NEOADJUVANT CHEMOTHERAPY FOR BLADDER CANCER

For patients with bladder cancer, chemotherapy before surgery improves survival when compared with surgery alone. But there is a question over which neoadjuvant chemotherapy (NAC) therapy should be used.

Although gemcitabine with cisplatin (GC) has become a standard NAC regimen, some institutions are adopting a dose-dense combination of methotrexate, vinblastine, doxorubicin, and cisplatin (ddMVAC).

A new study shows that this less-frequently-used ddMVAC combination appears to be associated with significantly higher rates of complete response and disease downstaging in patients undergoing radical cystectomy for muscle-invasive bladder cancer (MIBC).

The study, led by Scott M. Gilbert, MD, MS, from the H. Lee Moffitt Cancer Center and Research Institute in Tampa, Florida, was published online August 30 in JAMA Oncology.

The cross-sectional analysis of more than 1000 patients who underwent cystectomy compared patients who received ddMVAC to those treated with other regimens or with cystectomy alone.

Among 46 patients who received an average of 3.3 cycles of ddMVAC before surgery, 19 (41.3%) had a complete response.

By comparison, of the 204 patients who received an average of 3.7 cycles of standard-of-care GC, there was a complete response in 50 (24.5%).

"Although gemcitabine with cisplatin [GC] is the most frequently prescribed neoadjuvant chemotherapy regimen for patients with muscle-invasive bladder cancer, for eligible patients, treatment with dose-dense methotrexate, vinblastine, doxorubicin, and cisplatin [ddMVAC] may lead to better outcomes," the authors write.

"These data highlight and suggest the need to further investigate ddMVAC vs standard NAC in a prospective, randomized fashion."

Study Details 

For the study, the patient cohort was assembled from a registry of 1186 patients who underwent cystectomy at the Moffitt Cancer Center during the 10-year period from January 1, 2007, to May 31, 2017.

Of the 824 patients with MIBC, 332 (40%) were treated with NAC. Patients who did not receive NAC served as controls. Overall survival time was measured from the time of cystectomy to the last follow-up or death from any cause.

The study showed that in 32 patients treated with gemcitabine-carboplatin, a NAC regimen commonly used in cases of renal insufficiency, 9.4% (3 patients) had a complete response. This was lower than the complete response rate of 10.7% for cystectomy alone, raising questions about the role of gemcitabine-carboplatin in advanced bladder cancer, the researchers said.

"[N]eo-adjuvant gemcitabine-carboplatin appears essentially ineffective. Complete response rates were low, and more concerning still, the adjusted risk of death was significantly higher than for the reference gemcitabine-cisplatin group (HR [hazard ratio], 2.0)," they note.

The analysis also showed a greater likelihood of downstaging in patients treated with ddMVAC (19 patients [52.2%]) than in those treated with GC (50 patients [41.3%]) or with gemcitabine and carboplatin (10 patients [27.0%]). The researchers defined downstaging as any decrease in stage or complete pathologic response using the TNM malignant tumor classification pT0N0 or ypT0N0.

While neoadjuvant ddMVAC was associated with longer survival intervals and a lower risk for death than the other NAC regimens, this benefit did not reach statistical significance (HR, 0.44; P = .16). Still, the researchers emphasized that the survival differences were large enough to be clinically relevant.

"[W]e were able to demonstrate a direct and significant relationship between ypT0N0 downstaging and survival, adding plausibility to the survival benefit of ddMVAC compared with gemcitabine-cisplatin…. Larger comparative studies are needed to definitively answer questions regarding survival," they conclude.

Previous Studies Show Benefit of NAC 

The investigators cite several studies that highlight the benefit of neoadjuvant chemotherapy in patients with bladder cancer.

A 2003 study showed that NAC before cystectomy was associated with a 6% survival benefit at 10 years. This landmark trial comparing neoadjuvant MVAC to cystectomy alone reported significant improvement in complete pathologic response (38% vs 15%; P < .001) and median overall survival (77 vs 46 months; P = .05) with MVAC.

However, that 2003 trial also showed that more than 50% of patients treated with MVAC experienced serious toxic effects including myelosuppression and mucositis. "These adverse events have limited the widespread use of MVAC to date," Gilbert and colleagues commented.

For this reason, GC has been recommended as first-line therapy by the American Urological Association/ Society of Urologic Oncology, the National Comprehensive Cancer Network, and the European Association of Urology, the researchers note. Despite this, adoption rates for GC as the standard of care have been modest, they said.

More Research Is Needed 

When asked to comment, David J. McConkey, PhD, director of Johns Hopkins Greenberg Bladder Cancer Institute in Baltimore, Maryland, agreed that more research is needed. Like the authors, he noted the low number of patients in the ddMVAC group despite the high number of patients in the cohort overall.

"This study has produced some provocative results which might be leading us in a particular direction, but the findings are not conclusive so the jury is still out. What we need is a real head-to head comparison under prospective conditions," he added.

McConkey predicted that ongoing research focusing on the impact of NAC on the immune microenvironment will be more effective than studies looking at the superiority of one agent over another in terms of survival.

"Biomarkers will make it possible to identify subgroups of patients who will benefit from NAC," McConkey told Medscape Medical News. "If one regimen provides more impact on the immune microenvironment, there will be some very exciting results, so stay tuned," he said.

He was referring to the Southwest Oncology Group's (SWOG)-S1314 trial, which is looking at tumor biomarkers using a computational method called Co-eXpression ExtrapolatioN (COXEN).

In previous work, a research team led by McConkey — who was then at the University of Texas MD Anderson Cancer Center in Houston — found that gene expression profiling can be used to predict sensitivity and resistance of different urothelial subtypes to conventional cisplatin-based combination chemotherapy. That 2016 study showed that the basal subtype was associated with better survival, while the p53-like subtype was associated with bone metastases and chemoresistant disease.

We can no longer think of urothelial cancer as a single disease Dr David McConkey

"We can no longer think of urothelial cancer as a single disease," McConkey and colleagues wrote. "Gene expression profiling identifies subtypes of urothelial cancer that differ in their natural history and sensitivity to chemotherapy."

Another expert approached for comment, Jean Heather Hoffman-Censits, MD, associate professor of oncology at Johns Hopkins School of Medicine in Baltimore, Maryland, agreed.

"For patients undergoing neoadjuvant chemotherapy, we have learned that urothelial bladder tumors with defects in DNA damage repair mechanisms are more responsive to chemotherapy," she told Medscape Medical News. 

Studies to evaluate prospectively novel treatment paradigms based on this biomarker are ongoing, she noted. "These and other individualized novel therapies based on tumor characteristics give us hope that better outcomes for our patients with bladder cancer are on the horizon."

Although the phase 2 COXEN trial is not designed to evaluate a difference in efficacy between CG and accelerated MVAC (aMVAC), it will "provide prospective assessment of the toxicity and completion rates of these regimens in a neoadjuvant setting," Hoffman-Censits predicted.

The ongoing phase 3 European VESPER study, which is designed to evaluate progression-free survival and tolerability using GC or aMVAC in the perioperative setting, "will also be informative," she said.

Like the study authors, Hoffman-Censits noted that the current study is one of several retrospective studies comparing the efficacy of neoadjuvant aMVAC or traditional MVAC to GC.

"Though informative and hypothesis generating, these studies are all limited by their retrospective nature," she said.

Several other prospective neoadjuvant studies of aMVAC have shown it to be a safe, efficient, and effective regimen, with downstaging rates commensurate with those originally reported with traditional multiday MVAC, she pointed out.

The presence of lymphovascular invasion, hydronephrosis, and variant histology are also important factors in interpreting chemotherapy response in the neoadjuvant setting, even though they are not always reported, Hoffman-Censits said.

In the current study, as well as in a previous report, patients receiving aMVAC were slightly younger than those receiving gemcitabine and cisplatin. This could reflect selection bias, she suggested.

She also noted that 91.3% of patients receiving ddMVAC and 73.7% of patients receiving GC received more than three cycles of chemotherapy. "Whether this is an indication of treatment tolerability, patient selection, or other unmeasured factors is not known. The ongoing SWOG-1314 COXEN trial may enlighten our field to some of these findings." 

The current study showed that ddMVAC treatment — from initiation of NAC to the date of surgery—took less time than other NAC regimens, letting patients complete their global treatment more quickly. "This may be relevant in bladder cancer, where time to definitive local therapy may impact outcome," said Hoffman-Censits.

The finding that neoadjuvant gemcitabine and carboplatin was no more effective than cystectomy alone was not a surprise, she added.

"Achievement of pathologic complete response in invasive bladder cancer is predicated upon adequate preoperative tumor staging with transurethral resection of bladder tumor (TURBT) and effective chemotherapy. We have long known that for urothelial cancer, carboplatin-based regimens are inferior to cisplatin regimens. Outside of a clinical trial, our field does not endorse preoperative carboplatin chemotherapy, which not only delays the potentially curative radical cystectomy but can add potential toxicity which may further delay or complicate surgery," she commented.  

Hoffman-Censits pointed out that only 40% of the patients in the study seen at the tertiary referral center received neoadjuvant chemotherapy, and 31% received regimens that were definitely cisplatin based. "While these statistics are vastly improved from reports of neoadjuvant chemotherapy utilization a decade ago, we still have far to go," she said.

"Preoperative cisplatin based chemotherapy is supported by level 1 data with overall survival improvement compared to surgery alone," she said. "Best care of patients with invasive bladder cancer employs a multidisciplinary approach where discussion and assessment for multimodality therapy occur in a timely fashion, and where standard evidence-based chemotherapy regimens are delivered." 

The study also highlights that for up to 50% of patients with invasive urothelial cancer who are not candidates for cisplatin chemotherapy, novel effective and tolerable perioperative regimens are needed, Hoffman-Censits said.

The current study was funded by the National Cancer Institute. Gilbert and the study coauthors have disclosed no relevant financial relationships. McConkey disclosed financial relationships with Apocell Inc and Astra-Zeneca, and Hoffman-Censits reported a financial relationship with Genentech. 

JAMA Oncol. Published online on August 30, 2018. Abstract

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ASCO 2018-MSI-H FREQUENCY IN VARIOUS TUMORS

Results from a study evaluating the relationship between the number of somatic mutations (SMs) in four mismatch repair (MMR) genes and the microsatellite instability (MSI) phenotype showed specific mutations in DNA repair genes associated with younger age, and specific cancer types. Researchers reported results from a large genomic study of over 24,000 tumour samples at the 2018 American Society of Clinical Oncology (ASCO) Annual Meeting, held 1 to 5 June in Chicago, USA.

Somatic mutations (SM) that disrupt DNA repair mechanisms are commonly detected in cancer. SM in the mismatch repair (MMR) genes, including MLH1, MSH2, MSH6, and PMS2 contribute to MMR deficiency, leading to the accumulation of mutation within the cell and to the MSI phenotype.

The frequency of mutation in DNA repair genes determined for distinct tumour types

MSI is a genomic marker that indicates a defect in the ability of a tumour cell to repair damaged DNA. Bi-allelic SMs (bSM) of an MMR gene are known to cause MMR deficiency in colorectal and endometrial cancers. However, the frequency of mono-allelic SM (mSM) and bSM of MMR genes in othefined and ther tumours was unde clinical or molecular correlates of MMR gene mSM and bSM were not well described.

Therefore, Joseph Nicholas Bodor of the Fox Chase Cancer Centre in Philadelphia, USA and colleagues assessed 24,223 tumour samples in the Caris Life Sciences database tumours harbouring one or more SM of an MMR gene using next generation sequencing (NGS; Illumina NextSeq 592 gene panel).

The investigators also determined the association of mSM or bSM with clinical factors, and MSI, tumour mutational burden (TMB), as well as examining SM in non-MMR DNA repair pathways. Associations were tested by Fisher’s exact test and logistic regression.

Younger age of patient associated with bSM MMR mutations

The investigators found that470 of the tumours had ≥1 SM; of these, 80 had bSM within an MMR gene. The highest frequency (46) of bSM was found in the MSH6gene. The bSM in MSH6 were primarily due to recurrent SM at F1088fs, a coding microsatellite.

An evaluation of the association of bSM with clinical characteristics revealed that tumours with bSM were more commonly detected in younger patients having a medium age of 57.5 years (median 57.5 years bSM versus 63 years mSM; p = 0.003).

In addition, bi-allelic (bSM) MMR gene mutations were associated with high TMB, and also with more mutations in non-MMR DNA repair genes, including those for nucleotide excision repair and homologous recombination (HR) genes, such as BRCA1/2. They found that bSM associated with high TMB (p < 0.001), with SM in nucleotide excision repair genes (p = 0.003), and with HR genes (p = 0.01), such as ATM where 62 of 470 (13.2%) tumours contained bSM. bSM also associated with BRCA1 and 2, with 91 of 470 (19.4%) tumours having bSM.

At the single gene level, mono-allelic (mSM) in MSH2 (p = 0.001) and MSH6 (p = 0.01) were positively associated with TMB, but inversely with PMS2 (p < 0.001).

MSI was only found to associate with mSM in MLH1 (p < 0.001). Furthermore, SMs in HR genes were associated with mSM in MLH1, MSH2, and MSH6 (all p < 0.01), but SM in nucleotide excision repair genes were associated only with mSM in MSH6 (p = 0.004).

An analysis of SM by tumour type showed that mSM were common in endometrial (n = 84), colorectal (n = 90), and lung (n = 45) cancers. Frequency of MMR bSM by tumour histology showed next distribution: endometrial cancer (n = 34), colorectal cancer (n = 21), ovarian cancer (n = 14) and other. Differences in bSM frequency in left- (30%) versus right-sided (12.5%) colorectal cancer were not seen (p = 0.10).

bSM are nearly entirely restricted to Lynch syndrome spectrum tumours

Nearly all bi-allelic MMR somatic mutations (98%) were found in tumours within the Lynch syndrome spectrum, which are hereditary non-polyposis colorectal cancers and the most common form of hereditary colorectal cancer. Lynch syndrome cancers are most frequently diagnosed in younger individuals.

Study limitations

The authors pointed out that the study has some limitations: no paired germline data, therefore it is uknown if the somatic mutations observed are also found in germline, though a number of the mutations identified have been reported in germline series. The bSM were assumed to be in trans as the likelyhood of two pathogenic mutations on the same MMR gene allele is very low. Loss of heterozigosity studies was not conducted. There is no individual-level family history data or treatment data.

Conclusions

These findings demonstrate that MMR gene mSM occur in diverse tumour types, but bSM occur almost exclusively in Lynch syndrome-spectrum tumours.

The occurrence of mSM in tumours of patients with a younger age suggested to the authors that germline mutations may precede some bSM events.

The investigators concluded that the observed association of the number of MMR gene mutations and high TMB, MSI-H and non-MMR DNA repair gene mutations suggests cascade effects of DNA repair deficiency and reveals possible treatment targets.

Disclosure

ASCO-2018 THE CONCEPT OF OLIGOMETASTATIC CANCER

General physicians and many oncologists probably think of metastatic cancer as being "widely disseminated and incurable" in most cases involving solid tumors in adults, said Ralph Weichselbaum, MD, a radiation oncologist at the University of Chicago here at the American Society of Clinical Oncology (ASCO) 2018 annual meeting.

But for some metastatic cancers, dissemination is limited, and such cancers may be curable with local therapy, he explained at an honorary lecture at the meeting.

The term for these cancers is oligometastatic ("oligos" is Greek for "few" or "scanty"). It was coined by Weichselbaum and colleague Samuel Hellman, MD, in an article published 13 years ago (J Clin Oncol. 1995;13:8-10).

Weichselbaum was addressing the meeting as winner of the 2018 David A. Karnofsky Memorial Award, bestowed on him by ASCO for his work in this area.

He told the audience that the concept of oligometastasis was poorly received at first. Reviewers of the pair's groundbreaking 1995 article "hated" the hypothesis, as did some of their colleagues at the University of Chicago. But the editor of the Journal of Clinical Oncology liked it, and the article was published as an editorial, said Weichselbaum.

Oligometastasis is underrecognized, but fairly common, he said.

For the four most frequent cancers in the United States, there are about 90,000 oligometastatic presentations each year, he said. These include an estimated 10,000 prostate cancers, 14,000 breast cancers, 14,000 colorectal cancers, and 50,000 lung cancers.

Another expert believes most oncologists are aware of one type of oligometastastic cancer but may not know the concept applies to all solid tumors.

It is widely recognized that some colon cancers have limited liver metastases that can be surgically removed, said Joshua Bauml, MD, a medical oncologist at the University of Pennsylvania in Philadelphia, who has written about oligometastasis. After local surgical therapy, a subset of these patients are cured. "This flies in the face of our prior understanding of what metastatic disease is," he told Medscape Medical News.

"The old paradigm of cancer metastases is, once cancer gets into [distant] lymph nodes or the blood vessels, there is no chance of cure," Bauml commented. Weichselbaum and Hellman showed that this paradigm is "not exactly accurate."

Bauml further commented: "We haven't really identified how to separate out those patients [who are curable], but just the concept that such a subgroup exists is really revolutionary."

"We haven't really identified how to separate out those patients [who are curable], but just the concept that such a subgroup exists is really revolutionary. Dr Joshua BaumlWeichselbaum told the ASCO audience that "metastasis represents a spectrum of disease by [their] number, by [involved] organs, and by pace [of progression]."

Subsets of patients are "potentially curable" with "metastasis-directed therapies," he said. These include surgery, ablation, chemoradiotherapy, and stereotactic body radiotherapy.

Metastases are usually treated with systemic agents, which are not curative, said Weichselbaum. There are exceptions to this, including chemotherapy for germ cell tumors and immunotherapies for melanoma and certain lung cancers.

During his talk, Weichselbaum extensively discussed the role of local ablative therapy for oligometastases. Multiple randomized clinical trials have shown superior progression-free survival (PFS) in oligometastatic patients treated with ablative therapy (radiotherapy) and/or surgery compared to patients who receive standard treatment (typically, observation or chemotherapy alone). These trials include the MDACC/Colorado and UTSouthwestern trials in non–small cell lung cancer (NSCLC) and the STOMP and ORIOLE trials in prostate cancer.

There is also evidence from clinical trials that ablative therapy improves survival in patients with oligometastatic cancer, he said. For example, in a phase 2 study from the EORTC Intergroup in colorectal cancer patients with ≤10 liver metastases, the 8-year rate of overall survival with radiofrequency ablation combined with systemic chemotherapy was much better than with chemo alone (35.9% vs 8.9%; P = .01) (Ann Oncol. 2012;23:2619–2626).

The Karnofsky award winner also described research he was involved in to characterize the pathogenesis of oligometastasis; molecular subtypes complement clinical risk stratification, and gene expression informs therapy.

Multiple studies are now underway in a variety of oligometastatic cancers. In cases in which spread of the disease is limited, clinicians may want to refer patients to a trial, suggested Bauml.

An issue that "plagues" this area of cancer research is how to define oligometastases, he said. Definitions vary by researchers, and different definitions specify different numbers of metastases, as well as different locations and tumor types.

Nonetheless, researchers carry on, with some impressive results, said Bauml.

A recent randomized controlled trial showed that locally ablative therapy significantly improved median PFS in oligometastatic lung cancer patients compared to treatment without ablation (Lancet Oncol. 2016;17:1672-1682).

In this trial, all patients received initial palliative chemotherapy. Those who had persistent oligometastatic disease (and thus did not experience progression) were randomly assigned to receive locally ablative therapy plus chemotherapy or to continue palliative chemotherapy alone.

After 49 patients were randomized, the study was halted, owing to apparent efficacy. The median PFS was much better among patients who received locally ablative therapy (11.9 vs 3.9 months; P = .0054).

As a reflection of this and other research, the American Joint Committee on Cancer stage IV NSCLC guidance now indicates that patients with one or a small number of metastases can be offered definitive treatment modalities with the goal of becoming disease free.

Weichselbaum told the ASCO attendees that the "overarching clinical question for all of us, no matter what oncological discipline we're in, is, can we cure more patients with metastatic disease?"

He estimated that metastasis accounts for 85% to 90% of cancer deaths.

Fortunately, metastasis is "a very inefficient process," Weichselbaum added.

He described the process whereby tumors have to detach, survive in the circulation, adhere to the blood vessel wall, extravasate, and colonize. These processes are governed by genes and proteins, which are modified and imperfect. "So it wasn't a stretch to think that there could be a spectrum of metastasis," said Weichselbaum about his oligometastasis hypothesis.

Dr Weichselbaum has disclosed multiple relationships with industry. Dr Bauml has disclosed no relevant financial relationships.

American Society of Clinical Oncology (ASCO) 2018. Presented June 3, 2018.

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ASCO 2018-NEOADJUVANT USE OF PARP INHIBITORS FOR BRCA+ BREAST CANCER

In a small phase II study of early-stage breast cancer patients with BRCA1/2mutations, researchers at The University of Texas MD Anderson Cancer Centerfound that more than half of the women who took the PARP inhibitor talazoparib once daily prior to surgery had no evidence of disease at the time of surgery. If further validated in larger, confirmatory trials, the oral medication could replace chemotherapy for these patients.

The trial, which expands upon a feasibility study published by Litton et al in npj Breast Cancer, was presented as an oral presentation at the 2018 ASCO Annual Meeting by Jennifer Litton, MD, Associate Professor of Breast Medical Oncology (Abstract 508).

“To my knowledge, this study is the first time that a single-agent targeted therapy has shown a pathologic complete response in women with BRCA mutations, including those with triple-negative breast cancer,” said Dr. Litton.

Mutations in the BRCA1/2 genes account for 5% to 10% of all breast cancers, including most hereditary cancers—a population often diagnosed at a younger age—and 10% to 25% of triple-negative breast cancers. PARP inhibitors block an additional DNA repair pathway, and the antitumor effects of PARP inhibitors can be intensified in patients with BRCA mutations. Talazoparib works by not only inhibiting the PARP enzyme, but by trapping the enzyme on DNA to further prevent DNA repair.

This new research follows the randomized, phase III EMBRACA trial, which found talazoparib extended progression-free survival and improved quality-of-life measures over available chemotherapies for patients with metastatic breast cancer and BRCA mutations.

While the goal always is to move promising drugs from the metastatic setting to the front line, previous studies with PARP inhibitors combined with chemotherapies resulted in high rates of toxicities for patients, explained Dr. Litton. “Given the toxicities and the fear that young women may not want to forgo upfront chemotherapy because many had aggressive disease, there were concerns that patients would even want to enroll on the pilot study. Instead, we had incredibly strong accrual and our median tumor volume decrease by ultrasound was 88% after just 2 months of patients receiving a single dose of talazoparib once a day,” said Litton. “With these dramatic findings, the feasibility study was stopped and redesigned into the current trial.”

Trial Findings

For the single-institution phase II study, Dr. Litton and her colleagues enrolled 20 women with stage I–III BRCA mutation–positive breast cancer. Of note, 17 of the women had triple-negative disease. None of the patients had received previous therapy for invasive breast cancer. All but one patient completed 6 months of talazoparib once daily; one woman completed 5 months of the therapy and then withdrew consent. Participants then had surgery followed by the appropriate chemotherapy regimen. The study’s primary endpoint was residual cancer burden (RCB) or complete resolution of tumor.

At the time of surgery, the researchers found that 53% of the women (10 of 19) achieved pathologic complete response, or a score of RCB0; combined, 63% (12 of 19) received a score of RCB0 and RCB1. Both scores have the same positive expected outcome. Of those women who received a RCB0 or RCB1, 10 had triple-negative breast cancer.

Toxicities included blood count deficiencies, which could be managed by close monitoring of cell counts and platelets and by giving dose reductions and transfusions. Some patients also experienced grade 1 alopecia.

“Our findings are very early, and future studies will need to validate our results,” said Dr. Litton. “However, the idea of taking a pill once a day and having similar—if not better—response rates without the quality-of-life issues women experience on chemotherapy could be tremendous for our patients.” 

Dr. Litton and her colleagues also were able to make parallel mouse models of the patients’ breast tumors to better study responses and resistance, as well as provide the models to other investigators to expand the collective knowledge of PARP inhibitors.

As follow-up, a phase II, single-arm trial with a similar design is open; Dr. Litton is the national principal investigator.

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.

ASCO 2018-ERDAFITINIB FOR FGFR3 MUTATED UROTHELIAL CANCER

In an international phase II trial led by researchers at The University of Texas MD Anderson Cancer Center, treatment with the oral FGFR inhibitor erdafitinib was well tolerated and achieved a robust response for patients with metastatic urothelial cancers harboring mutations in the FGFR3 gene. These findings were presented by Siefker-Radtke et al at the 2018 ASCO Annual Meeting (Abstract 4503). The results were also granted the Best of ASCO designation.

“Given the limited treatment options for urothelial cancer, we still have a long way to go to benefit our patients. Having a therapy with a response rate around 40%, with the convenience of being an oral medication, certainly fits an unmet need,” said Arlene O. Siefker-Radtke, MD, Professor, Department of Genitourinary Medical Oncology, Division of Cancer Medicine at MD Anderson.

For several decades, the standard of care for urothelial cancers has been chemotherapy with a cisplatin-based regimen, but five new checkpoint blockade inhibitors have been approved in recent years, explained Dr. Siefker-Radtke. Nevertheless, the overall response rate is just 15% to 20% with these immunotherapies, she said.

Erdafitinib is an oral medication that blocks activity of all FGFR proteins, including FGFR3. Genetic alterations in FGFR3 can be found in approximately 15% to 20% of patients with metastatic bladder cancer and are thought to drive development of the disease. Further, tumors with FGFR3 mutations do not appear to display signs of immune activation, and there is growing evidence suggesting these tumors may not respond as well to immunotherapy, explained Dr. Siefker-Radtke.

Trial Findings

For the international, open-label, phase II trial, 99 patients were enrolled and treated with a median of five cycles of the optimized erdafitinib regimen, consisting of 8 mg/d for 28 days, with escalation to 9 mg/d allowed in the absence of significant adverse events. All patients had metastatic or surgically unresectable urothelial cancer with a verified mutation in FGFR3 or fusion in FGFR2 or FGFR3. Previous treatment with chemotherapy and/or immune checkpoint inhibitors was allowed.

Treatment with erdafitinib met the primary objective with a 40% overall response rate, including complete response in 3% of patients and partial response in 37%. An additional 39% of patients had stable disease without progression. Preliminary data from the trial indicate a median overall survival of 13.8 months. Among 22 patients who previously had been treated with checkpoint blockade inhibitors, erdafitinib treatment yielded an overall response in 59% of patients.

Treatment-related adverse events were manageable, with 10% of patients discontinuing treatment due to symptoms. There were no treatment-related deaths and no grade 4 events. The most common adverse events were grade 1 and 2, including hyperphosphatemia (72 patients, grade ≥ 3 in 2 patients), stomatitis (54 patients, grade ≥ 3 in 9 patients), and diarrhea (37 patients, grade ≥ 3 in 4 patients).

“Erdafitinib treatment has been very tolerable. There have been few dose reductions, and most patients have been able to continue on treatment,” said Dr. Siefker-Radtke. “Even with evidence of high phosphate levels or other toxicities, usually a period of just holding the drug was enough to reduce symptoms.”

She continued, “We will need confirmation in future studies, but there may be more benefit from an FGFR-targeted therapy in patients with an FGFR alteration as compared to immunotherapy. It's an exciting time, as we are heading into the field of personalized therapy for urothelial cancer.”

A phase III trial currently underway is evaluating the efficacy of erdafitinib relative to chemotherapy or the checkpoint blockade inhibitor pembrolizumab (Keytruda) in patients with metastatic urothelial cancer and FGFR3 mutations. Based on the phase II study, the U.S. Food and Drug Administration granted a Breakthrough Therapy designation to erdafitinib earlier this year, which will expedite development and review of the drug for metastatic urothelial cancer.

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.

ASCO 2018-UPDATED DATA FOR AVELUMAB IN MERKEL CELL CARCINOMA

Updated efficacy and safety data from the international, multicenter JAVELIN Merkel 200 trial of avelumab (Bavencio) in patients with metastatic Merkel cell carcinoma were presented by Nghiem et al at the 2018 ASCO Annual Meeting (Abstract 9507).

2-Year Follow-up

At the 2-year follow-up update of the study, avelumab continues to demonstrate clinically meaningful durable responses and stable rates of progression-free and overall survival from previous analyses in patients who responded to this treatment. Clinical activity was observed across all patient subgroups, irrespective of programmed cell death ligand 1 (PD-L1) expression in tumor tissue or Merkel cell polyomavirus status. The safety profile for avelumab in this trial has not changed with longer follow-up and remains consistent with that observed in the overall JAVELIN clinical development program.

In JAVELIN Merkel 200—an open-label, single-arm, phase II study—patients with histologically confirmed metastatic Merkel cell carcinoma whose disease had progressed on or after chemotherapy administrated for distant metastatic disease received avelumab at 10 mg/kg intravenously every 2 weeks until disease progression or unacceptable toxicity. A total of 88 patients were followed for a median of 29.2 months (range = 24.8–38.1 months).

The confirmed overall response rate of 33% (95% confidence interval [CI] = 23.3%–43.8%; complete response in 11.4%) remained unchanged from previous analyses reported at both 1 year and 18 months. Responses remained ongoing in 19 of 29 patients who responded to treatment, including 12 patients whose duration of response exceeded 2 years. Durable responses led to stable rates of progression-free survival (29% at 12 months, 29% at 18 months, and 26% at 24 months). Median overall survival was 12.6 months (95% CI = 7.5–17.1) and the 2-year overall survival rate was 36% (50% at 12 months and 39% at 18 months).

With a minimum follow-up of 2 years, no new safety signals were identified for avelumab and the safety profile was consistent with prior reports. Sixty-seven patients (76.1%) had a treatment-related adverse event, 10 patients (11.4%) had a grade 3 or less treatment-related adverse event, and 20 patients (22.7%) had an immune-related adverse event. No treatment-related deaths occurred.

About JAVELIN Merkel 200 

Patients in the JAVELIN Merkel 200 study were generally elderly (median age = 72.5 years, range = 33–88 years) and pretreated, with at least 1 line of chemotherapy (1 [59.1%], 2 [29.5%], or 3 or more [11.4%] previous treatments). Patients received avelumab at 10 mg/kg intravenously once every 2 weeks.

The protocol-defined analysis set for efficacy and safety consisted of all patients who received at least one dose of study treatment. The cutoff date for the planned primary analysis was 6 months after start of study treatment of the last patient.

The primary endpoint of the study was confirmed best overall response according to Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1 and assessed by an independent review committee. Secondary endpoints were duration of response, progression free survival, overall survival, response status by RECIST at 6 and 12 months, safety and tolerability, pharmacokinetics, and immunogenicity of avelumab.

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.

ASCO 2018-A DRUG FOR TENOSYNOVIAL GIANT CELL TUMOR

The phase III ENLIVEN study showed a statistically significant 39% overall response rate at week 25 based on central review of magnetic resonance imaging (MRI) scans using Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1 (the primary endpoint) for patients treated with oral pexidartinib compared to no tumor response among patients who received placebo (P < .0001). Patients enrolled in the trial were those with tenosynovial giant cell tumor (TGCT) for whom surgery would be associated with potentially worse function or severe morbidity. After a median 6-month follow-up (longest = 17 months), no responders in the ENLIVEN study had shown disease progression. These findings were presented by Tap et al at the 2018 ASCO Annual Meeting (Abstract 11502).

“Current treatment options for TGCT are largely limited to surgery in order to remove as much of the tumor as possible. Despite the best surgical intervention, the recurrence rate of diffuse TGCT is high, and the disease may advance to the point where surgery is no longer an option,” said William D. Tap, MD, lead investigator of the study and Chief of the Sarcoma Medical Oncology Service at Memorial Sloan Kettering Cancer Center. “Pexidartinib may offer a relevant treatment option for patients with TGCT, which is associated with severe morbidity or functional limitations, and for which surgery is not recommended.”

Pexidartinib is an investigational, oral small molecule that potently inhibits colony-stimulating factor 1 receptor, a primary growth driver of abnormal cells in the synovium that cause TGCT.

Further Findings

In the ENLIVEN study, hepatic toxicities were more frequent with pexidartinib vs placebo (aspartate transaminase or alanine transaminase levels ≥ 3× the upper limit of normal: 33%, total bilirubin levels ≥ 2× the upper limit of normal: 5%; n = 61). Eight patients discontinued pexidartinib due to hepatic adverse events; 4 were serious nonfatal adverse events with increased bilirubin, one lasting ~7 months. In non-TGCT development studies using pexidartinib, 2 severe liver toxicity cases were observed (1 required liver transplant, 1 was associated with death).

Other adverse events with a frequency > 10% noted in ENLIVEN and more common with pexidartinib included hair color changes, pruritus, rash, vomiting, abdominal pain, constipation, fatigue, dysgeusia, facial edema, peripheral edema, periorbital edema, decreased appetite, and hypertension.

Secondary efficacy endpoints demonstrated that patients treated with pexidartinib had a 56% overall response rate by tumor volume score, compared to no response in patients who received placebo (P < .0001). Clinically meaningful improvement vs placebo was observed in other secondary efficacy endpoints, including range of motion (+15% vs +6%, P = .0043), PROMIS physical function (+4.1 vs –0.9, P = .0019), and worst stiffness (–2.5 vs –0.3, P < .0001). There was also a nonsignificant improvement in pain response (31% vs 15%).

About the ENLIVEN Study 

ENLIVEN, a double-blind, randomized, global, multicenter, phase III study, evaluated pexidartinib in patients with symptomatic advanced TGCT for whom surgical removal of the tumor would be associated with potentially worsening functional limitation or severe morbidity. The first part of the study, the double-blind phase, enrolled 120 patients who were randomly assigned (1:1) to receive either pexidartinib or placebo at 1,000 mg/d for 2 weeks followed by 800 mg/d for 22 weeks in order to evaluate the efficacy and safety of pexidartinib vs placebo.

The primary endpoint of the study was the percentage of patients achieving a complete or partial response after 24 weeks of treatment (week 25), as assessed with centrally read MRI scans using RECIST 1.1 criteria. Key secondary endpoints included range of motion, response by tumor volume score, PROMIS physical function, stiffness, and measures of pain reduction.

After completing the first part of the study, patients randomized to either pexidartinib or placebo were eligible to take part in the second part of ENLIVEN, a long-term, open-label part where patients could continue to receive or start to receive pexidartinib. In October 2016, following 2 reported cases of serious, nonfatal liver toxicity in the ENLIVEN study, the data monitoring committee (DMC) recommended that patients receiving placebo in the first part of the study should no longer be eligible to start pexidartinib in the second part of the study. A total of 120 patients who were enrolled prior to the DMC recommendation continued with the study according to the revised protocol. 

ASCO 2018-IMMUNOTHERAPY FOR PROSTATE CANCER

A small proportion of men with advanced prostate cancer for whom other treatments have failed may experience a significant and ongoing benefit with the programmed death ligand 1 (PD-L1) inhibitor pembrolizumab (Keytruda, Merck), say UK researchers who are now working on how to reliably identify those men.

Intriguingly, the immunotherapy, which continued to show a benefit after a year in 11% of the 258 men with metastatic castration-resistant prostate cancer (mCRPC), appeared to have a benefit even in men who did not express PD-L1.

Presenting the new data here at the American Society of Clinical Oncology (ASCO) 2018 Annual Meeting, Professor Johann De Bono, from the Royal Marsden Hospital, London, suggested that genetic biomarkers may point to those who are at risk, although the data were preliminary.

He said: "In a small population of patients with advance prostate cancer, pembrolizumab clearly has some anti-tumour activity, and activity was observed in PD-L1 positive and negative groups."

De Bono added: "Biomarker work is ongoing and we have clearly seen of antitumour activity in mismatch repair defective cancers, in at least one definite BRAC2 mutated cancer, as well as some patients that we still don't fully understand why they responded.

"Further evaluation of the subset that respond is ongoing, as are combination trials in this population of patients."

'Smarter, Kinder Treatment' 

Professor Paul Workman, Chief Executive of The Institute of Cancer Research, London, whose researchers also took part in the trial, said in a press release: "Immunotherapy has proven to be a smarter, kinder treatment for many types of cancer, but it still only works for a minority of patients.

"The challenges we now face are how to predict in advance who will benefit, and how to make immunotherapy work for more people."

Workman added that, if if gene mutations can be shown to identify the patients who will respond, "it should be possible to provide some men with advanced prostate cancer with an exciting new treatment option."

Latest Research 

Although PD-1 and PD-L1 inhibitors have shown activity in numerous cancers, there have been few signs of activity in prostate cancer.

However, two recent studies, including KEYNOTE-028, suggested that pembrolizumab may achieve objective responses in some men with previously treated PD-L1-positive mCRPC.

De Bono told the audience that KEYNOTE-199 was therefore launched to try to confirm this activity and determine which patents might benefit from PD-L1 blockade.

Of the five cohorts included in the study, he focused on three, which included mCRPC patients who had received ≥1 prior targeted endocrine therapy and who had undergone 1–2 prior chemotherapy regimens, including docetaxel (Taxotere, Sanofi-Aventis). All patients also had an ECOG performance status of 0–2.

In cohort one (n=131), all of the men had PD-L1-positive mCPRC, while those in cohort two (n=67) had PD-L1-negative disease. In both groups, the patients had measurable disease as per the Response Evaluation Criteria In Solid Tumours (RECIST) v1.1 criteria.

In cohort three (n=60), the patients had bone metastases but no measurable disease on RECIST v1.1, and had any PD-L1 status.

Patients in all three cohorts were treated with pembrolizumab 200 mg for 35 weeks or until confirmed progressive disease, intolerable toxicity, investigator decision or patient withdrawal.

The patients, who fitted the typical post-chemotherapy patient profile, underwent imaging every 9 weeks for 1 year and then every 12 weeks. The primary endpoint was the objective response rate as per RECIST v1.1 in cohorts one and two.

After a median follow-up of 8.1 months in cohort one, 11% of patients were still being treated at the data cut-off for the study. In cohort two, 9% were still receiving treatment after a median of 7.9 months, while, in cohort three, 12% were still on treatment after 11.8 months of follow-up.

In cohorts one and two, 10% of patients had a change in the sum of the target lesions from baseline of ≥30% with pembrolizumab, while 11% of patients in all three cohorts had a reduction in prostate-specific antigen levels from baseline of ≥50%.

In both cases, the responders to pembrolizumab therapy included those who did not have any measurable PD-L1.

Central review of the best responses indicated that, in cohort one, 2% of patients had a complete response, 4% had a partial response, and 17% had stable disease, with 4% having stable disease for ≥6 months.

In cohort two, 3% of patients had a partial response and 21% had stable disease, which lasted for ≥6 months in 3%. There were no responses to treatments in cohort three on central review.

The researchers calculated that the disease control rate lasting ≥6 months, which included the best response of complete or partial response of stable disease, across all three cohorts was 11%.

"So we have clearly evidence of a small population that is benefiting," said De Bono.

After 12 months, 39% of patients in cohort one were still alive, while 38% of cohort two patients were still alive, alongside 61% of cohort three patients, although De Bono emphasised that the non-randomised nature of the trial means that it is "hard to draw conclusions" from the data.

Interestingly, genomic analysis of responders to pembrolizumab suggested that there may be some gene mutations that could be associated with response, such as in the BRCA2 gene.

Indeed, analysis of response by the presence of somatic aberrations in DNA repair genes indicated that patients with BRCA1/2 or ATM gene mutations had a disease control rate of 22%.

De Bono noted that 59% of patients across the trial cohorts had any treatment-related adverse events, and 14% had grade 3–5 adverse events.

The most common treatment-related events were fatigue (15%) and diarrhoea (10%), while the immune-mediated events included hyperthyroidism and hypothyroidism.

'Curious' 

Study Discussant Dr Douglas McNeel, from the University of Wisconsin School of Medicine and Public Health, Madison, in the US, said following its presentation, that the objective response rates in cohorts one and two are "fairly small, and it's curious that there is no difference between the patients who are PD-L1 positive and PD-L1 negative".

He added: "While I think there's activity there, it's smaller and definitely different from what we've seen with PD-L1 blockade in other diseases."

McNeel agreed with the conclusion that DNA repair defects may be associated with the antitumour activity seen in the study, saying that this "could be important, since the rate of homologous recombination repair mutations is likely higher than microsatellite instability."

He said that the data suggests that this, nevertheless, "may be a premature conclusion but certainly worth more attention".

The study was funded by Merck Sharp & Dohme.

Johann De Bono: Honoraria - Astellas Pharma; AstraZeneca; Genentech/Roche; Pfizer; Sanofi; Consulting or Advisory Role - Astellas Pharma; AstraZeneca; Bayer; Boehringer Ingelheim; Genentech/Roche; Merck Serono; Merck Sharp & Dohme; Pfizer; Sanofi; Research Funding - AstraZeneca (Inst); Genentech (Inst); Sanofi (Inst); Patents, Royalties, Other Intellectual Property - Abiraterone Rewards to Inventors (Inst); PARP inhibitors and DNA repair defects (Inst); Travel, Accommodations, Expenses - Astellas Pharma; AstraZeneca; Genmab; GlaxoSmithKline; Orion Pharma GmbH; Qiagen; Sanofi; Taiho Pharmaceutical; Vertex.

Douglas McNeel: Leadership - Madison Vaccines, Inc.; Stock and Other Ownership Interests  - Madison Vaccines, Inc.; Consulting or Advisory Role - Dendreon; Genocea Biosciences; Madison Vaccines, Inc.; Research Funding - Bristol-Myers Squibb (Inst); Dendreon (Inst); Janssen (Inst); Madison Vaccines, Inc.; Madison Vaccines, Inc. (Inst); Medivation (Inst); Patents, Royalties, Other Intellectual Property - Patents that have been licensed by UW to Madison Vaccines, Inc; Travel, Accommodations, Expenses - Genocea Biosciences; Madison Vaccines, Inc.

American Society of Clinical Oncology (ASCO) 2018 Annual Meeting. Presented June 4, 2018. Abstract 5007.

ASCO 2018-NEOADJUVANT CHEMORADIOTHERAPY FOR PANCREATIC CANCER

Patients with pancreatic cancer who were given chemoradiotherapy (CRT) before surgery showed improved survival compared with patients who went straight to surgery, according to new findings from a phase 3 trial, known as PEROPANC-1. Both groups also had chemotherapy after surgery.

The 2-year overall survival rate with neoadjuvant CRT was 42% compared with 30% for patients who had surgery first.

"The results are preliminary and we do hope that with the final results of this trial , we can show that preoperative chemoradiotherapy is better than postoperative chemotherapy," said lead author Geertjan van Tienhoven, MD, PhD, radiation oncologist at the Department of Radiation Oncology, Academic Medical Center, Amsterdam, the Netherlands.

"We do need the final results before we can draw any definitive conclusions, but these results suggest a benefit for chemoradiation prior to surgery over surgery and adjuvant chemotherapy," he said.

The new data were presented here at the American Society of Clinical Oncology (ASCO) 2018.

Improvement in All Endpoints

A total of 246 patients with borderline resectable pancreatic cancer were randomly assigned to immediate surgery (arm A) or preoperative CRT (arm B).

Both groups received chemotherapy after surgery, and the total amount of chemotherapy given was equal in both groups. 

The preoperative CRT regimen consisted of 15 rounds of 2.4 Gy combined with gemcitabine, 1000 mg/m² on days 1, 8, and 15, preceded and followed by a cycle of gemcitabine.

Resection was performed in 72% of patients in the immediate-surgery group and 62% in the CRT group (P = .065). Among the patients who underwent resection, the R0 rate was higher in a greater proportion of patients who received preoperative treatment (63% vs 31%; P < .001).

The median overall survival was 17.1 months with preoperative CRT compared with 13.7 months (P = .074) with immediate surgery. Disease-free survival was also longer with preoperative therapy (

9.9 months vs 7.9 months; hazard ratio [HR], 0.71; P = .023).

In the subset of patients in which the tumor was surgically removed successfully, the difference in median survival was even greater: 42.1 months with preoperative treatment vs 16.8 months with immediate surgery.  

Secondary endpoints also favored the neoadjuvant CRT arm : For distant metastasis-free survival, the median was 10.2 vs 17.1 months (HR, 0.63; P = .012); likewise, for locoregional recurrence-free survival, the median was 11.8 months vs not reached in the surgery-first group (HR, 0.47; P < .001).

Disease progression was seen in 50% of the neoadjuvant chemoradiation group vs  80% of the surgery-first group (P = .002), and there were more deaths (65% vs 55%;  P = .074).

Van Tienhoven emphasized that these were preliminary results and that 26 more events are needed before the final analysis can be completed.

Is This Practice Changing? 

In a discussion of the paper, Colin D. Weekes, MD, PhD, from Massachusetts General Hospital, Boston, pointed our that patients who received neoadjuvant therapy got "better bang for the buck" because there was a doubling in the R0 resection in the chemoradiation group. "This translated into improved disease-free survival, distant metastasis–free interval, and locoregional recurrence–free interval."

However, the intent-to-treat population analysis did not meet the criteria for statistically significant improvement in overall survival. "It's important to think about that many of these patients are going to have disease progression, and this could skew the analysis more in favor of those who are receiving postoperative therapy," he said.

"So although this study did not meet its endpoint in the intent-to-treat analysis, it does suggest that neoadjuvant therapy may be important for these patients," Weekes explained. "In the postresection analysis, there is an improvement in overall survival."

He pointed out that while the authors concluded that the results demonstrate a benefit for chemoradiation over upfront surgery, "I don't think you can conclude that based on the design of the study."

The study design cannot definitively define that neoadjuvant chemoradiation is better than direct surgical resection, he commented. But the results of this trial in aggregate with other recently published prospective trials demonstrate the benefit of radiation therapy in the neoadjuvant setting, he noted.

One question is whether the use of modern combination chemotherapy will increase the magnitude of benefit of neoadjuvant/perioperative chemoradiation-based therapy. Several ongoing studies are exploring this,  Weekes added.

Approached for comment, Benjamin Golas, MD, associate site chief of surgical oncology at Mount Sinai West and Mount Sinai St. Luke's Hospital and assistant professor of surgery at the Icahn School of Medicine in New York City, said, "As the outcomes for pancreatic cancer are so poor, any randomized controlled trial that shows an increase in survival is encouraging."

But as far as any immediate clinical implications from these data, he said that neoadjuvant therapy is already used in clinical practice. Most centers that treat high volumes of pancreatic disease are probably treating borderline-resectable tumors with some type of neoadjuvant therapy — whether systemic chemotherapy or chemoradiation, he said.

"I think the biology of the disease dictates that we treat it in the neoadjuvant setting, although we don't really know what that is yet," he told Medscape Medical News.

He noted that this study used gemcitabine, but FOLFIRINOX (composed of oxaliplatin, leucovorin, irinotecan, and 5-fluorouracil)  is also being investigated. "The next trial should be radiation combined with FOLFIRINOX or some variation of that upfront, and hypothetically that may have an influence on survival," he said.

Also commenting, Igor Astsaturov, MD, PhD, associate professor and co-director of the Marvin and Concetta Greenberg Pancreatic Cancer Institute at Fox Chase Cancer Center, Philadelphia, Pennsylvania, said that these new "results reinforce the idea now widely accepted in the USA that a neoadjuvant approach is beneficial to patients with resectable pancreatic cancer."

The PEROPANC-1 trial showed statistically improved survival in the preoperative treatment group (overall survival, 17 months) compared with the surgery-alone group (overall survival, 13.5 months), he summarized.  This is somewhat inferior to the previously established benchmark in ESPAC-4 (28 months) or the even higher survival (54.5 months with modified FOLFIRINOX and 35 months with gemcitabine) just reported here at ASCO 2018.

"Factors contributing to such outcomes may include unresectable, metastatic cancers or positive margins, so the full presentation of these new results will be of interest to these specific points," he added.

"In our practice, we have adopted a more aggressive neoadjuvant chemotherapy and radiation approach," said Astsaturov. "With ongoing trials testing gemcitabine and Abraxane vs FOLFIRINOX, these presented results send a signal that we are on the right track of aggressive therapy for localized pancreatic cancer."

This study received funding from the Dutch Cancer Society KWF. Van Tienhoven has disclosed no relevant financial relationships. Weekes has disclosed relationships with Celgene, Lilly, Merrimack, Genentech/Roche, AbbVie, Millennium, and Bayer. Astsaturov and Golas have disclosed no relevant financial relationships.

American Society of Clinical Oncology (ASCO) 2018. Presented June 4, 2018. Abstract LBA4002

ASCO 2018-NEPRECTOMY NOT NECCESSARY FOR METASTATIC RENAL CANCER-CARMENA STUDY

People who received sunitinib treatment alone survived at least as long as those who received the drug after surgical removal of their kidney, according to a randomized study of 450 patients with synchronous metastatic renal cell carcinoma.

A team led by Dr. Arnaud Mejean of Hopital Europeen Georges-Pompidou in Paris found that conventional surgery and sunitinib produced a median overall survival time of 13.9 months while skipping surgery extended that time to 18.4 months, a non-significant difference, and eliminated the risks of infection, blood loss and other surgical complications.

Among the 40,000 to 50,000 people worldwide in whom renal-cell carcinoma is diagnosed, it has typically metastasized in 20% of patients.

The better outcome with sunitinib alone may be due to the fact that kidney removal usually delays sunitinib therapy by four to six weeks so the patient can recover, making it harder for the drug to do its work, the researchers speculate.

There were non-significant increases in the time to disease progression and median survival for patients with both an intermediate and a poor prognosis.

Patients with only one metastasis were not included in the trial, known as CARMENA.

The findings were presented June 3 at the American Society of Clinical Oncology annual meeting in Chicago.

ASCO 2018-A MORE EFFECTIVE RET INHIBITOR

An experimental cancer drug from Loxo Oncology performed even better in patients with a rare mutation of the RET gene than previously reported, according to updated results from an early stage clinical trial presented on Saturday.

Last month, Loxo released preliminary data that showed its drug, LOXO-292, targeting RET mutations shrank tumors in 69 percent of advanced cancer patients regardless of whether their disease originated in the lung, pancreas or thyroid. Loxo shares rose 20 percent on the news.

The new results, which included additional patients and more months of treatment, showed an overall response in 77 percent of those with RET fusion mutations who received the Loxo pill, researchers said on Saturday at the American Society of Clinical Oncology meeting in Chicago.

The 77 percent was seen in patients whose RET gene was abnormally fused with another gene, driving cancer growth. In medullary thyroid cancer with a different type of RET mutation, LOXO-292 shrank tumors in 45 percent of patients.

"The activity was pretty impressive," said Dr. Alexander Drilon, the study's lead investigator from Memorial Sloan Kettering Cancer Center in New York. "To date, there is no drug approved for RET fusions or RET mutations."

Loxo attracted attention at last year's ASCO meeting with data showing that its drug larotrectinib shrank tumors in patients with more than a dozen different types of cancer all driven by a mutation known as TRK fusion.

Loxo's discoveries have highlighted the value of more widespread genomic testing of tumors to find the best treatment. Both the TRK and RET mutations are rare but occur in different types of cancer.

The company has since forged a partnership with Germany's Bayer and its stock price has quadrupled in value.

Larotrectinib is expected to be Loxo's first drug on the market, with Wall Street analysts forecasting eventual annual sales reaching $500 million to $1 billion. Earlier this week, U.S. drug regulators said it would receive an expedited review, with an approval decision likely by late November.

RET fusions occur in about 2 percent of lung cancers, 10 to 20 percent of papillary thyroid cancers, and a small number of other cancers. Activating RET point mutations account for about 60 percent of medullary thyroid cancers, which comprise 3 percent of all thyroid cancers.

The Loxo study showed early evidence of lasting benefit of its drug in RET-driven cancers, with about 90 percent of patients still on therapy as of an April cut-off, with the earliest patients still responding after 10 months.

Blueprint Medicines is developing a rival RET drug.

Drilon, who consults on RET-targeted drugs from both companies, said it was too early to determine which is better. "These trials started a year ago. It's not reasonable to say this or that about the Blueprint versus Loxo drug," he said.

SOURCE: http://bit.ly/2GIjW3R

ASCO 2018.