize its companion diagnostic test, BRCAnalysis CDx, for use in patients with pancreatic cancer.5 The test was able to successfully identify patients with metastatic pancreatic cancer who had BRCA mutations and would likely benefit from treatment with olaparib.

Immunotherapy has shown benefit for patients with MSI-high and TMB-high tumors; however, just 0.1% and 0.5% of PDACs in the cohort were assessed to be MSI high and TMB high, respectively.

MSI-high PDACs treated with the antiPD-1 inhibitor pembrolizumab (Keytruda), which was approved for a tumor-agnostic indication in mis-match-repair deficiency, had an overall response rate of 62% and a disease control rate of 75% in 8 patients in a phase II trial. Disappointingly, the prevalence of MSI-high status in patients with PDAC has been historically infrequent.

Uncertainty remains about the clinical relevance of TMB across tumors types. This is aggravated by the fact that individual disease types reflect different cutoff points for what is considered high and low expression of TMB.

In this study, investigators used &ge;20 mutations per megabase of sequenced DNA as the cutoff for high TMB. Further analysis is needed to determine the upper limits of TMB expression in PDAC and what it means for use of immunotherapy in those tumors.

Further correlations were observed between genomic alterations and presentation of disease. Primary PDACs were more commonly associated with

mutations, whereas metastatic disease was associated with CDKN2A, CDKN2B, MYC, MLL2, ERBB2, CDK6, RB1, and MYST3 alterations.

Subanalyses showed that patients with liver metastases more commonly harbored mutations, including TP53 and CDK6. Conversely, GNAS mutations were less likely to be present in the liver but were more often detected in lung metastases.

Patients &ge;50 years were more likely to have genetic alterations in the KRAS, SMAD4, DNMT3A, and APC genes, whereas patients <50 more commonly had

By gender, female patients were more likely to have alterations in KRAS, SMAD4, and CDKN2A compared with male patients, who often exhibited GNAS, KDM6A, ATM, and SF3B1.

The presence of GNAS alterations in PDAC was specific for tumors arising from intraductal papillary mucinous neoplasms (IPMNs) and has been shown to occur early in the progres- sion of these noninvasive precursors to PDAC. Therefore, genomic alterations in GNAS may be involved in the pathogenesis of IPMN-associated PDACs. These alterations can be assessed by aspirating pancreatic cyst fluid and may present an early detection screening method for this PDAC subtype.

Singhi AD, George B, Greenbowe JR, et al. Real-time targeted genome profile analysis of pancreatic ductal adenocarcinomas identifies genetic alterations that might be targeted with existing drugs or used as biomark- ers [published online March 2, 2019]. Gastroenterology. doi: 10.1053/j. gastro.2019.02.037.

Pishvaian MJ, Rolfo CD, Liu SV, Multani PS, Maneval EC, Garrido-Laguna I. Clinical benefit of entrectinib for patients with metastatic pancreatic cancer who harbor NTRK and ROS1 fusions. J Clin Oncol. 2018;36(suppl 4; abstr 521). doi: 10.1200/JCO.2018.36.4_suppl.521.

Kaufman B, Shapira-Frommer R, Schmutzler RK, et al. Olaparib monotherapy in patients with advanced cancer and a germline BRCA1/2 mutation. J Clin Oncol. 2015;33(3):244-250. doi: 10.1200.JCO.2014.56.2728. 4. Fourth orphan drug designation in the US for AstraZeneca and MSD&rsquo;s Lynparza [news release]. Kenilwoth, NJ: AstraZeneca and Merck & Co, Inc; October 16, 2018. bit.ly/2pYa7c8. Accessed March 25, 2019.

Myriad&rsquo;s BRACAnalysis CDx Test successfully identified patients with metastatic pancreatic cancer who benefitted from treatment with olaparib [news release]. Salt Lake City, UT: Myriad Genetics, Inc; February 26, 2019. bit.ly/2V6MGeK. Accessed March 25, 2019.

Samstein RM, Lee C-H, Shoushtari AN, et al. Tumor mutational load predicts survival after immunotherapy across multiple cancer types. Nat Genet. 2019;51(2):202-206. doi: 10.1038/s41588-018-0312-8.

Findings from a study of tumor samples collected from patients with pancreatic ductal adenocarcinoma revealed that 17% of tumors harbored a known genomic alteration for which targeted therapies have already been developed, conferring feasibility to implementing precision medicine in a disease that has seen little progress in the development of effective therapeutic agents.

Existing Drugs May Offer Treatment Opportunities in Pancreatic Ductal Adenocarcinoma

The results of several studies presented at the 2019 Genitourinary (GU) Cancers Symposium confirmed that the combination of PD-1/PD-L1 checkpoint inhibitors with tyrosine kinase inhibitors (TKIs) of the VEGF pathway was superior to VEGF inhibitors alone in patients with clear cell renal cell carcinoma (RCC), which accounts for about 70% of patients with kidney cancer.

Combination regimens of antiangiogenic therapies with checkpoint inhibitors in the first-line setting have shown superior antitumor activity in patients with metastatic or advanced RCC compared with standard-of-care, single-agent therapies, according to investigator presentations. But questions remain: Are the combined therapies superior to the previous standard of care with TKIs? And is first-line immunotherapy treatment effective in patients with advanced nonclear cell (ncc)RCC?

&ldquo;The big conference news was that the KEYNOTE-426 study showed that pembrolizumab [Keytruda] with axitinib [Inlyta] crushed sunitinib [Sutent] on nearly all major endpoints: the response rate, progression-free survival [PFS], and most significantly in the overall survival [OS] rates,&rdquo; said David F. McDermott, MD, professor of medicine at Harvard Medical School and chief of medical oncology at the Leon V. & Marilyn L. Rosenberg Clinical Cancer Center at Beth Israel Deaconess Medical Center, both in Boston, Massachusetts.

Patients with previously untreated advanced clear cell RCC (n = 861) were randomized 1:1 to receive intravenous (IV) pembrolizumab 200 mg every 3 weeks for a maximum of 35 cycles plus oral axitinib 5 mg twice daily (n = 432) or oral sunitinib 50 mg daily for the first 4 weeks of each 6-week cycle (n = 429).

The 12-month OS rate was 89.9% in patients receiving the PD-1 inhibitor pembrolizumab plus axitinib, a second-generation small molecule inhibitor of VEGFR, compared with 78.3% in those receiving sunitinib (HR, 0.53; 95% CI, 0.38-0.74; P <.0001). This hazard ratio for OS in the open-label phase III trial was the lowest seen to date among frontline therapy trials, noted McDermott.

With a median follow-up of 12.8 months, the median PFS was 15.1 months in the pembrolizumab/axitinib group compared with 11.1 months in the sunitinib group (HR, 0.69; 95% CI, 0.57-0.84; P = .0001). The confirmed objective response rates (ORRs) were 59.3% (95% CI, 54.5%-63.9%) in the pembrolizumab/axitinib group versus 35.7% (95% CI, 31.1%-40.4%) in the sunitinib group (P <.0001) (

According to the presentation, grade &ge;3 adverse events (AEs) of any cause occurred in 75.8% of patients in the pembrolizumab/axitinib group and in 70.6% in the sunitinib group. Results of the phase Ib dose-finding study of the pembrolizumab/axitinib combination presented at the 2018 GU Cancers Symposium showed a similar safety profile as well as antitumor activity.

In February, the FDA granted priority review for a new supplemental biologics license application (sBLA) for pembrolizumab in combination with axitinib as a frontline treatment for patients with advanced RCC based on data from KEYNOTE-426, with a target action date for the application of June 20194 and the results of the trial were subsequently published in the New England Journal of Medicine.

&ldquo;We anticipate that this combination will become a standard of care for untreated patients with kidney disease,&rdquo; said McDermott.

Another combination that may move to the first line is the PD-L1 inhibitor avelumab (Bavencio) plus axitinib. The FDA granted another priority review to the sBLA for the avelumab/axitinib combination for patients with advanced RCC based on data from the JAVELIN Renal 101 trial. The application has been given a target action date of June 2019.

Data from this clinical trial that were presented at the symposium and updated in the New England Journal of Med- icine showed that avelumab added to axitinib outperformed sunitinib, with a longer median PFS (13.8 vs 8.4 months; HR, 0.69; P <.001) and a higher ORR (51.4% vs 25.7%).

The benefits were observed in all patients regardless of PD-1/ PD-LI status and in all prognostic risk groups. However, 1 limitation of these data is that the combination has yet to demonstrate an OS benefit.

&ldquo;Now that it has been proved that an antiPD-1 plus VEGF [inhibitor] is superior to VEGF alone, an important question to consider is which combination is best for which patients: Is it anti&ndash;PD-1 and VEGF or anti&ndash;PD-1 and anti&ndash;CTLA-4?&rdquo; asked McDermott.

Other combinations of antiPD-1 and targeted VEGF therapies appear promising based on phase I trial data presented in posters at the symposium. In patients previously treated for metastatic RCC, pembrolizumab plus cabozantinib (Cabometyx) demonstrated antitumor activity and was tolerated; the maximum tolerated dose (MTD) was determined.

Based on the data, a 2-stage phase II study with the MTD of 60 mg cabozantinib daily plus 200 mg IV pembrolizumab every 3 weeks has begun in patients with RCC with either clear cell or ncc histology (NCT03149822).

Investigators also presented 30-month follow-up data from the phase III CheckMate 214 trial. The combination of the PD-1 inhibitor nivolumab (Opdivo) and the CTLA-4 inhibitor ipilimumab (Yervoy) sustained strong responses and an OS benefit as a frontline treatment in intermediate- and poor-risk patients with advanced RCC. At 30 months, the OS rate by International Metastatic Renal Cell Carcinoma Database Consortium risk was 60% with the immunotherapy combination versus 47% with sunitinib (HR, 0.66; 95% CI, 0.54-0.80; P <.0001) and 64% versus 56% in the intention-to-treat (ITT) population (HR, 0.71; 95% CI, 0.59-0.86; P = .0003), respectively. The ORR for the combination was 42.0%, with 11.3% achieving a complete response (CR), compared with 29.0% and 1.2% with sunitinib, respectively.

Among the responders, 52% of patients receiving nivolumab/ipilimumab had a response lasting &ge;18 months compared with 28% of patients on sunitinib. No new safety signals were detected at the longer follow-up.

Of the 1096 patients in the ITT population, 23% were considered favorable risk; 61%, intermediate risk; and 17%, poor risk in each arm. Additionally, about one-fourth in the ITT population had PD-L1 expression &ge;1%.

The patients were randomized 1:1 to receive the combination of 3 mg/kg of nivolumab plus 1 mg/kg of ipilimumab every 3 weeks for 4 doses, followed by nivolumab every 2 weeks (n = 425) or sunitinib 50 mg once daily for a 4-weeks-on/2-weeks-off schedule (n = 422). Patients in the experimental arm receiving nivolumab monotherapy could switch to a 240-mg flat dose until disease progression or unacceptable toxicity, and those receiving sunitinib were permitted to cross over to receive the immunotherapy combination.

The FDA approved the combination of nivolumab and ipilimumab in April 2018 as a frontline treatment for intermediate- and poor-risk previously untreated advanced RCC based on the primary data analysis, which showed a 37% reduction in the risk of death versus sunitinib regardless of PD-L1 expression status (HR, 0.63; 99.8% CI, 0.44-0.89; P <.001).

&ldquo;When the data were first presented at the European Society for Medical Oncology 2017 Congress, we were excited about the higher CR rate of 9.4%,13&rdquo; said Bradley A. McGregor, MD, clinical director of the Lank Center for Genitourinary Oncology at the Dana-Farber Cancer Institute in Boston. &ldquo;With the 30-month follow-up data from phase III, we see that the CR rate is slightly higher, and the majority of patients maintained their CRs even after treatment ended. This gives us hope that patients will have a durable remission.&rdquo;

McDermott, a coinvestigator on CheckMate 214, noted that the CR rate with nivolumab and ipilimumab was nearly double that observed in KEYNOTE-426 with pembrolizumab and axitinib (11.3% vs 5.8%, respectively).

&ldquo;Those CR differences are not likely statistically significant, but they may be relevant in clinical decision making for some patients and physicians. With single-agent immunotherapies (eg high-dose IL-2 and antiPD-1), we have seen how deep responses (eg CRs) can translate into long-term survival and, in a small subset, remis- sions of advanced disease,&rdquo; McDermott said. However, &ldquo;some physicians will choose the anti&ndash; VEGF/PD-1 strategy because the current efficacy signal is impressive and the toxicity profile may be more familiar and easier to manage,&rdquo; he added.

Of note, improved OS, PFS, and ORR endpoints for the CheckMate 214 trial were maintained only for patients with intermediate- and poor- risk disease compared with all subgroups in the KEYNOTE-426 trial.

The ongoing single-arm phase I/II CALYPSO trial, which had interim data presented at the symposium, is looking at the combination of the PD-LI inhibitor durvalumab (Imfinzi) and the novel MET inhibitor savolitinib with a 4-week savolitinib run-in, in patients with treatment-naïve or previously treated metastatic papillary renal cancer. Response rate by RECIST 1.1 is the primary endpoint, with PFS, tolerability, and OS as secondary endpoints. Efficacy data is immature but showed an ORR of 27%. The rates of median OS and PFS at the analysis were not reached and 5.3 months, respectively, with the combination.

McDermott, the principal investigator of the KEYNOTE-427 study, presented data on the first-line treatment of patients with nccRCC with single-agent pembrolizumab, which showed encouraging antitumor activity, especially with papillary or unclassified histology.

KEYNOTE-427 was a 2-cohort study of patients with recurrent or advanced metastatic RCC, measurable disease, and a Karnofsky performance status &ge;70%. No prior systemic therapy was allowed. Histology was confirmed by a central pathologist. In cohort B, which comprised 165 patients with nccRCC, 72% of patients had papillary, 13% had chromophobe, and 16% had unclassified histology. Sixty-eight percent of patients were considered intermediate/poor risk, and 62% were PD-L1 positive, according to the data presented.

The ORR was 24.8% in the patients with nccRCC (95% CI, 18.5%-32.2%). By histology subgroups, the ORRs were 25.4% (95% CI, 17.9%-34.3%) in the patients with papillary histology, 34.6% (95% CI, 17.2%-55.7%) in those with unclassified histology, and 9.5% (95% CI, 1.2-30.4) in those with chromophobe histology.

At a median follow-up of 11.1 months, the median PFS was 4.1 months (95% CI, 2.8-5.6) and the estimate for 12-month OS rate was 72%. Grade &ge;3 treatment-related AEs (TRAEs) occurred in 11% of patients, and 6% discontinued because of TRAEs. Six patients died as a result of AEs, 1 each from grade 5 pneumonia and cardiac arrest.

The ORRs were 28.3% (95% CI, 16.8%-42.3%) in favorable-risk and 23.2% (95% CI, 15.8%-32.1%) in intermediate/poor-risk patients. By PD-L1 expression, ORRs were 33.3% (95% CI, 24.3%- 43.4%) and 10.3% (95% CI, 3.9%-21.2%) in patients with a combined positive score (CPS) &ge;1 and CPS <1, respectively.

McDermott noted that patients with nccRCC have historically been excluded from clinical trials largely based on their lack of response to cytokine-based immune therapy. The National Comprehensive Cancer Network guidelines for advanced nccRCC recommend that these patients enroll in an appropriate clinical trial or be treated with sunitinib based on its efficacy in clear cell RCC.

In addition, there are no FDA-approved therapies for this type of cancer.

&ldquo;There is a significant and unmet need for safe and effective treatment options for patients with nccRCC,&rdquo; McDermott said during his presenta- tion at the symposium.

Patients received IV pembrolizumab 200 mg every 3 weeks for up to 35 cycles or until disease progression, unacceptable toxicity, or withdrawal. Response was assessed at week 12 and then every 6 weeks until week 54 and every 12 weeks thereafter. At analysis, 49 patients had died and 3 had withdrawn. At a median follow-up duration of 11.1 months (range, 0.9-21.3), 56% of patients discontinued pembrolizumab because of disease progression or clinical progression, according to the presentation.

The cohort A data were reported at the 2018 American Society of Clinical Oncology (ASCO) Annual Meeting and showed promising antitu- mor activity in 110 patients with advanced clear cell RCC who received pembrolizumab. The ORR was 38.2%, with a CR rate of 2.7% and a partial response rate of 35.5%. The safety profile was similar to that previously reported for pembrolizumab in other tumor types.

&ldquo;The results were surprisingly good in both cohorts, with higher response rates and less toxicity than expected. This supports further evaluation of pembrolizumab particularly in patients with advanced nccRCC,&rdquo; said McDermott.

&ldquo;These advances in clear cell RCC with immunotherapy and targeted therapy are now making their way to nccRCC,&rdquo; said McGregor. &ldquo;The data seen in smaller, phase II trials support the role of continuing this approach in nccRCC.&rdquo;

McGregor was also an investigator on a phase II single-arm, open-label trial evaluating the efficacy of the antiPD-L1 agent atezolizumab (Tecentriq) plus bevacizumab (Avastin) in patients with nccRCC or clear cell RCC with >20% sarcomatoid differentiation. The results showed that atezolizumab plus bevacizumab therapy was safe and demonstrated antitumor activity in both types of RCC.

A total of 65 patients were enrolled in the multicenter trial, and 52 had &ge;1 response assessment and were included in this analysis. Thirty-six patients had nccRCC, and 16 patients had clear cell RCC with sarcomatoid differentiation. Of the 17 patients who received prior systemic therapy, 16 had nccRCC. Prior PD-1/PD-L1 therapy was not allowed.

The ORR was 31% in the overall cohort, with rates of 44% and 25% in patients with clear cell and nccRCC, respectively. Ten patients (19%) developed grade 3 TRAEs, half of which were immune related. There were no grade &ge;4 AEs. This regimen was well tolerated, with responses exceeding those seen with TKI monotherapy.

Further analyses will report on the ORR by histo- logic subtype and PD-L1 expression status. There is an ongoing analysis of tissue and blood-based biomarkers involved in responses, said McGregor.

Longer follow-up and potentially different trial designs are necessary to address remaining questions related to immunotherapy and TKI combinations in RCC. Investigators will need to determine whether benefits of these agents are synergistic or additive and whether similar results will be achievable through sequential use of these agents.

&ldquo;These comparative questions are currently based on opinion rather than facts. We need head-to-head randomized trials to answer those questions, which is unlikely to happen anytime soon,&rdquo; said McDermott.

The results of several studies presented at the 2019 Genitourinary Cancers Symposium confirmed that the combination of PD-1/PD-L1 checkpoint inhibitors with tyrosine kinase inhibitors of the VEGF pathway was superior to VEGF inhibitors alone in patients with clear cell renal cell carcinoma, which accounts for about 70% of patients with kidney cancer.

April 2 2019