The OBR Blog

February 19, 2020 - 05:02 pm comments0 Comments

Major themes which emerged from ASCO GU 2020 included a plethora of studies utilizing various permutations of targeted therapies along with immunotherapy and/or chemotherapy in bladder, prostate and renal cell cancers (RCC) with generally modest incremental improvements reported in various clinical endpoints.

Blood based cancer component assessments, termed “liquid biopsies” were much in vogue throughout ASCO GU 2010.  Liquid biopsies include identification of intact circulating tumor cells, tumor specific cell free DNA mutations, copy number variants, methylation signatures, transcriptomics, micro RNA signatures, exosomes, microvesicles as well as tumor-educated platelets.

KIDNEY CANCER

Liquid biopsy applications within RCC. Abstracts: 721, 728, 740, 743

Nivolumab and ipilumab in first line metastatic clear cell kidney cancer, as analyzed at 42 months, now reveals a distinct tail on the survival curve of 25-30% of patients so treated. Abstract 605

COMMENTARY:  Such long-term benefit has yet to emerge from other trials including trials of checkpoint inhibitors plus TKIs, however longer follow up will be required from these studies to validate these outcome differences.  Of note however, from these same studies an early survival advantage is seen during the first 6-8 months with checkpoint inhibition plus TKI treatment of RCC which was not found with nivo plus ipi in Keynote 214 wherein the survival curves remained superimposed over the initial 6 to 12 months.  This suggests that an early response might be an advantage with checkpoint inhibition plus TKI while dual immunotherapy may allow for more durable responses.

The role of cytoreductive nephrectomy in the age of IO and TKIs for clear cell RCC Is examined. Abstracts: 608, 646, 652, 688, 703, 707, 748

Real World Evidence (RWE) is a topic of numerous abstracts in all GU malignancies:
Prostate: 29, 33, 35, 36, 41, 43, 48, 59, 223, 229
Testis: 393

Bladder: 447, 451, 452, 457, 458, 493
Kidney: 628, 639, 647, 682, 683, 709

PROSTATE CANCER

Liquid Biopsy. Abstracts: 98, 110, 147, 154, 160, 168, 170, 173, 174, 176, 180, 183, 186, 190, 200, 201
[insert Andrew Armstrong, question 1]
PARP inhibitors in prostate cancer treatment. Abstracts: 43, 118, 119, 134, 150, 178
COMMENTARY: Positive outcomes reported most significantly with BRCA 2 mutations and much less so with other DDR mutations.

PSMA based imaging in prostate cancer. Abstracts: 9, 21, 22, 23, 24, 25, 26, 292, 295, 334

PSMA targeted treatment for prostate cancer. Abstracts: 45, 99, 129,124,155

Mutational identification and prognostic implications. DDR Abstracts: 43, 63, 119, 121, 134, 172, 185, 187. BRCA Abstracts:  44,63,65,127,152,178

COMMENTARY: DNA Damage Repair (DDR) and BRCA in prostatectomy cancer was also a major center of interest.  BRCA2 germline and somatic mutations appear to predict a much higher probability of favorable response to PARP inhibitors compared to other DDR mutational events.

Radium 233 in the treatment of metastatic prostate cancer — both alone and in combination with other therapies. Abstracts: 32, 41, 47, 50, 59, 117, 121,125, 130, 136, 223, 225, 228, 236

Proton beam therapy in prostate cancer. Abstract: 305

COMMENTARY: Fascinating to see so little reporting during ASCO GU 2020 on what has been historically such a controversial topic

AR-V7 splice variant implications for prostate cancer. Abstracts: 184, 245

COMMENTARY:  AR V7 splice variant seems to be generating less interest as a specific predictive biomarker as the sequential utilization of novel antiandrogens is falling out of favor.

CAR T cell therapy studies are now accruing in metastatic prostate cancer. Abstracts: TPS 250 and TPS 266

Prostate irradiation in the setting of oligometastatic prostate cancer. Abstracts 93, 101, 116, 319

UROTHELIAL CANCERS

Liquid biopsies in bladder cancer. Abstracts: 525, 558, 565, 567, 562

Neoadjuvant treatment of muscle invasive bladder cancer. Abstracts: 439, 441, 445, 474, 505, 506, 507, 509, 522, 523, 533, 539, 540, 541, 542, 543, 547, 554, 562

FGFR mutations and treatments. Abstracts: 432, 489, 493, 510, 511, 527, 542, 565, 576

Enfortumab Vedotin in bladder cancer. Abstracts: 441, 546

TESTICULAR CANCER

Post-treatment management of residual retroperitoneal masses. Abstracts: 388, 389, 390, 391

MicroRNAs as tumor markers in testicular cancer. Abstracts 371, 375, 414, 416, 417

COMMENTARY: miRNA371a, while not yet commercially available, appears to have far greater sensitivity and specificity that the current serum tumor markers utilized in the management of germ cell tumors.

FINAL COMMENTARY: The near absence of investigations into the microbiome of patients with genitourinary malignancies was notable.  Indeed, data is now accumulating that the microbiome may play a very significant role in therapeutic outcomes from treatment in many malignancies.  Perhaps ASCO GU 2021 will provide greater illumination on this timely topic.

By Dean Gesme, MD; Immediate Past President, Minnesota Oncology

January 28, 2020 - 04:01 pm comments0 Comments

ASCO GI 2020 was held in San Francisco January 23-25. Numerous studies involving Phase 1/2 evaluations of new drugs in gastrointestinal (GI) malignancies were reported. All of the drugs investigated were said to have tolerable safety profiles and encouraging efficacy thus leading to recommendations for future Phase 3 studies.

That said, I would like to highlight some specific emerging trends to take away from the meeting which struck me as newsworthy for both oncology clinicians and researchers.

Liquid Biopsies

Twenty-five abstracts dealt with cell free tumor DNA (ctDNA) analyzed from peripheral blood samples in individuals with GI malignancies. These studies focused on ctDNA as specific liquid biomarkers, which allow monitoring for tumor recurrence, treatment response, and tumor progression, which greatly outperforms current standards of care (i.e., MRD detection). Several abstracts presented suggest ctDNA will supplement or replace cancer screening studies. Validation studies are underway with these assays and their applications to affirm sensitivity, specificity, and clinical benefit as well as cost effectiveness.

Abstracts:  # 5, 15, 18, 29, 48, 66, 68, 194,195, 203, 207, 230, 238, 243, 244, TPS261, 283, 451, 579, 645, 730, 753, 758, 763, 799, 833

PARP Inhibition in Locally Advanced or Metastatic Pancreatic Cancer

Nine abstracts addressed the use of PARP inhibitors in pancreatic cancer. All of these abstracts found significant efficacy in patients with BRCA2, BRCA1, or PALB mutations, and acceptable toxicity profiles.

Abstracts:  # 472, 476, 639, 648, 653, 686, 709, 750

TKI Plus Checkpoint Inhibition in GI Malignancies

Numerous Phase 1/2 studies addressed the combination of TKI and immunotherapy agents in a variety of GI tumors. Several also combined checkpoint inhibitors with standard chemotherapies. Encouraging efficacy signals were identified along with reasonable safety parameters for which Phase 3 trials were recommended.

Abstracts:  # 101, 133, 153, 218, 278

Colorectal Cancer in Young Adults

Seven abstracts addressed the recent epidemiologic findings of dramatically increasing numbers of young individuals with colorectal cancer. These abstracts defined specific clinical and genomic prognostic factors which may differentiate colorectal cancer in young individuals from that of older individuals. Interestingly macrobiotic factors may place a significant role in the changing demographics of colorectal cancers.

Abstracts:  #64, 82, 85, 72, 256, 257, 805

Real World Evidence in GI Malignancies

Forty abstracts dealt with real world evidence (RWE) regarding GI malignancies. Additional abstracts utilizing data from the National Cancer Database (NCDB) or from traditional cancer registries were also reported. Clearly the use of electronic medical records (EMRs) is offering the medical community the opportunity to better access and analyze real world patient data regarding many health conditions including gastrointestinal cancers.

Abstracts:  #64, 82, 85, 72, 256, 257, 805

Role of Checkpoint Inhibitors in Hepatocellular Cancer

Presentations and discussions strongly affirmed findings that patients with hepatocellular cancer responding to checkpoint inhibitors often have very long durations of response—particularly those patients achieving a complete response (CR). Thus, most patients with advanced hepatocellular cancer should be exposed to these agents during their course of treatment.

Additionally, several discussions focused upon data presented last month at ESMO ASIA concerning the surprisingly high rates of response to bevacizumab + atezolizub and unprecedented durations of response. This treatment combination (Bev + Atezo) may be practice changing if/when  incorporated into NCCN  guidelines.

Abstracts:  # 476, 513, 564

NETest in Neuroendocrine Carcinomas

Validation studies were presented (3 abstracts) of a transcriptome based testing (NETest) which boasts very high specificity and sensitivity for neuroendocrine malignancies. This NETest should be cost effective and will largely replace serum chromogranin measurement and reduce the frequency of imaging studies.

Abstracts: # 605, 606, 625, 631

Targetable Mutations in Biliary Tract Cancers

Several abstracts defined excellent responses in Phase 1/2 studies of patients with primary biliary tract malignancies possessing either IDH mutations or FGFR2 fusions.

Abstracts:  # 538, 539, 579

Synchronous Colorectal Cancers and Upper GI Malignancies

Abstracts from China and Japan identified very significant propensities for synchronous primary malignancies of the GI tract. Evaluation of the lower GI tract in patients with upper GI malignancies identified an incidence of potentially curable colorectal malignancies in over 5% of such patients. An additional 46% of studied patients were found to have synchronous resectable colorectal adenomas.

Abstracts: # 290, 337

Role of the Microbiome

Last, but not least, several abstracts and presentations began to scratch the surface as to the role of the microbiome in the causation, promotion and treatment of malignancies of the gastrointesintal tract. Everyone appears excited by the plethora of necessary investigation that is needed to determine the role of the microbiome both intratumorally and externally that may fundamentally alter our approach to GI cancers.

Abstracts:  # 4, 171, 241, 744

by Dean Gesme, MD

Immediate Past President, Minnesota Oncology

November 26, 2019 - 01:11 pm comments0 Comments

During a pre-meeting webinar devoted to ASH 2019, experts highlighted important advances and practice-changing studies to be presented in Orlando, FL, December 7-10, 2019.

 CAR T-cell Therapy Advances

Experts singled out 4 abstracts related to CAR T-cell therapy of particular import. “Most of you are aware that CAR-T therapies have captured the imagination of researchers, oncologists, and patients, because they are highly effective in B-cell leukemias and lymphomas. However, there are drawbacks, such as the time it takes to manufacture this personalized form of cell therapy. Only two thirds of candidates get CAR-T therapy because of the time involved in manufacturing it,” said Robert A. Brodsky, MD, ASH Secretary, who is affiliated with Johns Hopkins School of Medicine, Baltimore, MD.

All four abstracts focus on advances with potential to overcome obstacles associated with CAR T-cell therapy,

Abstract 301 is a proof-of-concept study supporting an off-the-shelf CAR-natural killer (NK) cell therapy for B-cell malignancies. This form of therapy relies on inducing pluripotent stem cells and differentiating them from NK cells that attack cancer. CAR-NK is engineered to target the CD19 antigen on B cells and have been found effective in preliminary studies of cell lines.

“CAR-NK is a big advance that offers the potential for a readily available source of CAR-NK cells,” Dr. Brodsky explained. The availability of an off-the-shelf product would overcome the manufacturing constraints of CAR T-cell therapy.

Abstract 577 describes promising early results of the phase 1b/2 CARTITUDE study of JNJ-4528, a CAR T-cell therapy directed against B-cell maturation antigen (BCMA) on malignant plasma cells in patients with relapsed/refractory multiple myeloma. The study included 25 patients first treated with chemotherapy followed by CAR T-cell therapy. At a median follow-up of 3 months, response rate was 91%, including 2 complete responses in patients who were relapsed/refractory to CAR T-cell therapy. Many other patients had deep responses, Dr. Brodsky noted.

Abstract 930 focuses on data from a phase 1 dose-escalation trial of BM38CAR-T in patients with relapsed/refractory multiple myeloma. BM38CAR-T is a bispecific CAR T-cell therapy that targets both BCMA and CD38 on malignant plasma cells.

“This product is designed to try to prevent resistance to CAR-T and preliminary results were interesting,” Dr. Brodsky said.

Patients (n=16) who received at least 2 prior treatment regimens were treated with lymphodepleting therapy with cytotoxin and fludarabine daily prior to BM38CAR-T infusion. At a median follow-up of 36 weeks after BM38CAR-T infusion, response rate was 87.5%, and 9-month progression-free survival was 75%. Although the data are early, Dr. Brodsky considered them “promising.”

“Abstract 6 is the most exciting [of the CAR-T abstracts discussed],” Dr. Brodsky said.

In an open-label, multicenter, phase 1/1b study, the bispecific antibody mosunetuzumab

showed favorable tolerability and durable efficacy in 218 patients with heavily pre-treated, relapsed/refractory B-cell non-Hodgkin lymphoma (NHL), including complete responses in patients with disease progression after CAR T-cell therapy. Twenty-three patients had previously received CAR-T. Response rate was 64% and complete response rate was 42%. Median duration of response in aggressive NHL is now 9 months.

“Mosunetuzumab is not a CAR-T therapy. It is an off-the-shelf bispecific antibody that targets CD3 and CD20 that engages patients’ own T-cells to do what a CAR-T would do,” Dr. Brodsky said.

“This product is simpler and faster to produce [than CAR-T], is likely to be cheaper and much less toxic,” he said.

Venous Thromboembolism

Roy L Silverstein, MD, ASH President, discussed Abstract 164, which highlights results of the phase 3 Einstein Jr. study, showing that a dosing algorithm of the direct acting oral anticoagulant (DOAC) rivaroxaban based on body weight was as safe and effective as the standard of care to prevent VTE, low molecular weight heparin (LMWH), in more than 350 children hospitalized for cancer or congenital heart disease. LMWH requires daily and twice daily subcutaneous injections, while a new liquid formulation of rivaroxaban is much easier to administer.

“This will be the new standard of care for children when approved,” Dr. Silverstein predicted.

Inclusive Medicine

Dr. Silverstein turned his attention to five abstracts related to “inclusive medicine,” that is, the impact of socioeconomic status and demographic factors on access to clinical trials and treatments for hematologic cancers.

The first two studies he discussed relied on large datasets to draw conclusions.

Abstract 782 basically “breaks the glass ceiling of age for autologous hematopoietic cell transplant [AHCT] in patients with multiple myeloma,” Dr. Silverstein said. Although multiple myeloma is mainly a disease in older people, AHCT is typically reserved for patients under the age of 70 years. Using the Center for International Blood and Marrow Transplant Research (CIBMTR) database to identify 15,999 patients aged 20 or older who received AHCT within 1 year of multiple myeloma diagnosis, the researchers found that no difference in outcomes in patients over the age of 70 compared with those aged 60 to 70. They also found that 60% of patients received lower than standard dose of melphalan for conditioning, and this group had a worse outcome compared with those who got standard-dose melphalan along with AHCT.

“This study suggests that we are probably under-referring patients with multiple myeloma for AHCT based on age alone and under-treating them. Age should not be used as an exclusion/inclusion criterion for clinical trials of AHCT,” Dr. Silverstein said.

Abstract 793 was based on a Center for Medicare and Medicaid Services (CMS) claims database showing real-world descriptive data on 167 patients who were treated with CAR-T therapy for NHL.

“This is the first real-world look at healthcare utilization and costs associated with CAR-T therapy,” Dr. Silverstein said.

Mean age was 70 years old; 75% of patients were alive at 6 months. There was a 40% decrease in utilization of health care resources for these patients following CAR-T therapy.

“It is encouraging that real-world data show elderly patients with multiple comorbidities are doing well. Response rates are high and following CAR-T therapy, patients use fewer resources, such as emergency room visits, hospitalizations, and additional chemotherapy. If you consider the total costs of care, CAR-T may not be as expensive as presumed,” Dr. Silverstein said.

Data from a single-institution study of 196 patients with de novo diffuse large B-cell lymphoma (DLBCL) treated at the Levine Cancer Institute in Charlotte, NC, suggest that African-Americans with mild-to-moderate abnormalities in kidney function testing do not have worse survival outcomes than Caucasians (Abstract 425).

“African-Americans tend to have more abnormalities in kidney function testing than Caucasians. These data suggest that we should not be excluding African-Americans from clinical trials because of kidney function tests,” Dr. Silverstein emphasized.

“The fact that minorities have not been referred to experienced specialists probably underlies worse outcomes seen in other studies,” he added.

Abstract 703 is based on two different studies of children with newly diagnosed acute myeloid leukemia (AML) conducted by the Children’s Oncology Group (COG). Among 1467 children included in the final analysis, the risk of mortality was 25% lower for children from middle and high income areas compared with low income areas. Lower education was also associated with inferior event-free and overall survival in this retrospective study of mortality in pediatric AML.

“These findings suggest we need to pay attention to services we provide to children with AML who come from less advantaged neighborhoods,” Dr. Silverstein stated.

Dr. Brodsky gave a tantalizing preview of the 6 late-breaking abstracts to be presented Tuesday morning December 10. “Keep an eye on the late-breakers. Many are truly practice-changing,” he said.

 

By John McCleery, Content Director, OBR

October 07, 2019 - 10:10 am comments0 Comments

Targeted oral tyrosine kinase inhibitors (TKIs) have an established role in third-line treatment of metastatic colorectal cancer (mCRC), but an expert outlined an entirely new direction of investigation with these drugs at the 2019 European Society of Medical Oncology (ESMO) Congress. The underlying theory that agents within this class might make mCRC susceptible to checkpoint inhibition has finally been given some credibility with positive results in a clinical study.

“This is an incredibly exciting time,” said Heinz Josef Lenz, MD, associate director of clinical research, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles. “There is a feeling that maybe we are unraveling a new option in metastatic CRC with response rates we have not seen in any third line scenarios.”

The story that led to the as-yet unpublished clinical study involves converging progress in understanding how macrophages mediate checkpoint inhibitor resistance and how multikinase inhibitors alter macrophage activity, particularly through effects on colony stimulating factor 1 (CSF-1) receptors. The clinical trial was initiated when regorafenib, which has an established role in mCRC, downregulated tumor-associated macrophages (TAM) in the experimental setting.

“This is looking like a very good strategy to make cold tumors hot,” Dr. Lenz explained.

The principles involved in this approach for converting tumors resistant to immunotherapy to those susceptible might apply across multiple tumor types, but the initial study was conducted in cancers of the gastrointestinal tract. The clinical study that Dr. Lenz found so impressive was recently presented as a poster at the 2019 meeting of the American Society of Clinical Oncology (Fukuoaka S et al. abstract 2522).

In this study, regorafenib and the checkpoint inhibitor nivolumab were evaluated in 25 patients with mCRC and 25 patients with advanced gastric cancer. Patients had a median of three prior lines of treatment. The objective response rate was 38%, a rate in this setting that “has never been seen before,” according to Dr. Lenz.

“Even more impressive, and potentially proving the point that regorafenib is overcoming immunotherapy resistance, three of the responses were observed in patients who had previously failed a checkpoint inhibitor,” Dr. Lenz said.

The potential for targeted therapies to alter the tumor microenvironment in order to enhance T cell infiltration and the anti-tumor efficacy of checkpoint inhibitors has long been appreciated. However, clinical studies until now have been disappointing. Dr. Lenz cited several, including the phase 2 MODUL trial, which found no significant benefit with a combination of atezolizumab and the anti-VEGF drug bevacizumab in mCRC.

Like bevacizumab, regorafenib also inhibits angiogenic activity by targeting VEGF, but a broader range of effects includes inhibition of other growth factors, such as PDGFR and FGFR, as well as oncogenic kinases, such as KIT, RET, and B-RAF. While all of these targets are implicated in an anti-tumor effect, it is the inhibition of the CSF-1 receptor that has become a major focus in the effort to understand its role in immune regulation.

“The CSF-1 axis appears to be important to immune regulation and inhibition, and we are now seeing evidence that activity on this target might be important through its inhibition of tumor associated macrophages,” Dr. Lenz said.

This all adds up to a rationale for the multiple ongoing trials now combining multikinase inhibitors with immune checkpoint inhibitors, including a mCRC study of regorafenib with pembrolizumab that is enrolling patients at Dr. Lenz’s center.

This new direction of study with regorafenib is being initiated just as a dosing optimization scheme has improved its clinical utility. In the pivotal CORRECT trial (Grothey A et al Lancet 2013; 2013:303-312), the overall survival benefit associated with regorafenib in mCRC was accompanied by a challenging rate of initial toxicities. However, a study called ReDOS that was published just weeks prior to the 2019 ESMO Congress has altered its benefit-to-risk ratio.

On the basis of the ReDOS study (Bekaii-Saab et al. Lancet Oncol 2019;20:1070-1082), “we now know how to dose this drug and not compromise quality of life,” said Alex Grothey, MD, Research Institute, Germantown, Tennessee. The principal investigator of CORRECT, Dr. Grothey emphasized that if clinicians have been slow to move to this therapy due to concern about adverse events, the ReDOS study has given regorafenib “a new life.”

In the multicenter ReDOS, 123 mCRC patients were randomized to the standard schedule of 160 mg regorafenib daily for 21 days of a 28-day cycle or to a starting dose of 80 mg/day with weekly 40 mg dose escalations as tolerated to a maximum of 160 mg day. The experimental arm also included one week off therapy in each 28-day cycle. When compared, about twice as many patients in the experimental arm (43% vs. 26%; P=0.04) met the primary endpoint, which was to start a third cycle of therapy.

“On standard dosing, the first cycle was always the most difficult,” said Dr. Grothey, explaining why evaluating a graduated dose made sense. These data are important, because “for a cytotstatic drug like regorafenib, it is the duration of therapy that matters.”

On another front regarding mCRC at the 2019 ESMO Congress, phase 1 results with AMG 510, a TKI targeting the KRAS G12C mutation, proved disappointing despite the promise in tumor models. In 29 patients with mCRC, there was only one partial response. In advanced non-small cell lung cancer (NSCLC) with the KRAS G12C mutation, 11 of 23 patients achieved an objective response, according to data reported from the same study a month ago.

The study did not associate AMB 510 with any dose-limiting toxicities, which was the primary focus of the study. Moreover, the principal investigator, Ramaswamy Govindan, MD, Siteman Cancer Center, Washington University, St. Louis, reported that the data are too limited to rule out clinical activity in mCRC. However, higher rates of response had been expected on the basis of the NSCLC activity, leading several experts to question the viability of the KRAS G12C to be a viable isolated target in mCRC.

by Ted Bosworth

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