Renal Cell Carcinoma

Shorter time to metastatic development was associated with shorter time to treatment failure and shorter overall survival in an international review of over 7,000 renal cell carcinoma (RCC) patients treated with first-line tyrosine kinase inhibitors.

“Patients with synchronous disease, compared with patients with metachronous disease, have more adverse prognostic features, significantly shorter TTF [time to treatment failure], and poorer survival. This may help in patient counseling and may be taken into consideration in clinical trial designs in the future, in order to avoid an imbalance between treatment arms,” wrote investigators led by Frede Donskov, MD, a clinical professor at Aarhus (Denmark) University Hospital, in European Urology Oncology.

In the largest study to date to address the impact of timing of metastases on outcomes from tyrosine kinase inhibitor (TKI) treatment, something that’s been unclear until now, Dr. Donskov and associates turned to the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) to compare outcomes of 3,906 patients with synchronous metastases, meaning metastases within 3 months of initial RCC diagnosis, with 3,480 with metachronous disease, meaning metastases after that point.

They found that more patients with synchronous versus metachronous disease had higher T stage (T1-2, 19% vs. 34%), N1 disease (21% vs. 6%), presence of sarcomatoid differentiation (15.8% vs. 7.9%), Karnofsky performance status less than 80 (25.9% vs. 15.1%), anemia (62.5% vs. 42.3%), elevated neutrophils (18.9% vs. 10.9%), elevated platelets (21.6% vs. 11.4%), bone metastases (40.4% vs. 29.8%); and IMDC poor risk (40.6% vs.11.3%).

Synchronous versus metachronous disease by intervals of more than 3-12 months, more than 1-2 years, more than 2-7 years, and more than 7 years correlated with poor TTF (5.6 months vs. 7.3, 8.0, 10.8, and 13.3 months; P less than .0001) and poor overall survival (median, 16.7 months vs. 23.8, 30.2, 34.8, and 41.7 months; P less than .0001).

On multivariable regressions adjusting for baseline variables, metachronous disease was protective versus synchronous RCC on overall survival and TTF, with a greater protective effect the longer it took for the disease to metastasize.

“Synchronous disease may represent a distinct pathologic and molecular phenotype ... a high proportion of patients with synchronous disease have tumors with punctuated evolution, harboring aggressive disease features, consolidating in worse risk factors, requiring systemic therapy earlier, and having almost half the expected survival after the initiation of targeted therapy, compared with the latest metastatic timing, as shown in our study,” the investigators wrote.

The findings “reflect the underlying aggressive tumor biology. Whether [time to metastasis] impacts outcome to checkpoint immunotherapy is yet to be elucidated,” they added.

Patients were a median of 59 years at diagnosis, and 72.9% were men. None of the synchronous patients had a surgical nephrectomy, compared with 95.4% of metachronous patients; 67.2% of patients in both groups were treated with the TKI sunitinib (Sutent).

The work was funded by the IMDC. The lead investigator reported institutional grants from Ipsen and Pfizer, maker of sunitinib.
 

[email protected]

SOURCE: Donskov F et al. Eur Urol Oncol. 2020 Feb 6. doi: 10.1016/j.euo.2020.01.001.

Shorter time to metastatic development was associated with shorter time to treatment failure and shorter overall survival in an international review of over 7,000 renal cell carcinoma (RCC) patients treated with first-line tyrosine kinase inhibitors.

“Patients with synchronous disease, compared with patients with metachronous disease, have more adverse prognostic features, significantly shorter TTF [time to treatment failure], and poorer survival. This may help in patient counseling and may be taken into consideration in clinical trial designs in the future, in order to avoid an imbalance between treatment arms,” wrote investigators led by Frede Donskov, MD, a clinical professor at Aarhus (Denmark) University Hospital, in European Urology Oncology.

In the largest study to date to address the impact of timing of metastases on outcomes from tyrosine kinase inhibitor (TKI) treatment, something that’s been unclear until now, Dr. Donskov and associates turned to the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) to compare outcomes of 3,906 patients with synchronous metastases, meaning metastases within 3 months of initial RCC diagnosis, with 3,480 with metachronous disease, meaning metastases after that point.

They found that more patients with synchronous versus metachronous disease had higher T stage (T1-2, 19% vs. 34%), N1 disease (21% vs. 6%), presence of sarcomatoid differentiation (15.8% vs. 7.9%), Karnofsky performance status less than 80 (25.9% vs. 15.1%), anemia (62.5% vs. 42.3%), elevated neutrophils (18.9% vs. 10.9%), elevated platelets (21.6% vs. 11.4%), bone metastases (40.4% vs. 29.8%); and IMDC poor risk (40.6% vs.11.3%).

Synchronous versus metachronous disease by intervals of more than 3-12 months, more than 1-2 years, more than 2-7 years, and more than 7 years correlated with poor TTF (5.6 months vs. 7.3, 8.0, 10.8, and 13.3 months; P less than .0001) and poor overall survival (median, 16.7 months vs. 23.8, 30.2, 34.8, and 41.7 months; P less than .0001).

On multivariable regressions adjusting for baseline variables, metachronous disease was protective versus synchronous RCC on overall survival and TTF, with a greater protective effect the longer it took for the disease to metastasize.

“Synchronous disease may represent a distinct pathologic and molecular phenotype ... a high proportion of patients with synchronous disease have tumors with punctuated evolution, harboring aggressive disease features, consolidating in worse risk factors, requiring systemic therapy earlier, and having almost half the expected survival after the initiation of targeted therapy, compared with the latest metastatic timing, as shown in our study,” the investigators wrote.

The findings “reflect the underlying aggressive tumor biology. Whether [time to metastasis] impacts outcome to checkpoint immunotherapy is yet to be elucidated,” they added.

Patients were a median of 59 years at diagnosis, and 72.9% were men. None of the synchronous patients had a surgical nephrectomy, compared with 95.4% of metachronous patients; 67.2% of patients in both groups were treated with the TKI sunitinib (Sutent).

The work was funded by the IMDC. The lead investigator reported institutional grants from Ipsen and Pfizer, maker of sunitinib.
 

[email protected]

SOURCE: Donskov F et al. Eur Urol Oncol. 2020 Feb 6. doi: 10.1016/j.euo.2020.01.001.

Shorter time to metastatic development was associated with shorter time to treatment failure and shorter overall survival in an international review of over 7,000 renal cell carcinoma (RCC) patients treated with first-line tyrosine kinase inhibitors.

“Patients with synchronous disease, compared with patients with metachronous disease, have more adverse prognostic features, significantly shorter TTF [time to treatment failure], and poorer survival. This may help in patient counseling and may be taken into consideration in clinical trial designs in the future, in order to avoid an imbalance between treatment arms,” wrote investigators led by Frede Donskov, MD, a clinical professor at Aarhus (Denmark) University Hospital, in European Urology Oncology.

In the largest study to date to address the impact of timing of metastases on outcomes from tyrosine kinase inhibitor (TKI) treatment, something that’s been unclear until now, Dr. Donskov and associates turned to the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) to compare outcomes of 3,906 patients with synchronous metastases, meaning metastases within 3 months of initial RCC diagnosis, with 3,480 with metachronous disease, meaning metastases after that point.

They found that more patients with synchronous versus metachronous disease had higher T stage (T1-2, 19% vs. 34%), N1 disease (21% vs. 6%), presence of sarcomatoid differentiation (15.8% vs. 7.9%), Karnofsky performance status less than 80 (25.9% vs. 15.1%), anemia (62.5% vs. 42.3%), elevated neutrophils (18.9% vs. 10.9%), elevated platelets (21.6% vs. 11.4%), bone metastases (40.4% vs. 29.8%); and IMDC poor risk (40.6% vs.11.3%).

Synchronous versus metachronous disease by intervals of more than 3-12 months, more than 1-2 years, more than 2-7 years, and more than 7 years correlated with poor TTF (5.6 months vs. 7.3, 8.0, 10.8, and 13.3 months; P less than .0001) and poor overall survival (median, 16.7 months vs. 23.8, 30.2, 34.8, and 41.7 months; P less than .0001).

On multivariable regressions adjusting for baseline variables, metachronous disease was protective versus synchronous RCC on overall survival and TTF, with a greater protective effect the longer it took for the disease to metastasize.

“Synchronous disease may represent a distinct pathologic and molecular phenotype ... a high proportion of patients with synchronous disease have tumors with punctuated evolution, harboring aggressive disease features, consolidating in worse risk factors, requiring systemic therapy earlier, and having almost half the expected survival after the initiation of targeted therapy, compared with the latest metastatic timing, as shown in our study,” the investigators wrote.

The findings “reflect the underlying aggressive tumor biology. Whether [time to metastasis] impacts outcome to checkpoint immunotherapy is yet to be elucidated,” they added.

Patients were a median of 59 years at diagnosis, and 72.9% were men. None of the synchronous patients had a surgical nephrectomy, compared with 95.4% of metachronous patients; 67.2% of patients in both groups were treated with the TKI sunitinib (Sutent).

The work was funded by the IMDC. The lead investigator reported institutional grants from Ipsen and Pfizer, maker of sunitinib.
 

[email protected]

SOURCE: Donskov F et al. Eur Urol Oncol. 2020 Feb 6. doi: 10.1016/j.euo.2020.01.001.

There is not enough evidence to suggest that radiofrequency radiation (RFR) associated with cell phone use causes cancer, according to a review by the Food and Drug Administration.

The FDA reviewed the published literature from 2008 to 2018 and concluded that the data don’t support any quantifiable adverse health risks from RFR. However, the evidence is not without limitations.

The FDA’s evaluation included evidence from in vivo animal studies from Jan. 1, 2008, to Aug. 1, 2018, and epidemiologic studies in humans from Jan. 1, 2008, to May 8, 2018. Both kinds of evidence had limitations, but neither produced strong indications of any causal risks from cell phone use.

The FDA noted that in vivo animal studies are limited by variability of methods and RFR exposure, which make comparisons of results difficult. These studies are also impacted by the indirect effects of temperature increases (the only currently established biological effect of RFR) and stress experienced by the animals, which make teasing out the direct effects of RFR difficult.

The FDA noted that strong epidemiologic studies can provide more relevant and accurate information than in vivo studies, but epidemiologic studies are not without limitations. For example, most have participants track and self-report their cell phone use. There’s also no way to directly track certain factors of RFR exposure, such as frequency, duration, or intensity.

Even with those caveats in mind, the FDA wrote that, “based on the studies that are described in detail in this report, there is insufficient evidence to support a causal association between RFR exposure and tumorigenesis. There is a lack of clear dose-response relationship, a lack of consistent findings or specificity, and a lack of biological mechanistic plausibility.”

The full review is available on the FDA website.

[email protected]

There is not enough evidence to suggest that radiofrequency radiation (RFR) associated with cell phone use causes cancer, according to a review by the Food and Drug Administration.

The FDA reviewed the published literature from 2008 to 2018 and concluded that the data don’t support any quantifiable adverse health risks from RFR. However, the evidence is not without limitations.

The FDA’s evaluation included evidence from in vivo animal studies from Jan. 1, 2008, to Aug. 1, 2018, and epidemiologic studies in humans from Jan. 1, 2008, to May 8, 2018. Both kinds of evidence had limitations, but neither produced strong indications of any causal risks from cell phone use.

The FDA noted that in vivo animal studies are limited by variability of methods and RFR exposure, which make comparisons of results difficult. These studies are also impacted by the indirect effects of temperature increases (the only currently established biological effect of RFR) and stress experienced by the animals, which make teasing out the direct effects of RFR difficult.

The FDA noted that strong epidemiologic studies can provide more relevant and accurate information than in vivo studies, but epidemiologic studies are not without limitations. For example, most have participants track and self-report their cell phone use. There’s also no way to directly track certain factors of RFR exposure, such as frequency, duration, or intensity.

Even with those caveats in mind, the FDA wrote that, “based on the studies that are described in detail in this report, there is insufficient evidence to support a causal association between RFR exposure and tumorigenesis. There is a lack of clear dose-response relationship, a lack of consistent findings or specificity, and a lack of biological mechanistic plausibility.”

The full review is available on the FDA website.

[email protected]

There is not enough evidence to suggest that radiofrequency radiation (RFR) associated with cell phone use causes cancer, according to a review by the Food and Drug Administration.

The FDA reviewed the published literature from 2008 to 2018 and concluded that the data don’t support any quantifiable adverse health risks from RFR. However, the evidence is not without limitations.

The FDA’s evaluation included evidence from in vivo animal studies from Jan. 1, 2008, to Aug. 1, 2018, and epidemiologic studies in humans from Jan. 1, 2008, to May 8, 2018. Both kinds of evidence had limitations, but neither produced strong indications of any causal risks from cell phone use.

The FDA noted that in vivo animal studies are limited by variability of methods and RFR exposure, which make comparisons of results difficult. These studies are also impacted by the indirect effects of temperature increases (the only currently established biological effect of RFR) and stress experienced by the animals, which make teasing out the direct effects of RFR difficult.

The FDA noted that strong epidemiologic studies can provide more relevant and accurate information than in vivo studies, but epidemiologic studies are not without limitations. For example, most have participants track and self-report their cell phone use. There’s also no way to directly track certain factors of RFR exposure, such as frequency, duration, or intensity.

Even with those caveats in mind, the FDA wrote that, “based on the studies that are described in detail in this report, there is insufficient evidence to support a causal association between RFR exposure and tumorigenesis. There is a lack of clear dose-response relationship, a lack of consistent findings or specificity, and a lack of biological mechanistic plausibility.”

The full review is available on the FDA website.

[email protected]

ORLANDO – Combining intratumoral injections of ilixadencel, an off-the-shelf dendritic cell–based primer, with sunitinib improved responses in patients with newly diagnosed synchronous metastatic renal cell carcinoma in the phase 2 MERECA trial.

Sharon Worcester/MDEdge News

The confirmed overall response rate was 42.2% (19/45) in patients who received ilixadencel plus sunitinib and 24.0% (6/25) in patients who received sunitinib monotherapy. Magnus Lindskog, MD, PhD, of Uppsala (Sweden) University Hospital, reported these results at the ASCO-SITC Immuno-Oncology Symposium.

The complete response rate was 11.1% with ilixadencel plus sunitinib and 4% with sunitinib monotherapy. The confirmed complete response rates were 6.7% and 0%, respectively.

The median duration of response was 7.1 months with ilixadencel plus sunitinib and 2.9 months with sunitinib monotherapy. The median progression-free survival was 11.8 months and 11.0 months, respectively.

There was no difference in median overall survival – a coprimary endpoint – at 18 months, nor was there a difference in progression-free survival at that time. “We do find it interesting that there is a late separation of both [survival] curves like we see in many immunotherapy trials,” Dr. Lindskog said, noting that all five complete responders in the combination therapy arm were alive at 33 months, whereas the single patient with a complete response in the monotherapy group died after 41 months.

“So far, we have 54% versus 37% still alive in the ilixadencel versus sunitinib groups,” Dr. Lindskog said, adding that the observed activity of ilixadencel appears to be driven by responses in patients with intermediate risk.

The overall survival data in the intermediate-risk patients is not mature. The overall survival in poor-risk patients was 11.6 months in the combination group and 9.3 months in the monotherapy group.

MERECA study participants were adults with a mean age of 62-64 years who were considered surgical candidates. They were enrolled from eight centers in Europe and the United States between April 2014 and January 2017 and randomized 2:1 to the combination and monotherapy arms. In all, 45 patients received their assigned treatment in the combination arm, and 25 patients received their assigned treatment in the monotherapy arm.

Patients in the ilixadencel arm were injected twice, 2 weeks apart, at the primary tumor site using CT guidance. Patients in the monotherapy arm were observed until nephrectomy. Both groups received sunitinib after nephrectomy, which was performed within 6 weeks, and all were followed for 18 months.

Treatment was well tolerated. Ilixadencel did not add any clinically meaningful treatment-related grade 3-4 adverse events or serious adverse events, Dr. Lindskog said. He noted that the most common ilixadencel-related adverse event was uncomplicated pyrexia.

There were no signs of induced autoimmunity, and although 57% of patients in the combination therapy group developed ilixadencel-specific alloantibodies, this had no relationship to responses, Dr. Lindskog said.

“From this phase 2 study, we have confirmed the feasibility and safety of ilixadencel and sunitinib combined in newly diagnosed synchronous metastatic renal cell carcinoma patients,” he said.

He added that longer follow-up is needed to understand the late divergence in survival curves between the groups. Survival follow-up will continue for 5 years.

This study was funded by Immunicum. Dr. Lindskog disclosed relationships with Pfizer, Bristol-Myers Squibb, and Ipsen.

[email protected]

SOURCE: Lindskog M et al. ASCO-SITC 2020, Abstract 11.

ORLANDO – Combining intratumoral injections of ilixadencel, an off-the-shelf dendritic cell–based primer, with sunitinib improved responses in patients with newly diagnosed synchronous metastatic renal cell carcinoma in the phase 2 MERECA trial.

Sharon Worcester/MDEdge News

The confirmed overall response rate was 42.2% (19/45) in patients who received ilixadencel plus sunitinib and 24.0% (6/25) in patients who received sunitinib monotherapy. Magnus Lindskog, MD, PhD, of Uppsala (Sweden) University Hospital, reported these results at the ASCO-SITC Immuno-Oncology Symposium.

The complete response rate was 11.1% with ilixadencel plus sunitinib and 4% with sunitinib monotherapy. The confirmed complete response rates were 6.7% and 0%, respectively.

The median duration of response was 7.1 months with ilixadencel plus sunitinib and 2.9 months with sunitinib monotherapy. The median progression-free survival was 11.8 months and 11.0 months, respectively.

There was no difference in median overall survival – a coprimary endpoint – at 18 months, nor was there a difference in progression-free survival at that time. “We do find it interesting that there is a late separation of both [survival] curves like we see in many immunotherapy trials,” Dr. Lindskog said, noting that all five complete responders in the combination therapy arm were alive at 33 months, whereas the single patient with a complete response in the monotherapy group died after 41 months.

“So far, we have 54% versus 37% still alive in the ilixadencel versus sunitinib groups,” Dr. Lindskog said, adding that the observed activity of ilixadencel appears to be driven by responses in patients with intermediate risk.

The overall survival data in the intermediate-risk patients is not mature. The overall survival in poor-risk patients was 11.6 months in the combination group and 9.3 months in the monotherapy group.

MERECA study participants were adults with a mean age of 62-64 years who were considered surgical candidates. They were enrolled from eight centers in Europe and the United States between April 2014 and January 2017 and randomized 2:1 to the combination and monotherapy arms. In all, 45 patients received their assigned treatment in the combination arm, and 25 patients received their assigned treatment in the monotherapy arm.

Patients in the ilixadencel arm were injected twice, 2 weeks apart, at the primary tumor site using CT guidance. Patients in the monotherapy arm were observed until nephrectomy. Both groups received sunitinib after nephrectomy, which was performed within 6 weeks, and all were followed for 18 months.

Treatment was well tolerated. Ilixadencel did not add any clinically meaningful treatment-related grade 3-4 adverse events or serious adverse events, Dr. Lindskog said. He noted that the most common ilixadencel-related adverse event was uncomplicated pyrexia.

There were no signs of induced autoimmunity, and although 57% of patients in the combination therapy group developed ilixadencel-specific alloantibodies, this had no relationship to responses, Dr. Lindskog said.

“From this phase 2 study, we have confirmed the feasibility and safety of ilixadencel and sunitinib combined in newly diagnosed synchronous metastatic renal cell carcinoma patients,” he said.

He added that longer follow-up is needed to understand the late divergence in survival curves between the groups. Survival follow-up will continue for 5 years.

This study was funded by Immunicum. Dr. Lindskog disclosed relationships with Pfizer, Bristol-Myers Squibb, and Ipsen.

[email protected]

SOURCE: Lindskog M et al. ASCO-SITC 2020, Abstract 11.

ORLANDO – Combining intratumoral injections of ilixadencel, an off-the-shelf dendritic cell–based primer, with sunitinib improved responses in patients with newly diagnosed synchronous metastatic renal cell carcinoma in the phase 2 MERECA trial.

Sharon Worcester/MDEdge News

The confirmed overall response rate was 42.2% (19/45) in patients who received ilixadencel plus sunitinib and 24.0% (6/25) in patients who received sunitinib monotherapy. Magnus Lindskog, MD, PhD, of Uppsala (Sweden) University Hospital, reported these results at the ASCO-SITC Immuno-Oncology Symposium.

The complete response rate was 11.1% with ilixadencel plus sunitinib and 4% with sunitinib monotherapy. The confirmed complete response rates were 6.7% and 0%, respectively.

The median duration of response was 7.1 months with ilixadencel plus sunitinib and 2.9 months with sunitinib monotherapy. The median progression-free survival was 11.8 months and 11.0 months, respectively.

There was no difference in median overall survival – a coprimary endpoint – at 18 months, nor was there a difference in progression-free survival at that time. “We do find it interesting that there is a late separation of both [survival] curves like we see in many immunotherapy trials,” Dr. Lindskog said, noting that all five complete responders in the combination therapy arm were alive at 33 months, whereas the single patient with a complete response in the monotherapy group died after 41 months.

“So far, we have 54% versus 37% still alive in the ilixadencel versus sunitinib groups,” Dr. Lindskog said, adding that the observed activity of ilixadencel appears to be driven by responses in patients with intermediate risk.

The overall survival data in the intermediate-risk patients is not mature. The overall survival in poor-risk patients was 11.6 months in the combination group and 9.3 months in the monotherapy group.

MERECA study participants were adults with a mean age of 62-64 years who were considered surgical candidates. They were enrolled from eight centers in Europe and the United States between April 2014 and January 2017 and randomized 2:1 to the combination and monotherapy arms. In all, 45 patients received their assigned treatment in the combination arm, and 25 patients received their assigned treatment in the monotherapy arm.

Patients in the ilixadencel arm were injected twice, 2 weeks apart, at the primary tumor site using CT guidance. Patients in the monotherapy arm were observed until nephrectomy. Both groups received sunitinib after nephrectomy, which was performed within 6 weeks, and all were followed for 18 months.

Treatment was well tolerated. Ilixadencel did not add any clinically meaningful treatment-related grade 3-4 adverse events or serious adverse events, Dr. Lindskog said. He noted that the most common ilixadencel-related adverse event was uncomplicated pyrexia.

There were no signs of induced autoimmunity, and although 57% of patients in the combination therapy group developed ilixadencel-specific alloantibodies, this had no relationship to responses, Dr. Lindskog said.

“From this phase 2 study, we have confirmed the feasibility and safety of ilixadencel and sunitinib combined in newly diagnosed synchronous metastatic renal cell carcinoma patients,” he said.

He added that longer follow-up is needed to understand the late divergence in survival curves between the groups. Survival follow-up will continue for 5 years.

This study was funded by Immunicum. Dr. Lindskog disclosed relationships with Pfizer, Bristol-Myers Squibb, and Ipsen.

[email protected]

SOURCE: Lindskog M et al. ASCO-SITC 2020, Abstract 11.

A massive collaborative project spanning four continents and 744 research centers has revealed driver mutations in both protein-coding and noncoding regions of 38 cancer types.

Pan-Cancer Analysis of Whole Genomes

The Pan-Cancer Analysis of Whole Genomes (PCAWG) is an integrative analysis of the whole-genome sequences from 2,658 donors across 38 common tumor types. The findings are expected to add exponentially to what’s currently known about the complex genetics of cancer, and they point to possible strategies for improving cancer prevention, diagnosis, and care.

Six articles summarizing the findings are presented in a series of papers in Nature, and 16 more appear in affiliated publications.

“It’s humbling that it was only 14 years ago that the genomics community sequenced its very first cancer exome, and it was able to identify mutations within the roughly 20,000 protein-coding genes in the human cell,” investigator Lincoln Stein, MD, PhD, of the Ontario Institute for Cancer Research in Toronto, said in a telephone briefing.

Exome sequencing, however, covers only protein-coding genomic regions, which constitute only about 1% of the entire genome, “so assembling an accurate portrait of the cancer genome using just the exome data is like trying to put together a 100,000-piece jigsaw puzzle when you’re missing 99% of the pieces and there’s no puzzle box with a completed picture to guide you,” Dr. Stein said.

Members of the PCAWG from centers in North America, Europe, Asia, and Australia screened 2,658 whole-cancer genomes and matched samples of noncancerous tissues from the same individuals, along with 1,188 transcriptomes cataloging the sequences and expression of RNA transcripts in a given tumor. The 6-year project netted more than 800 terabytes of genomic data, roughly equivalent to the digital holdings of the U.S. Library of Congress multiplied by 11.

The findings are summarized in papers focusing on cancer drivers, noncoding changes, mutational signatures, structural variants, cancer evolution over time, and RNA alterations.
 

Driver mutations

Investigators found that the average cancer genome contains four or five driver mutations located in both coding and noncoding regions. They also found, however, that in approximately 5% of cases no driver mutations could be identified.

A substantial proportion of tumors displayed “hallmarks of genomic catastrophes.” About 22% of tumors exhibited chromothripsis, a mutational process marked by hundreds or even thousands of clustered chromosomal rearrangements. About 18% showed chromoplexy, which is characterized by scattering and rearrangement of multiple strands of DNA from one or more chromosomes.

Analyzing driver point mutations and structural variants in noncoding regions, the investigators found the usual suspects – previously reported culprits – as well as novel candidates.

For example, they identified point mutations in the five prime region of the tumor suppressor gene TP53 and the three prime untranslated regions of NFKBIZ (a nuclear factor kappa B inhibitor) and TOB1 (an antiproliferative protein), focal deletion in BRD4 (a transcriptional and epigenetic regulator), and rearrangements in chromosomal loci in members of the AKR1C family of enzymes thought to play a role in disease progression.

In addition, investigators identified mutations in noncoding regions of TERT, a telomerase gene. These mutations result in ramped-up expression of telomerase, which in turn promotes uncontrollable division of tumor cells.
 

Mutational signatures

In a related line of research, PCAWG investigators identified new DNA mutational signatures ranging from single nucleotide polymorphisms to insertions and deletions, as well as to structural variants – rearrangements of large sections of the genome.

“The substantial size of our dataset, compared with previous analyses, enabled the discovery of new signatures, the separation of overlapping signatures, and the decomposition of signatures into components that may represent associated – but distinct – DNA damage, repair, and/or replication mechanisms. By estimating the contribution of each signature to the mutational catalogs of individual cancer genomes, we revealed associations of signatures to exogenous or endogenous exposures, as well as to defective DNA maintenance processes,” the investigators wrote.

They also acknowledged, however, that “many signatures are of unknown cause.”
 

Cancer evolution

One of the six main studies focused on the evolution of cancer over time. Instead of providing a “snapshot” of the genome as captured by sequencing tissue from a single biopsy, consortium investigators created full-length features of the “life history and evolution of mutational processes and driver mutation sequences.”

They found that early cancer development was marked by relatively few mutations in driver genes and by identifiable copy-number gains, including trisomy 7 in glioblastoma, and an abnormal mirroring of the arms (isochromosome) of chromosome 17 in medulloblastoma.

In 40% of the samples, however, there were significant changes in the mutational spectrum as the cancers grew, leading to a near quadrupling of driver genes and increased genomic instability in later-stage tumors.

“Copy-number alterations often occur in mitotic crises and lead to simultaneous gains of chromosomal segments,” the investigators wrote. “Timing analyses suggest that driver mutations often precede diagnosis by many years, if not decades. Together, these results determine the evolutionary trajectories of cancer and highlight opportunities for early cancer detection.”
 

Implications for cancer care

“When I used to treat patients with cancer, I was always completely amazed and puzzled by how two patients could have what looked like the same tumor. It would look the same under the microscope, have the same size, and the two patients would receive exactly the same treatment, but the two patients would have completely opposite outcomes; one would survive, and one would die. What this analysis … has done is really laid bare the reasons for that unpredictability in clinical outcomes,” Peter Campbell, MD, PhD, of the Wellcome Sanger Institute in Hinxton, England, said during the telebriefing.

“The most striking finding out of all of the suite of papers is just how different one person’s cancer genome is from another person’s. We see thousands of different combinations of mutations that can cause the cancer, and more than 80 different underlying processes generating the mutations in a cancer, and that leads to very different shapes and patterns in the genome that result,” he added.

On a positive note, the research shows that one or more driver mutations can be identified in about 95% of all cancer patients, and it elucidates the sequence of events leading to oncogenesis and tumor evolution, providing opportunities for earlier identification and potential interventions to prevent cancer, Dr. Campbell said.

The PCAWG was a collaborative multinational effort with multiple funding sources and many investigators.

SOURCE: Nature. 2020 Feb 5. https://www.nature.com/collections/pcawg/

A massive collaborative project spanning four continents and 744 research centers has revealed driver mutations in both protein-coding and noncoding regions of 38 cancer types.

Pan-Cancer Analysis of Whole Genomes

The Pan-Cancer Analysis of Whole Genomes (PCAWG) is an integrative analysis of the whole-genome sequences from 2,658 donors across 38 common tumor types. The findings are expected to add exponentially to what’s currently known about the complex genetics of cancer, and they point to possible strategies for improving cancer prevention, diagnosis, and care.

Six articles summarizing the findings are presented in a series of papers in Nature, and 16 more appear in affiliated publications.

“It’s humbling that it was only 14 years ago that the genomics community sequenced its very first cancer exome, and it was able to identify mutations within the roughly 20,000 protein-coding genes in the human cell,” investigator Lincoln Stein, MD, PhD, of the Ontario Institute for Cancer Research in Toronto, said in a telephone briefing.

Exome sequencing, however, covers only protein-coding genomic regions, which constitute only about 1% of the entire genome, “so assembling an accurate portrait of the cancer genome using just the exome data is like trying to put together a 100,000-piece jigsaw puzzle when you’re missing 99% of the pieces and there’s no puzzle box with a completed picture to guide you,” Dr. Stein said.

Members of the PCAWG from centers in North America, Europe, Asia, and Australia screened 2,658 whole-cancer genomes and matched samples of noncancerous tissues from the same individuals, along with 1,188 transcriptomes cataloging the sequences and expression of RNA transcripts in a given tumor. The 6-year project netted more than 800 terabytes of genomic data, roughly equivalent to the digital holdings of the U.S. Library of Congress multiplied by 11.

The findings are summarized in papers focusing on cancer drivers, noncoding changes, mutational signatures, structural variants, cancer evolution over time, and RNA alterations.
 

Driver mutations

Investigators found that the average cancer genome contains four or five driver mutations located in both coding and noncoding regions. They also found, however, that in approximately 5% of cases no driver mutations could be identified.

A substantial proportion of tumors displayed “hallmarks of genomic catastrophes.” About 22% of tumors exhibited chromothripsis, a mutational process marked by hundreds or even thousands of clustered chromosomal rearrangements. About 18% showed chromoplexy, which is characterized by scattering and rearrangement of multiple strands of DNA from one or more chromosomes.

Analyzing driver point mutations and structural variants in noncoding regions, the investigators found the usual suspects – previously reported culprits – as well as novel candidates.

For example, they identified point mutations in the five prime region of the tumor suppressor gene TP53 and the three prime untranslated regions of NFKBIZ (a nuclear factor kappa B inhibitor) and TOB1 (an antiproliferative protein), focal deletion in BRD4 (a transcriptional and epigenetic regulator), and rearrangements in chromosomal loci in members of the AKR1C family of enzymes thought to play a role in disease progression.

In addition, investigators identified mutations in noncoding regions of TERT, a telomerase gene. These mutations result in ramped-up expression of telomerase, which in turn promotes uncontrollable division of tumor cells.
 

Mutational signatures

In a related line of research, PCAWG investigators identified new DNA mutational signatures ranging from single nucleotide polymorphisms to insertions and deletions, as well as to structural variants – rearrangements of large sections of the genome.

“The substantial size of our dataset, compared with previous analyses, enabled the discovery of new signatures, the separation of overlapping signatures, and the decomposition of signatures into components that may represent associated – but distinct – DNA damage, repair, and/or replication mechanisms. By estimating the contribution of each signature to the mutational catalogs of individual cancer genomes, we revealed associations of signatures to exogenous or endogenous exposures, as well as to defective DNA maintenance processes,” the investigators wrote.

They also acknowledged, however, that “many signatures are of unknown cause.”
 

Cancer evolution

One of the six main studies focused on the evolution of cancer over time. Instead of providing a “snapshot” of the genome as captured by sequencing tissue from a single biopsy, consortium investigators created full-length features of the “life history and evolution of mutational processes and driver mutation sequences.”

They found that early cancer development was marked by relatively few mutations in driver genes and by identifiable copy-number gains, including trisomy 7 in glioblastoma, and an abnormal mirroring of the arms (isochromosome) of chromosome 17 in medulloblastoma.

In 40% of the samples, however, there were significant changes in the mutational spectrum as the cancers grew, leading to a near quadrupling of driver genes and increased genomic instability in later-stage tumors.

“Copy-number alterations often occur in mitotic crises and lead to simultaneous gains of chromosomal segments,” the investigators wrote. “Timing analyses suggest that driver mutations often precede diagnosis by many years, if not decades. Together, these results determine the evolutionary trajectories of cancer and highlight opportunities for early cancer detection.”
 

Implications for cancer care

“When I used to treat patients with cancer, I was always completely amazed and puzzled by how two patients could have what looked like the same tumor. It would look the same under the microscope, have the same size, and the two patients would receive exactly the same treatment, but the two patients would have completely opposite outcomes; one would survive, and one would die. What this analysis … has done is really laid bare the reasons for that unpredictability in clinical outcomes,” Peter Campbell, MD, PhD, of the Wellcome Sanger Institute in Hinxton, England, said during the telebriefing.

“The most striking finding out of all of the suite of papers is just how different one person’s cancer genome is from another person’s. We see thousands of different combinations of mutations that can cause the cancer, and more than 80 different underlying processes generating the mutations in a cancer, and that leads to very different shapes and patterns in the genome that result,” he added.

On a positive note, the research shows that one or more driver mutations can be identified in about 95% of all cancer patients, and it elucidates the sequence of events leading to oncogenesis and tumor evolution, providing opportunities for earlier identification and potential interventions to prevent cancer, Dr. Campbell said.

The PCAWG was a collaborative multinational effort with multiple funding sources and many investigators.

SOURCE: Nature. 2020 Feb 5. https://www.nature.com/collections/pcawg/

A massive collaborative project spanning four continents and 744 research centers has revealed driver mutations in both protein-coding and noncoding regions of 38 cancer types.

Pan-Cancer Analysis of Whole Genomes

The Pan-Cancer Analysis of Whole Genomes (PCAWG) is an integrative analysis of the whole-genome sequences from 2,658 donors across 38 common tumor types. The findings are expected to add exponentially to what’s currently known about the complex genetics of cancer, and they point to possible strategies for improving cancer prevention, diagnosis, and care.

Six articles summarizing the findings are presented in a series of papers in Nature, and 16 more appear in affiliated publications.

“It’s humbling that it was only 14 years ago that the genomics community sequenced its very first cancer exome, and it was able to identify mutations within the roughly 20,000 protein-coding genes in the human cell,” investigator Lincoln Stein, MD, PhD, of the Ontario Institute for Cancer Research in Toronto, said in a telephone briefing.

Exome sequencing, however, covers only protein-coding genomic regions, which constitute only about 1% of the entire genome, “so assembling an accurate portrait of the cancer genome using just the exome data is like trying to put together a 100,000-piece jigsaw puzzle when you’re missing 99% of the pieces and there’s no puzzle box with a completed picture to guide you,” Dr. Stein said.

Members of the PCAWG from centers in North America, Europe, Asia, and Australia screened 2,658 whole-cancer genomes and matched samples of noncancerous tissues from the same individuals, along with 1,188 transcriptomes cataloging the sequences and expression of RNA transcripts in a given tumor. The 6-year project netted more than 800 terabytes of genomic data, roughly equivalent to the digital holdings of the U.S. Library of Congress multiplied by 11.

The findings are summarized in papers focusing on cancer drivers, noncoding changes, mutational signatures, structural variants, cancer evolution over time, and RNA alterations.
 

Driver mutations

Investigators found that the average cancer genome contains four or five driver mutations located in both coding and noncoding regions. They also found, however, that in approximately 5% of cases no driver mutations could be identified.

A substantial proportion of tumors displayed “hallmarks of genomic catastrophes.” About 22% of tumors exhibited chromothripsis, a mutational process marked by hundreds or even thousands of clustered chromosomal rearrangements. About 18% showed chromoplexy, which is characterized by scattering and rearrangement of multiple strands of DNA from one or more chromosomes.

Analyzing driver point mutations and structural variants in noncoding regions, the investigators found the usual suspects – previously reported culprits – as well as novel candidates.

For example, they identified point mutations in the five prime region of the tumor suppressor gene TP53 and the three prime untranslated regions of NFKBIZ (a nuclear factor kappa B inhibitor) and TOB1 (an antiproliferative protein), focal deletion in BRD4 (a transcriptional and epigenetic regulator), and rearrangements in chromosomal loci in members of the AKR1C family of enzymes thought to play a role in disease progression.

In addition, investigators identified mutations in noncoding regions of TERT, a telomerase gene. These mutations result in ramped-up expression of telomerase, which in turn promotes uncontrollable division of tumor cells.
 

Mutational signatures

In a related line of research, PCAWG investigators identified new DNA mutational signatures ranging from single nucleotide polymorphisms to insertions and deletions, as well as to structural variants – rearrangements of large sections of the genome.

“The substantial size of our dataset, compared with previous analyses, enabled the discovery of new signatures, the separation of overlapping signatures, and the decomposition of signatures into components that may represent associated – but distinct – DNA damage, repair, and/or replication mechanisms. By estimating the contribution of each signature to the mutational catalogs of individual cancer genomes, we revealed associations of signatures to exogenous or endogenous exposures, as well as to defective DNA maintenance processes,” the investigators wrote.

They also acknowledged, however, that “many signatures are of unknown cause.”
 

Cancer evolution

One of the six main studies focused on the evolution of cancer over time. Instead of providing a “snapshot” of the genome as captured by sequencing tissue from a single biopsy, consortium investigators created full-length features of the “life history and evolution of mutational processes and driver mutation sequences.”

They found that early cancer development was marked by relatively few mutations in driver genes and by identifiable copy-number gains, including trisomy 7 in glioblastoma, and an abnormal mirroring of the arms (isochromosome) of chromosome 17 in medulloblastoma.

In 40% of the samples, however, there were significant changes in the mutational spectrum as the cancers grew, leading to a near quadrupling of driver genes and increased genomic instability in later-stage tumors.

“Copy-number alterations often occur in mitotic crises and lead to simultaneous gains of chromosomal segments,” the investigators wrote. “Timing analyses suggest that driver mutations often precede diagnosis by many years, if not decades. Together, these results determine the evolutionary trajectories of cancer and highlight opportunities for early cancer detection.”
 

Implications for cancer care

“When I used to treat patients with cancer, I was always completely amazed and puzzled by how two patients could have what looked like the same tumor. It would look the same under the microscope, have the same size, and the two patients would receive exactly the same treatment, but the two patients would have completely opposite outcomes; one would survive, and one would die. What this analysis … has done is really laid bare the reasons for that unpredictability in clinical outcomes,” Peter Campbell, MD, PhD, of the Wellcome Sanger Institute in Hinxton, England, said during the telebriefing.

“The most striking finding out of all of the suite of papers is just how different one person’s cancer genome is from another person’s. We see thousands of different combinations of mutations that can cause the cancer, and more than 80 different underlying processes generating the mutations in a cancer, and that leads to very different shapes and patterns in the genome that result,” he added.

On a positive note, the research shows that one or more driver mutations can be identified in about 95% of all cancer patients, and it elucidates the sequence of events leading to oncogenesis and tumor evolution, providing opportunities for earlier identification and potential interventions to prevent cancer, Dr. Campbell said.

The PCAWG was a collaborative multinational effort with multiple funding sources and many investigators.

SOURCE: Nature. 2020 Feb 5. https://www.nature.com/collections/pcawg/

A combination of the tyrosine kinase inhibitor lenvatinib (Lenvima) and the immune checkpoint inhibitor pembrolizumab (Keytruda) was safe and showed promising activity against advanced renal cell carcinoma and other solid tumors in a phase 1b/2 study.

Overall response rates (ORR) at 24 weeks ranged from 63% for patients with advanced renal cell carcinomas (RCC) to 25% for patients with urothelial cancers, reported Matthew H. Taylor, MD, of Knight Cancer Institute at Oregon Health & Science University in Portland, and colleagues.

The findings from this study sparked additional clinical trials for patients with gastric cancer, gastroesophageal cancer, and differentiated thyroid cancer, and set the stage for larger phase 3 trials in patients with advanced RCC, endometrial cancer, malignant melanoma, and non–small cell lung cancer (NSCLC).

“In the future, we also plan to study lenvatinib plus pembrolizumab in patients with RCC who have had disease progression after treatment with immune checkpoint inhibitors,” they wrote. The report was published in Journal of Clinical Oncology.

Lenvatinib is a multitargeted tyrosine kinase inhibitor (TKI) with action against vascular endothelial growth factor (VEGF) receptors 1-3, fibroblast growth factor (FGF) receptors 1-4, platelet-derived growth factor receptors alpha and the RET and KIT kinases.

“Preclinical and clinical studies suggest that modulation of VEGF-mediated immune suppression via angiogenesis inhibition could potentially augment the immunotherapeutic activity of immune checkpoint inhibitors,” the investigators wrote.

They reported results from the dose finding (1b) phase including 13 patients and initial phase 2 expansion cohorts with a total of 124 patients.

The maximum tolerated dose of lenvatinib in combination with pembrolizumab was established as 20 mg/day.

At 24 weeks of follow-up, the ORR for 30 patients with RCC was 63%; two additional patients had responses after week 24, for a total ORR at study cutoff in this cohort of 70%. The median duration of response for these patients was 20 months, and the median progression-free survival (PFS) was 19.8 months. At the time of data cutoff for this analysis, 9 of the 30 patients with RCC were still on treatment.

For 23 patients with endometrial cancer, the 24-week and overall ORR were 52%, with a median duration of response not reached, and a median PFS of 9.7 months. Seven patients were still on treatment at data cutoff.

For 21 patients with melanoma, the 24-week and overall ORR were 48%, median duration of response was 12.5 months, and median PFS was 5.5 months. Two of the patients were still on treatment at data cutoff.

For the 22 patients with squamous cell cancer of the head and neck, the 24-week ORR was 36%, with two patients having a response after week 24 for a total ORR at data cutoff of 46%. The median duration of response was 8.2 months and the median PFS was 4.7 months. Three patients remained on treatment at data cutoff.

For 21 patients with NSCLC, the 24-week and overall ORR were 33%, the median duration of response was 10.9 months, and median PFS was 5.9 months. Six of the patients were still receiving treatment at data cutoff.

For 20 patients with urothelial cancer, the 24-week and overall ORR were 25%, with a median duration of response not reached, and a median PFS of 5.4 months. Three patients were still receiving the combination at the time of data cutoff.

Treatment related adverse events (TRAEs) occurred in 133 of all 137 patients enrolled in the two study phases. The adverse events were similar across all cohorts, with any grade of events including fatigue in 58%, diarrhea in 52%, hypertension in 47%, hypothyroidism in 42%, and decreased appetite in 39%.

The most frequent grade 3 or 4 TRAEs were hypertension in 20%, fatigue in 12%, diarrhea in 9%, proteinuria in 8%, and increased lipase levels in 7%.

In all, 85% of patients had a TRAE leading to lenvatinib dose reduction and/or interruption, and 13% required lenvatinib discontinuation.

Events leading to pembrolizumab dose interruption occurred in 45% of patients, and pembrolizumab discontinuation in 15%.

The study was sponsored by Eisai with collaboration from Merck Sharp & Dohme. Dr. Taylor disclosed a consulting or advisory role for Bristol-Myers Squibb, Eisai, Array BioPharma, Loxo, Bayer, ArQule, Blueprint Medicines, Novartis, and Sanofi/Genzyme, and speakers bureau activities for BMS and Eisai.

SOURCE: Taylor MH et al. J Clin Oncol. 2020 Jan. 21 doi: 10.1200/JCO.19.01598.

A combination of the tyrosine kinase inhibitor lenvatinib (Lenvima) and the immune checkpoint inhibitor pembrolizumab (Keytruda) was safe and showed promising activity against advanced renal cell carcinoma and other solid tumors in a phase 1b/2 study.

Overall response rates (ORR) at 24 weeks ranged from 63% for patients with advanced renal cell carcinomas (RCC) to 25% for patients with urothelial cancers, reported Matthew H. Taylor, MD, of Knight Cancer Institute at Oregon Health & Science University in Portland, and colleagues.

The findings from this study sparked additional clinical trials for patients with gastric cancer, gastroesophageal cancer, and differentiated thyroid cancer, and set the stage for larger phase 3 trials in patients with advanced RCC, endometrial cancer, malignant melanoma, and non–small cell lung cancer (NSCLC).

“In the future, we also plan to study lenvatinib plus pembrolizumab in patients with RCC who have had disease progression after treatment with immune checkpoint inhibitors,” they wrote. The report was published in Journal of Clinical Oncology.

Lenvatinib is a multitargeted tyrosine kinase inhibitor (TKI) with action against vascular endothelial growth factor (VEGF) receptors 1-3, fibroblast growth factor (FGF) receptors 1-4, platelet-derived growth factor receptors alpha and the RET and KIT kinases.

“Preclinical and clinical studies suggest that modulation of VEGF-mediated immune suppression via angiogenesis inhibition could potentially augment the immunotherapeutic activity of immune checkpoint inhibitors,” the investigators wrote.

They reported results from the dose finding (1b) phase including 13 patients and initial phase 2 expansion cohorts with a total of 124 patients.

The maximum tolerated dose of lenvatinib in combination with pembrolizumab was established as 20 mg/day.

At 24 weeks of follow-up, the ORR for 30 patients with RCC was 63%; two additional patients had responses after week 24, for a total ORR at study cutoff in this cohort of 70%. The median duration of response for these patients was 20 months, and the median progression-free survival (PFS) was 19.8 months. At the time of data cutoff for this analysis, 9 of the 30 patients with RCC were still on treatment.

For 23 patients with endometrial cancer, the 24-week and overall ORR were 52%, with a median duration of response not reached, and a median PFS of 9.7 months. Seven patients were still on treatment at data cutoff.

For 21 patients with melanoma, the 24-week and overall ORR were 48%, median duration of response was 12.5 months, and median PFS was 5.5 months. Two of the patients were still on treatment at data cutoff.

For the 22 patients with squamous cell cancer of the head and neck, the 24-week ORR was 36%, with two patients having a response after week 24 for a total ORR at data cutoff of 46%. The median duration of response was 8.2 months and the median PFS was 4.7 months. Three patients remained on treatment at data cutoff.

For 21 patients with NSCLC, the 24-week and overall ORR were 33%, the median duration of response was 10.9 months, and median PFS was 5.9 months. Six of the patients were still receiving treatment at data cutoff.

For 20 patients with urothelial cancer, the 24-week and overall ORR were 25%, with a median duration of response not reached, and a median PFS of 5.4 months. Three patients were still receiving the combination at the time of data cutoff.

Treatment related adverse events (TRAEs) occurred in 133 of all 137 patients enrolled in the two study phases. The adverse events were similar across all cohorts, with any grade of events including fatigue in 58%, diarrhea in 52%, hypertension in 47%, hypothyroidism in 42%, and decreased appetite in 39%.

The most frequent grade 3 or 4 TRAEs were hypertension in 20%, fatigue in 12%, diarrhea in 9%, proteinuria in 8%, and increased lipase levels in 7%.

In all, 85% of patients had a TRAE leading to lenvatinib dose reduction and/or interruption, and 13% required lenvatinib discontinuation.

Events leading to pembrolizumab dose interruption occurred in 45% of patients, and pembrolizumab discontinuation in 15%.

The study was sponsored by Eisai with collaboration from Merck Sharp & Dohme. Dr. Taylor disclosed a consulting or advisory role for Bristol-Myers Squibb, Eisai, Array BioPharma, Loxo, Bayer, ArQule, Blueprint Medicines, Novartis, and Sanofi/Genzyme, and speakers bureau activities for BMS and Eisai.

SOURCE: Taylor MH et al. J Clin Oncol. 2020 Jan. 21 doi: 10.1200/JCO.19.01598.

A combination of the tyrosine kinase inhibitor lenvatinib (Lenvima) and the immune checkpoint inhibitor pembrolizumab (Keytruda) was safe and showed promising activity against advanced renal cell carcinoma and other solid tumors in a phase 1b/2 study.

Overall response rates (ORR) at 24 weeks ranged from 63% for patients with advanced renal cell carcinomas (RCC) to 25% for patients with urothelial cancers, reported Matthew H. Taylor, MD, of Knight Cancer Institute at Oregon Health & Science University in Portland, and colleagues.

The findings from this study sparked additional clinical trials for patients with gastric cancer, gastroesophageal cancer, and differentiated thyroid cancer, and set the stage for larger phase 3 trials in patients with advanced RCC, endometrial cancer, malignant melanoma, and non–small cell lung cancer (NSCLC).

“In the future, we also plan to study lenvatinib plus pembrolizumab in patients with RCC who have had disease progression after treatment with immune checkpoint inhibitors,” they wrote. The report was published in Journal of Clinical Oncology.

Lenvatinib is a multitargeted tyrosine kinase inhibitor (TKI) with action against vascular endothelial growth factor (VEGF) receptors 1-3, fibroblast growth factor (FGF) receptors 1-4, platelet-derived growth factor receptors alpha and the RET and KIT kinases.

“Preclinical and clinical studies suggest that modulation of VEGF-mediated immune suppression via angiogenesis inhibition could potentially augment the immunotherapeutic activity of immune checkpoint inhibitors,” the investigators wrote.

They reported results from the dose finding (1b) phase including 13 patients and initial phase 2 expansion cohorts with a total of 124 patients.

The maximum tolerated dose of lenvatinib in combination with pembrolizumab was established as 20 mg/day.

At 24 weeks of follow-up, the ORR for 30 patients with RCC was 63%; two additional patients had responses after week 24, for a total ORR at study cutoff in this cohort of 70%. The median duration of response for these patients was 20 months, and the median progression-free survival (PFS) was 19.8 months. At the time of data cutoff for this analysis, 9 of the 30 patients with RCC were still on treatment.

For 23 patients with endometrial cancer, the 24-week and overall ORR were 52%, with a median duration of response not reached, and a median PFS of 9.7 months. Seven patients were still on treatment at data cutoff.

For 21 patients with melanoma, the 24-week and overall ORR were 48%, median duration of response was 12.5 months, and median PFS was 5.5 months. Two of the patients were still on treatment at data cutoff.

For the 22 patients with squamous cell cancer of the head and neck, the 24-week ORR was 36%, with two patients having a response after week 24 for a total ORR at data cutoff of 46%. The median duration of response was 8.2 months and the median PFS was 4.7 months. Three patients remained on treatment at data cutoff.

For 21 patients with NSCLC, the 24-week and overall ORR were 33%, the median duration of response was 10.9 months, and median PFS was 5.9 months. Six of the patients were still receiving treatment at data cutoff.

For 20 patients with urothelial cancer, the 24-week and overall ORR were 25%, with a median duration of response not reached, and a median PFS of 5.4 months. Three patients were still receiving the combination at the time of data cutoff.

Treatment related adverse events (TRAEs) occurred in 133 of all 137 patients enrolled in the two study phases. The adverse events were similar across all cohorts, with any grade of events including fatigue in 58%, diarrhea in 52%, hypertension in 47%, hypothyroidism in 42%, and decreased appetite in 39%.

The most frequent grade 3 or 4 TRAEs were hypertension in 20%, fatigue in 12%, diarrhea in 9%, proteinuria in 8%, and increased lipase levels in 7%.

In all, 85% of patients had a TRAE leading to lenvatinib dose reduction and/or interruption, and 13% required lenvatinib discontinuation.

Events leading to pembrolizumab dose interruption occurred in 45% of patients, and pembrolizumab discontinuation in 15%.

The study was sponsored by Eisai with collaboration from Merck Sharp & Dohme. Dr. Taylor disclosed a consulting or advisory role for Bristol-Myers Squibb, Eisai, Array BioPharma, Loxo, Bayer, ArQule, Blueprint Medicines, Novartis, and Sanofi/Genzyme, and speakers bureau activities for BMS and Eisai.

SOURCE: Taylor MH et al. J Clin Oncol. 2020 Jan. 21 doi: 10.1200/JCO.19.01598.

For third- or fourth-line treatment of metastatic renal cell carcinoma, the vascular epidermal growth factor receptor (VEGFR) tyrosine kinase inhibitor tivozanib may offer better progression-free survival than sorafenib, another VEGFR inhibitor, based on results from the TIVO-3 trial.

Susan London/MDedge News

Tivozanib also had fewer dose reductions and dose interruptions than sorafenib, likely because of less off-target activity, reported lead author Brian I. Rini, MD, of the Cleveland Clinic and Case Western Reserve University, also in Cleveland, and colleagues.

“These results support tivozanib as a treatment option for patients with recurrent and progressive renal cell carcinoma, including those who have progressed after previous immunotherapy,” the investigators wrote in Lancet Oncology.

The open-label, phase 3 trial involved 350 patients with metastatic renal cell carcinoma who had been treated with two or more systemic therapies, at least one of which was a VEGFR inhibitor. Patients were randomized in 1:1 ratio to receive either tivozanib 1.5 mg orally once daily in 4-week cycles or sorafenib 400 mg orally twice daily on a continuous basis. The primary endpoint was progression-free survival. Secondary endpoints included overall survival, objective response rates, and duration of response. Endpoints were evaluated by independent review. Safety was reported for all patients who received one or more doses of therapy.

After a median follow-up of 19 months, tivozanib was associated with a median progression-free survival of 5.6 months, compared with 3.9 months for sorafenib (P = .016). Significantly more patients in the tivozanib group achieved a response, and at 1 year, 71% of patients in the tivozanib group maintained a response, compared with 46% of the patients in the sorafenib group. At data cutoff, median overall survival was not significantly different between groups.

The most common treatment-related grade 3-4 adverse event was hypertension, which occurred in a slightly higher rate among those treated with tivozanib (20% vs. 14%). Serious treatment-related adverse events occurred at comparable rates in each treatment arm, at 11% for tivozanib and 10% for sorafenib. Compared with patients who received sorafenib, those in the tivozanib group had fewer dose reductions (24% vs. 38%) and dose interruptions (48% vs. 63%) because of adverse events, a benefit that the investigators attributed to relatively lower class-related off-target activity.

“To our knowledge, TIVO-3 provides the largest amount of prospective data generated to date regarding the use of VEGFR tyrosine kinase inhibitors after checkpoint inhibitor treatment,” the investigators wrote. “Notably, the benefit of tivozanib extended to patients who had previously received checkpoint inhibitors and those treated with two previous tyrosine kinase inhibitors.”

The study was funded by AVEO Oncology. The investigators reported additional relationships with Pfizer, Eisai, Astellas, and others.

SOURCE: Rini BI et al. Lancet Oncol. 2019 Dec 3. doi: 10.1016/S1470-2045(19)30735-1.

For third- or fourth-line treatment of metastatic renal cell carcinoma, the vascular epidermal growth factor receptor (VEGFR) tyrosine kinase inhibitor tivozanib may offer better progression-free survival than sorafenib, another VEGFR inhibitor, based on results from the TIVO-3 trial.

Susan London/MDedge News

Tivozanib also had fewer dose reductions and dose interruptions than sorafenib, likely because of less off-target activity, reported lead author Brian I. Rini, MD, of the Cleveland Clinic and Case Western Reserve University, also in Cleveland, and colleagues.

“These results support tivozanib as a treatment option for patients with recurrent and progressive renal cell carcinoma, including those who have progressed after previous immunotherapy,” the investigators wrote in Lancet Oncology.

The open-label, phase 3 trial involved 350 patients with metastatic renal cell carcinoma who had been treated with two or more systemic therapies, at least one of which was a VEGFR inhibitor. Patients were randomized in 1:1 ratio to receive either tivozanib 1.5 mg orally once daily in 4-week cycles or sorafenib 400 mg orally twice daily on a continuous basis. The primary endpoint was progression-free survival. Secondary endpoints included overall survival, objective response rates, and duration of response. Endpoints were evaluated by independent review. Safety was reported for all patients who received one or more doses of therapy.

After a median follow-up of 19 months, tivozanib was associated with a median progression-free survival of 5.6 months, compared with 3.9 months for sorafenib (P = .016). Significantly more patients in the tivozanib group achieved a response, and at 1 year, 71% of patients in the tivozanib group maintained a response, compared with 46% of the patients in the sorafenib group. At data cutoff, median overall survival was not significantly different between groups.

The most common treatment-related grade 3-4 adverse event was hypertension, which occurred in a slightly higher rate among those treated with tivozanib (20% vs. 14%). Serious treatment-related adverse events occurred at comparable rates in each treatment arm, at 11% for tivozanib and 10% for sorafenib. Compared with patients who received sorafenib, those in the tivozanib group had fewer dose reductions (24% vs. 38%) and dose interruptions (48% vs. 63%) because of adverse events, a benefit that the investigators attributed to relatively lower class-related off-target activity.

“To our knowledge, TIVO-3 provides the largest amount of prospective data generated to date regarding the use of VEGFR tyrosine kinase inhibitors after checkpoint inhibitor treatment,” the investigators wrote. “Notably, the benefit of tivozanib extended to patients who had previously received checkpoint inhibitors and those treated with two previous tyrosine kinase inhibitors.”

The study was funded by AVEO Oncology. The investigators reported additional relationships with Pfizer, Eisai, Astellas, and others.

SOURCE: Rini BI et al. Lancet Oncol. 2019 Dec 3. doi: 10.1016/S1470-2045(19)30735-1.

For third- or fourth-line treatment of metastatic renal cell carcinoma, the vascular epidermal growth factor receptor (VEGFR) tyrosine kinase inhibitor tivozanib may offer better progression-free survival than sorafenib, another VEGFR inhibitor, based on results from the TIVO-3 trial.

Susan London/MDedge News

Tivozanib also had fewer dose reductions and dose interruptions than sorafenib, likely because of less off-target activity, reported lead author Brian I. Rini, MD, of the Cleveland Clinic and Case Western Reserve University, also in Cleveland, and colleagues.

“These results support tivozanib as a treatment option for patients with recurrent and progressive renal cell carcinoma, including those who have progressed after previous immunotherapy,” the investigators wrote in Lancet Oncology.

The open-label, phase 3 trial involved 350 patients with metastatic renal cell carcinoma who had been treated with two or more systemic therapies, at least one of which was a VEGFR inhibitor. Patients were randomized in 1:1 ratio to receive either tivozanib 1.5 mg orally once daily in 4-week cycles or sorafenib 400 mg orally twice daily on a continuous basis. The primary endpoint was progression-free survival. Secondary endpoints included overall survival, objective response rates, and duration of response. Endpoints were evaluated by independent review. Safety was reported for all patients who received one or more doses of therapy.

After a median follow-up of 19 months, tivozanib was associated with a median progression-free survival of 5.6 months, compared with 3.9 months for sorafenib (P = .016). Significantly more patients in the tivozanib group achieved a response, and at 1 year, 71% of patients in the tivozanib group maintained a response, compared with 46% of the patients in the sorafenib group. At data cutoff, median overall survival was not significantly different between groups.

The most common treatment-related grade 3-4 adverse event was hypertension, which occurred in a slightly higher rate among those treated with tivozanib (20% vs. 14%). Serious treatment-related adverse events occurred at comparable rates in each treatment arm, at 11% for tivozanib and 10% for sorafenib. Compared with patients who received sorafenib, those in the tivozanib group had fewer dose reductions (24% vs. 38%) and dose interruptions (48% vs. 63%) because of adverse events, a benefit that the investigators attributed to relatively lower class-related off-target activity.

“To our knowledge, TIVO-3 provides the largest amount of prospective data generated to date regarding the use of VEGFR tyrosine kinase inhibitors after checkpoint inhibitor treatment,” the investigators wrote. “Notably, the benefit of tivozanib extended to patients who had previously received checkpoint inhibitors and those treated with two previous tyrosine kinase inhibitors.”

The study was funded by AVEO Oncology. The investigators reported additional relationships with Pfizer, Eisai, Astellas, and others.

SOURCE: Rini BI et al. Lancet Oncol. 2019 Dec 3. doi: 10.1016/S1470-2045(19)30735-1.

The combination of atezolizumab plus bevacizumab may offer some benefit to patients with advanced renal cell carcinoma, especially those who are positive for programmed death-ligand 1 (PD-L1), investigators report.

The overall response rate (ORR) among such patients was 60%, compared with 19% in PD-L1–negative patients, Bradley A. McGregor, MD, clinical director for the Lank Center of Genitourinary Oncology at Dana-Farber Cancer Institute in Boston, and colleagues reported in the Journal of Clinical Oncology.

The data were presented last summer at the American Society of Clinical Oncology Annual Meeting in Chicago.

The phase 2 study comprised 60 patients, 42 of whom had variant histology RCC, and 18 of whom had clear cell RCC (ccRCC ) with at least 20% sarcomatoid differentiation. All patients had advanced renal cell carcinoma of various histologies, including papillary (12), chromophobe (10), unclassified (9), TFE3 translocation (5), collecting duct (5), and medullary (1). Most (65%) had not received prior systemic therapy.

They all received infusions of atezolizumab 1,200 mg plus bevacizumab 15 mg/kg every 3 weeks. No dose modifications were allowed. Dose delays were allowed, and patients could also drop one agent and continue with the other. Treatment continued until disease progression, toxicity, or intolerable side effects.

The median number of cycles was 9.5, although the range was wide (1-42). At analysis, 15 were still on the treatment, but 45 had dropped out. Reasons were disease progression (34), death (1), toxicity (5), or unspecified (8). Six patients delayed bevacizumab doses, half because of adverse events.

After a median follow-up of 13 months, the ORR was 33%. Those with ccRCC with sarcomatoid differentiation responded best to the combination (ORR, 50%). Those with variant-histology RCC responded less robustly (ORR, 26%).

ORR varied by baseline risk category, being 33% in favorable-, 45% in intermediate-, and 11% in poor-risk patients. Median time to response was 2.7 months, median response duration was 8.9 months, and median progression-free survival was 8.3 months.

PD-L1 status was determined in 36 patients; 15 were positive. Among the positive patents, ORR was 60%, compared with 19% in PD-L1 negative patients. Response rates varied with tumor characteristics. Among patients with ccRCC with sarcomatoid differentiation, the ORR was 50% in PD-L1–positive patients and 29% in negative patients. In patients with variant histology RCC, the ORR was also better in PD-L1 positive patients (67% vs. 14%).

The most common treatment-related side effects were fatigue (35%), proteinuria (35%), musculoskeletal pain (33%), diarrhea (22%), rash (20%), hypertension (18%), pruritus (18%), thyroid dysfunction (17%), hepatitis (15%), fever (13%), and mucositis (12%). Thirty-four patients developed at least one grade 3 adverse event; there were no grade 4 or 5 toxicities. One patient died, presumably because of disease progression.

Quality of life scores were largely stable during treatment.

“The combination demonstrated responses across several subtypes of RCC, including collecting duct and medullary carcinoma, histologies that are often treated with cytotoxic chemotherapy,” the authors said. “This is notable given the generally poor prognosis and low response rate associated with variant histology RCC in trials to date.”

The study also suggests the PD-L1 status might be “intriguing as a biomarker for response to atezolizumab and bevacizumab in variant histology RCC. We plan to conduct additional correlative work, including genomic profiling and assessment of the immune microenvironment, to better elucidate markers of response and resistance,” the authors wrote.

SOURCE: McGregor BA et al. J Clin Oncol. 2019 Nov 13. doi: 10.1200/JCO.19.01882.

The combination of atezolizumab plus bevacizumab may offer some benefit to patients with advanced renal cell carcinoma, especially those who are positive for programmed death-ligand 1 (PD-L1), investigators report.

The overall response rate (ORR) among such patients was 60%, compared with 19% in PD-L1–negative patients, Bradley A. McGregor, MD, clinical director for the Lank Center of Genitourinary Oncology at Dana-Farber Cancer Institute in Boston, and colleagues reported in the Journal of Clinical Oncology.

The data were presented last summer at the American Society of Clinical Oncology Annual Meeting in Chicago.

The phase 2 study comprised 60 patients, 42 of whom had variant histology RCC, and 18 of whom had clear cell RCC (ccRCC ) with at least 20% sarcomatoid differentiation. All patients had advanced renal cell carcinoma of various histologies, including papillary (12), chromophobe (10), unclassified (9), TFE3 translocation (5), collecting duct (5), and medullary (1). Most (65%) had not received prior systemic therapy.

They all received infusions of atezolizumab 1,200 mg plus bevacizumab 15 mg/kg every 3 weeks. No dose modifications were allowed. Dose delays were allowed, and patients could also drop one agent and continue with the other. Treatment continued until disease progression, toxicity, or intolerable side effects.

The median number of cycles was 9.5, although the range was wide (1-42). At analysis, 15 were still on the treatment, but 45 had dropped out. Reasons were disease progression (34), death (1), toxicity (5), or unspecified (8). Six patients delayed bevacizumab doses, half because of adverse events.

After a median follow-up of 13 months, the ORR was 33%. Those with ccRCC with sarcomatoid differentiation responded best to the combination (ORR, 50%). Those with variant-histology RCC responded less robustly (ORR, 26%).

ORR varied by baseline risk category, being 33% in favorable-, 45% in intermediate-, and 11% in poor-risk patients. Median time to response was 2.7 months, median response duration was 8.9 months, and median progression-free survival was 8.3 months.

PD-L1 status was determined in 36 patients; 15 were positive. Among the positive patents, ORR was 60%, compared with 19% in PD-L1 negative patients. Response rates varied with tumor characteristics. Among patients with ccRCC with sarcomatoid differentiation, the ORR was 50% in PD-L1–positive patients and 29% in negative patients. In patients with variant histology RCC, the ORR was also better in PD-L1 positive patients (67% vs. 14%).

The most common treatment-related side effects were fatigue (35%), proteinuria (35%), musculoskeletal pain (33%), diarrhea (22%), rash (20%), hypertension (18%), pruritus (18%), thyroid dysfunction (17%), hepatitis (15%), fever (13%), and mucositis (12%). Thirty-four patients developed at least one grade 3 adverse event; there were no grade 4 or 5 toxicities. One patient died, presumably because of disease progression.

Quality of life scores were largely stable during treatment.

“The combination demonstrated responses across several subtypes of RCC, including collecting duct and medullary carcinoma, histologies that are often treated with cytotoxic chemotherapy,” the authors said. “This is notable given the generally poor prognosis and low response rate associated with variant histology RCC in trials to date.”

The study also suggests the PD-L1 status might be “intriguing as a biomarker for response to atezolizumab and bevacizumab in variant histology RCC. We plan to conduct additional correlative work, including genomic profiling and assessment of the immune microenvironment, to better elucidate markers of response and resistance,” the authors wrote.

SOURCE: McGregor BA et al. J Clin Oncol. 2019 Nov 13. doi: 10.1200/JCO.19.01882.

The combination of atezolizumab plus bevacizumab may offer some benefit to patients with advanced renal cell carcinoma, especially those who are positive for programmed death-ligand 1 (PD-L1), investigators report.

The overall response rate (ORR) among such patients was 60%, compared with 19% in PD-L1–negative patients, Bradley A. McGregor, MD, clinical director for the Lank Center of Genitourinary Oncology at Dana-Farber Cancer Institute in Boston, and colleagues reported in the Journal of Clinical Oncology.

The data were presented last summer at the American Society of Clinical Oncology Annual Meeting in Chicago.

The phase 2 study comprised 60 patients, 42 of whom had variant histology RCC, and 18 of whom had clear cell RCC (ccRCC ) with at least 20% sarcomatoid differentiation. All patients had advanced renal cell carcinoma of various histologies, including papillary (12), chromophobe (10), unclassified (9), TFE3 translocation (5), collecting duct (5), and medullary (1). Most (65%) had not received prior systemic therapy.

They all received infusions of atezolizumab 1,200 mg plus bevacizumab 15 mg/kg every 3 weeks. No dose modifications were allowed. Dose delays were allowed, and patients could also drop one agent and continue with the other. Treatment continued until disease progression, toxicity, or intolerable side effects.

The median number of cycles was 9.5, although the range was wide (1-42). At analysis, 15 were still on the treatment, but 45 had dropped out. Reasons were disease progression (34), death (1), toxicity (5), or unspecified (8). Six patients delayed bevacizumab doses, half because of adverse events.

After a median follow-up of 13 months, the ORR was 33%. Those with ccRCC with sarcomatoid differentiation responded best to the combination (ORR, 50%). Those with variant-histology RCC responded less robustly (ORR, 26%).

ORR varied by baseline risk category, being 33% in favorable-, 45% in intermediate-, and 11% in poor-risk patients. Median time to response was 2.7 months, median response duration was 8.9 months, and median progression-free survival was 8.3 months.

PD-L1 status was determined in 36 patients; 15 were positive. Among the positive patents, ORR was 60%, compared with 19% in PD-L1 negative patients. Response rates varied with tumor characteristics. Among patients with ccRCC with sarcomatoid differentiation, the ORR was 50% in PD-L1–positive patients and 29% in negative patients. In patients with variant histology RCC, the ORR was also better in PD-L1 positive patients (67% vs. 14%).

The most common treatment-related side effects were fatigue (35%), proteinuria (35%), musculoskeletal pain (33%), diarrhea (22%), rash (20%), hypertension (18%), pruritus (18%), thyroid dysfunction (17%), hepatitis (15%), fever (13%), and mucositis (12%). Thirty-four patients developed at least one grade 3 adverse event; there were no grade 4 or 5 toxicities. One patient died, presumably because of disease progression.

Quality of life scores were largely stable during treatment.

“The combination demonstrated responses across several subtypes of RCC, including collecting duct and medullary carcinoma, histologies that are often treated with cytotoxic chemotherapy,” the authors said. “This is notable given the generally poor prognosis and low response rate associated with variant histology RCC in trials to date.”

The study also suggests the PD-L1 status might be “intriguing as a biomarker for response to atezolizumab and bevacizumab in variant histology RCC. We plan to conduct additional correlative work, including genomic profiling and assessment of the immune microenvironment, to better elucidate markers of response and resistance,” the authors wrote.

SOURCE: McGregor BA et al. J Clin Oncol. 2019 Nov 13. doi: 10.1200/JCO.19.01882.

In this edition of “How I Will Treat My Next Patient,” I highlight two articles that demonstrate the safety of established treatments – nephrectomy and stereotactic ablative body radiotherapy (SABR) – in patient populations that previously may have been excluded from those treatments at many centers.

Nephrectomy in advanced RCC

Nirmish Singla, MD, and colleagues reported a single-center retrospective cohort study, assessing outcomes of 11 nephrectomies (10 radical, 1 partial) in 10 patients with advanced renal cell carcinoma (RCC) who had received front- or later-line immune checkpoint inhibitor therapy (ICIs). Half had received nivolumab alone; the others received nivolumab plus ipilimumab. Surgery was performed laparoscopically in five cases (Urol Oncol. 2019 Dec;37[12]:924-31).

No patient experienced a major intraoperative complication. Four experienced postoperative complications, the majority of which were addressed with interventional radiology procedures. The median hospital stay was 4 days. One patient died of progressive disease more than 3 months after surgery, and another died of pulmonary embolism and sepsis. Six of the 10 patients did not have any complications or readmissions. There were no immune-related toxicities and no wound-healing issues. ICI therapy was resumed postoperatively in six patients.

At nephrectomy (plus or minus metastatectomy), one patient achieved a response to immunotherapy in the primary tumor, and three of four patients who underwent resection of hepatic, pulmonary, or adrenal metastases had no detectable cancer. All surgical margins were negative.

During a median postoperative follow-up of 180 days, nephrectomy following ICI was safe. Pathologic response in both the primary tumor and metastatic sites was encouraging.

What this means in clinical practice

In medical school, all of us are admonished not to be afraid to unlearn something and to learn something new. Historically, nephrectomy was felt to be helpful in improving overall survival in patients with advanced RCC. Effective targeted therapies and ICIs have caused us to question the role of nephrectomy and its timing, since 20%-40% of patients who have apparently localized RCC at the time of nephrectomy develop recurrences within 3 years. Preoperative therapy could mitigate potentially aggressive tumor biology, treat micrometastatic disease, and help select patients who should not be treated surgically.

In the CARMENA trial of the treatment of advanced RCC patients with the tyrosine kinase inhibitor sunitinib versus nephrectomy followed by sunitinib, most patients could avoid nephrectomy without compromising survival (N Engl J Med. 2018; 379:417-27). Results were updated at the 2019 annual meeting of the American Society of Clinical Oncology. Overall, nephrectomy was not beneficial. However, delayed nephrectomy (after sunitinib) appeared be beneficial for good responders with only one IMDC (International Metastatic RCC Database Consortium) risk factor and only one metastatic site.

The small study by Dr. Singla and colleagues illustrates that nephrectomy is feasible after ICI, plus or minus anti-CTLA4-targeted treatment, and that favorable histologic results can be achieved. With ICI plus or minus anti-CTLA4-targeted treatment, no patient had progressive disease prior to surgery. This experience is germane in view of recently updated results of the CheckMate 214 trial, showing superior overall survival, response rates, and response duration for nivolumab plus ipilimumab, in comparison with sunitinib.

There are still unresolved questions, including whether these favorable outcomes can be achieved in community practice and whether there are genomic or immunohistochemistry expression profiles to select patients who can benefit from this approach. It’s unclear whether there are practical issues that influence outcome, such as type of ICI, number of preoperative treatment cycles, and additional systemic therapies including postoperative treatment. However, the current series rings the starting bell for the study of those questions and a promising era for patients with this deadly disease.
 

SABR in moderately central NSCLC

SABR to peripheral, small non–small cell lung cancers (NSCLCs) produces high local control rates, with low grade 3-4 toxicity, and is an alternative to resection in patients who are unfit for surgery. In a pragmatic, community-based, prospective cohort experience in Scotland, Robert Rulach, MBChB, and colleagues, treated 50 T1-2N0M0 NSCLC patients with SABR 50-Gy in five fractions (Clin Oncol. 2019 Oct 10. doi: 10.1016/j.clon.2019.09.055). The dose and fractionation schedule was safe and effective in the phase 1/2 RTOG 0813 trial and is concordant with guidelines from the National Comprehensive Cancer Network (NCCN).

All of the tumors were moderately central, as in the RTOG trial. One patient had an additional tumor that was ultracentral. Notably, 84% of patients were deemed medically unfit for surgery.

All patients completed radiotherapy without treatment delays. Two patients died within 90 days of treatment. There were no grade 4 or grade 5 toxicities and the overall rate of grade 3 toxicity was 4%. With a median follow-up of 25.2 months, 34 patients died: 18 from causes unrelated to cancer and 16 from cancer recurrence. The median overall survival was 27 months. The 2-year overall survival rate was 67.6%, commensurate with the rate seen in RTOG 0813.

The researchers concluded that, for frail patients with centrally-located NSCLC treated uniformly in a community practice, SABR with the RTOG 0813 treatment protocol produced acceptable toxicity and overall survival comparable with the published literature.

What this means in clinical practice

The results and conclusions of the study by Dr. Rulach and colleagues are straightforward: SABR can be used for centrally-located NSCLC without producing massive hemoptysis, bronchial stricture, and fistula formation. Since the majority of patients had no histologic diagnosis, T1N0 lesions, and no routine follow-up CT scans beyond 3 months post treatment, conclusions beyond that are unjustified.

In a community-based practice, NCCN guideline–concordant SABR treatment in moderately centrally-located NSCLC was safely delivered. For the burgeoning population of medically inoperable and/or elderly NSCLC patients, this alone is reassuring for clinicians and is helpful information for patients who require and/or desire nonsurgical treatment.
 

Dr. Lyss has been a community-based medical oncologist and clinical researcher for more than 35 years, practicing in St. Louis. His clinical and research interests are in the prevention, diagnosis, and treatment of breast and lung cancers and in expanding access to clinical trials to medically underserved populations.

In this edition of “How I Will Treat My Next Patient,” I highlight two articles that demonstrate the safety of established treatments – nephrectomy and stereotactic ablative body radiotherapy (SABR) – in patient populations that previously may have been excluded from those treatments at many centers.

Nephrectomy in advanced RCC

Nirmish Singla, MD, and colleagues reported a single-center retrospective cohort study, assessing outcomes of 11 nephrectomies (10 radical, 1 partial) in 10 patients with advanced renal cell carcinoma (RCC) who had received front- or later-line immune checkpoint inhibitor therapy (ICIs). Half had received nivolumab alone; the others received nivolumab plus ipilimumab. Surgery was performed laparoscopically in five cases (Urol Oncol. 2019 Dec;37[12]:924-31).

No patient experienced a major intraoperative complication. Four experienced postoperative complications, the majority of which were addressed with interventional radiology procedures. The median hospital stay was 4 days. One patient died of progressive disease more than 3 months after surgery, and another died of pulmonary embolism and sepsis. Six of the 10 patients did not have any complications or readmissions. There were no immune-related toxicities and no wound-healing issues. ICI therapy was resumed postoperatively in six patients.

At nephrectomy (plus or minus metastatectomy), one patient achieved a response to immunotherapy in the primary tumor, and three of four patients who underwent resection of hepatic, pulmonary, or adrenal metastases had no detectable cancer. All surgical margins were negative.

During a median postoperative follow-up of 180 days, nephrectomy following ICI was safe. Pathologic response in both the primary tumor and metastatic sites was encouraging.

What this means in clinical practice

In medical school, all of us are admonished not to be afraid to unlearn something and to learn something new. Historically, nephrectomy was felt to be helpful in improving overall survival in patients with advanced RCC. Effective targeted therapies and ICIs have caused us to question the role of nephrectomy and its timing, since 20%-40% of patients who have apparently localized RCC at the time of nephrectomy develop recurrences within 3 years. Preoperative therapy could mitigate potentially aggressive tumor biology, treat micrometastatic disease, and help select patients who should not be treated surgically.

In the CARMENA trial of the treatment of advanced RCC patients with the tyrosine kinase inhibitor sunitinib versus nephrectomy followed by sunitinib, most patients could avoid nephrectomy without compromising survival (N Engl J Med. 2018; 379:417-27). Results were updated at the 2019 annual meeting of the American Society of Clinical Oncology. Overall, nephrectomy was not beneficial. However, delayed nephrectomy (after sunitinib) appeared be beneficial for good responders with only one IMDC (International Metastatic RCC Database Consortium) risk factor and only one metastatic site.

The small study by Dr. Singla and colleagues illustrates that nephrectomy is feasible after ICI, plus or minus anti-CTLA4-targeted treatment, and that favorable histologic results can be achieved. With ICI plus or minus anti-CTLA4-targeted treatment, no patient had progressive disease prior to surgery. This experience is germane in view of recently updated results of the CheckMate 214 trial, showing superior overall survival, response rates, and response duration for nivolumab plus ipilimumab, in comparison with sunitinib.

There are still unresolved questions, including whether these favorable outcomes can be achieved in community practice and whether there are genomic or immunohistochemistry expression profiles to select patients who can benefit from this approach. It’s unclear whether there are practical issues that influence outcome, such as type of ICI, number of preoperative treatment cycles, and additional systemic therapies including postoperative treatment. However, the current series rings the starting bell for the study of those questions and a promising era for patients with this deadly disease.
 

SABR in moderately central NSCLC

SABR to peripheral, small non–small cell lung cancers (NSCLCs) produces high local control rates, with low grade 3-4 toxicity, and is an alternative to resection in patients who are unfit for surgery. In a pragmatic, community-based, prospective cohort experience in Scotland, Robert Rulach, MBChB, and colleagues, treated 50 T1-2N0M0 NSCLC patients with SABR 50-Gy in five fractions (Clin Oncol. 2019 Oct 10. doi: 10.1016/j.clon.2019.09.055). The dose and fractionation schedule was safe and effective in the phase 1/2 RTOG 0813 trial and is concordant with guidelines from the National Comprehensive Cancer Network (NCCN).

All of the tumors were moderately central, as in the RTOG trial. One patient had an additional tumor that was ultracentral. Notably, 84% of patients were deemed medically unfit for surgery.

All patients completed radiotherapy without treatment delays. Two patients died within 90 days of treatment. There were no grade 4 or grade 5 toxicities and the overall rate of grade 3 toxicity was 4%. With a median follow-up of 25.2 months, 34 patients died: 18 from causes unrelated to cancer and 16 from cancer recurrence. The median overall survival was 27 months. The 2-year overall survival rate was 67.6%, commensurate with the rate seen in RTOG 0813.

The researchers concluded that, for frail patients with centrally-located NSCLC treated uniformly in a community practice, SABR with the RTOG 0813 treatment protocol produced acceptable toxicity and overall survival comparable with the published literature.

What this means in clinical practice

The results and conclusions of the study by Dr. Rulach and colleagues are straightforward: SABR can be used for centrally-located NSCLC without producing massive hemoptysis, bronchial stricture, and fistula formation. Since the majority of patients had no histologic diagnosis, T1N0 lesions, and no routine follow-up CT scans beyond 3 months post treatment, conclusions beyond that are unjustified.

In a community-based practice, NCCN guideline–concordant SABR treatment in moderately centrally-located NSCLC was safely delivered. For the burgeoning population of medically inoperable and/or elderly NSCLC patients, this alone is reassuring for clinicians and is helpful information for patients who require and/or desire nonsurgical treatment.
 

Dr. Lyss has been a community-based medical oncologist and clinical researcher for more than 35 years, practicing in St. Louis. His clinical and research interests are in the prevention, diagnosis, and treatment of breast and lung cancers and in expanding access to clinical trials to medically underserved populations.

In this edition of “How I Will Treat My Next Patient,” I highlight two articles that demonstrate the safety of established treatments – nephrectomy and stereotactic ablative body radiotherapy (SABR) – in patient populations that previously may have been excluded from those treatments at many centers.

Nephrectomy in advanced RCC

Nirmish Singla, MD, and colleagues reported a single-center retrospective cohort study, assessing outcomes of 11 nephrectomies (10 radical, 1 partial) in 10 patients with advanced renal cell carcinoma (RCC) who had received front- or later-line immune checkpoint inhibitor therapy (ICIs). Half had received nivolumab alone; the others received nivolumab plus ipilimumab. Surgery was performed laparoscopically in five cases (Urol Oncol. 2019 Dec;37[12]:924-31).

No patient experienced a major intraoperative complication. Four experienced postoperative complications, the majority of which were addressed with interventional radiology procedures. The median hospital stay was 4 days. One patient died of progressive disease more than 3 months after surgery, and another died of pulmonary embolism and sepsis. Six of the 10 patients did not have any complications or readmissions. There were no immune-related toxicities and no wound-healing issues. ICI therapy was resumed postoperatively in six patients.

At nephrectomy (plus or minus metastatectomy), one patient achieved a response to immunotherapy in the primary tumor, and three of four patients who underwent resection of hepatic, pulmonary, or adrenal metastases had no detectable cancer. All surgical margins were negative.

During a median postoperative follow-up of 180 days, nephrectomy following ICI was safe. Pathologic response in both the primary tumor and metastatic sites was encouraging.

What this means in clinical practice

In medical school, all of us are admonished not to be afraid to unlearn something and to learn something new. Historically, nephrectomy was felt to be helpful in improving overall survival in patients with advanced RCC. Effective targeted therapies and ICIs have caused us to question the role of nephrectomy and its timing, since 20%-40% of patients who have apparently localized RCC at the time of nephrectomy develop recurrences within 3 years. Preoperative therapy could mitigate potentially aggressive tumor biology, treat micrometastatic disease, and help select patients who should not be treated surgically.

In the CARMENA trial of the treatment of advanced RCC patients with the tyrosine kinase inhibitor sunitinib versus nephrectomy followed by sunitinib, most patients could avoid nephrectomy without compromising survival (N Engl J Med. 2018; 379:417-27). Results were updated at the 2019 annual meeting of the American Society of Clinical Oncology. Overall, nephrectomy was not beneficial. However, delayed nephrectomy (after sunitinib) appeared be beneficial for good responders with only one IMDC (International Metastatic RCC Database Consortium) risk factor and only one metastatic site.

The small study by Dr. Singla and colleagues illustrates that nephrectomy is feasible after ICI, plus or minus anti-CTLA4-targeted treatment, and that favorable histologic results can be achieved. With ICI plus or minus anti-CTLA4-targeted treatment, no patient had progressive disease prior to surgery. This experience is germane in view of recently updated results of the CheckMate 214 trial, showing superior overall survival, response rates, and response duration for nivolumab plus ipilimumab, in comparison with sunitinib.

There are still unresolved questions, including whether these favorable outcomes can be achieved in community practice and whether there are genomic or immunohistochemistry expression profiles to select patients who can benefit from this approach. It’s unclear whether there are practical issues that influence outcome, such as type of ICI, number of preoperative treatment cycles, and additional systemic therapies including postoperative treatment. However, the current series rings the starting bell for the study of those questions and a promising era for patients with this deadly disease.
 

SABR in moderately central NSCLC

SABR to peripheral, small non–small cell lung cancers (NSCLCs) produces high local control rates, with low grade 3-4 toxicity, and is an alternative to resection in patients who are unfit for surgery. In a pragmatic, community-based, prospective cohort experience in Scotland, Robert Rulach, MBChB, and colleagues, treated 50 T1-2N0M0 NSCLC patients with SABR 50-Gy in five fractions (Clin Oncol. 2019 Oct 10. doi: 10.1016/j.clon.2019.09.055). The dose and fractionation schedule was safe and effective in the phase 1/2 RTOG 0813 trial and is concordant with guidelines from the National Comprehensive Cancer Network (NCCN).

All of the tumors were moderately central, as in the RTOG trial. One patient had an additional tumor that was ultracentral. Notably, 84% of patients were deemed medically unfit for surgery.

All patients completed radiotherapy without treatment delays. Two patients died within 90 days of treatment. There were no grade 4 or grade 5 toxicities and the overall rate of grade 3 toxicity was 4%. With a median follow-up of 25.2 months, 34 patients died: 18 from causes unrelated to cancer and 16 from cancer recurrence. The median overall survival was 27 months. The 2-year overall survival rate was 67.6%, commensurate with the rate seen in RTOG 0813.

The researchers concluded that, for frail patients with centrally-located NSCLC treated uniformly in a community practice, SABR with the RTOG 0813 treatment protocol produced acceptable toxicity and overall survival comparable with the published literature.

What this means in clinical practice

The results and conclusions of the study by Dr. Rulach and colleagues are straightforward: SABR can be used for centrally-located NSCLC without producing massive hemoptysis, bronchial stricture, and fistula formation. Since the majority of patients had no histologic diagnosis, T1N0 lesions, and no routine follow-up CT scans beyond 3 months post treatment, conclusions beyond that are unjustified.

In a community-based practice, NCCN guideline–concordant SABR treatment in moderately centrally-located NSCLC was safely delivered. For the burgeoning population of medically inoperable and/or elderly NSCLC patients, this alone is reassuring for clinicians and is helpful information for patients who require and/or desire nonsurgical treatment.
 

Dr. Lyss has been a community-based medical oncologist and clinical researcher for more than 35 years, practicing in St. Louis. His clinical and research interests are in the prevention, diagnosis, and treatment of breast and lung cancers and in expanding access to clinical trials to medically underserved populations.

First-line sunitinib therapy for metastatic renal cell carcinoma (mRCC) has somewhat differing effectiveness and safety when used in real-world practice, compared with clinical trials, suggests the OSSMAR multicenter retrospective cohort study.

Investigators led by Marwan Ghosn, MD, Hotel-Dieu de France University Hospital and Saint Joseph University, Beirut, Lebanon, analyzed outcomes among 289 patients with mRCC started on sunitinib (Sutent), an oral multitargeted tyrosine kinase inhibitor, between 2006 and 2016 at 10 centers in Africa and the Middle East region.

The patients had a median age at diagnosis of 58.7 years, and 85.8% had clear cell histology. Two-thirds had metastases at diagnosis, and 15.2% and 31.4% had favorable- and poor-risk disease, respectively, according to expanded Memorial Sloan Kettering Cancer Center criteria. Overall, 52.2% had undergone partial or radical nephrectomy, and nearly all were receiving sunitinib as first-line therapy.

Study results, reported in the Journal of Global Oncology, showed that the mean total sunitinib starting dose was 48.1 mg, with most patients (87.6%) started on a dose of 50 mg. On average, the drug was given for 9.6 months.

The overall response rate was 20.8%, and responses lasted for a median of of 8.2 months. With a median follow-up of 7.8 months, patients had a median time to progression of 5.7 months and a median overall survival of 7.8 months. The 12- and 24-month rates of overall survival were 34.3% and 11.4%, respectively.

Although 60.9% of patients experienced adverse events, only 8.0% experienced serious adverse events. The main adverse events were gastrointestinal and hematologic, mirroring those seen previously in trials. About a third of the whole study cohort (28.7%) discontinued sunitinib therapy.

“OSSMAR is the first study in the Middle East involving several Arab countries and evaluating the use of real-time sunitinib in the treatment of mRCC. As a result, this study is of primary importance because it allows for a better assessment of the actual effectiveness and practical adverse events of sunitinib in the population in our region,” Dr. Ghosn and coinvestigators maintained.

Compared with patients in clinical trials, OSSMAR patients had poorer overall survival, possibly due to factors such as a relatively lower nephrectomy rate, real-world influences such as comorbidities, and losses to follow-up, the investigators proposed.

At the same time, the OSSMAR cohort also had a lower rate of adverse events, although this difference likely reflects less rigorous assessment of toxicity in real-world practice, they noted.

Dr. Ghosn disclosed that he has relationships with numerous pharmaceutical companies. The study did not receive any specific funding.

SOURCE: Ghosn M et al. J Glob Oncol. 2019 Oct 5. doi: 10.1200/JGO.18.00238.

First-line sunitinib therapy for metastatic renal cell carcinoma (mRCC) has somewhat differing effectiveness and safety when used in real-world practice, compared with clinical trials, suggests the OSSMAR multicenter retrospective cohort study.

Investigators led by Marwan Ghosn, MD, Hotel-Dieu de France University Hospital and Saint Joseph University, Beirut, Lebanon, analyzed outcomes among 289 patients with mRCC started on sunitinib (Sutent), an oral multitargeted tyrosine kinase inhibitor, between 2006 and 2016 at 10 centers in Africa and the Middle East region.

The patients had a median age at diagnosis of 58.7 years, and 85.8% had clear cell histology. Two-thirds had metastases at diagnosis, and 15.2% and 31.4% had favorable- and poor-risk disease, respectively, according to expanded Memorial Sloan Kettering Cancer Center criteria. Overall, 52.2% had undergone partial or radical nephrectomy, and nearly all were receiving sunitinib as first-line therapy.

Study results, reported in the Journal of Global Oncology, showed that the mean total sunitinib starting dose was 48.1 mg, with most patients (87.6%) started on a dose of 50 mg. On average, the drug was given for 9.6 months.

The overall response rate was 20.8%, and responses lasted for a median of of 8.2 months. With a median follow-up of 7.8 months, patients had a median time to progression of 5.7 months and a median overall survival of 7.8 months. The 12- and 24-month rates of overall survival were 34.3% and 11.4%, respectively.

Although 60.9% of patients experienced adverse events, only 8.0% experienced serious adverse events. The main adverse events were gastrointestinal and hematologic, mirroring those seen previously in trials. About a third of the whole study cohort (28.7%) discontinued sunitinib therapy.

“OSSMAR is the first study in the Middle East involving several Arab countries and evaluating the use of real-time sunitinib in the treatment of mRCC. As a result, this study is of primary importance because it allows for a better assessment of the actual effectiveness and practical adverse events of sunitinib in the population in our region,” Dr. Ghosn and coinvestigators maintained.

Compared with patients in clinical trials, OSSMAR patients had poorer overall survival, possibly due to factors such as a relatively lower nephrectomy rate, real-world influences such as comorbidities, and losses to follow-up, the investigators proposed.

At the same time, the OSSMAR cohort also had a lower rate of adverse events, although this difference likely reflects less rigorous assessment of toxicity in real-world practice, they noted.

Dr. Ghosn disclosed that he has relationships with numerous pharmaceutical companies. The study did not receive any specific funding.

SOURCE: Ghosn M et al. J Glob Oncol. 2019 Oct 5. doi: 10.1200/JGO.18.00238.

First-line sunitinib therapy for metastatic renal cell carcinoma (mRCC) has somewhat differing effectiveness and safety when used in real-world practice, compared with clinical trials, suggests the OSSMAR multicenter retrospective cohort study.

Investigators led by Marwan Ghosn, MD, Hotel-Dieu de France University Hospital and Saint Joseph University, Beirut, Lebanon, analyzed outcomes among 289 patients with mRCC started on sunitinib (Sutent), an oral multitargeted tyrosine kinase inhibitor, between 2006 and 2016 at 10 centers in Africa and the Middle East region.

The patients had a median age at diagnosis of 58.7 years, and 85.8% had clear cell histology. Two-thirds had metastases at diagnosis, and 15.2% and 31.4% had favorable- and poor-risk disease, respectively, according to expanded Memorial Sloan Kettering Cancer Center criteria. Overall, 52.2% had undergone partial or radical nephrectomy, and nearly all were receiving sunitinib as first-line therapy.

Study results, reported in the Journal of Global Oncology, showed that the mean total sunitinib starting dose was 48.1 mg, with most patients (87.6%) started on a dose of 50 mg. On average, the drug was given for 9.6 months.

The overall response rate was 20.8%, and responses lasted for a median of of 8.2 months. With a median follow-up of 7.8 months, patients had a median time to progression of 5.7 months and a median overall survival of 7.8 months. The 12- and 24-month rates of overall survival were 34.3% and 11.4%, respectively.

Although 60.9% of patients experienced adverse events, only 8.0% experienced serious adverse events. The main adverse events were gastrointestinal and hematologic, mirroring those seen previously in trials. About a third of the whole study cohort (28.7%) discontinued sunitinib therapy.

“OSSMAR is the first study in the Middle East involving several Arab countries and evaluating the use of real-time sunitinib in the treatment of mRCC. As a result, this study is of primary importance because it allows for a better assessment of the actual effectiveness and practical adverse events of sunitinib in the population in our region,” Dr. Ghosn and coinvestigators maintained.

Compared with patients in clinical trials, OSSMAR patients had poorer overall survival, possibly due to factors such as a relatively lower nephrectomy rate, real-world influences such as comorbidities, and losses to follow-up, the investigators proposed.

At the same time, the OSSMAR cohort also had a lower rate of adverse events, although this difference likely reflects less rigorous assessment of toxicity in real-world practice, they noted.

Dr. Ghosn disclosed that he has relationships with numerous pharmaceutical companies. The study did not receive any specific funding.

SOURCE: Ghosn M et al. J Glob Oncol. 2019 Oct 5. doi: 10.1200/JGO.18.00238.

Patients whose clear cell renal cell carcinoma (RCC) tumors lack the cytoskeleton linker protein ezrin have a poorer prognosis, finds a single-center retrospective cohort study.

The number of small renal masses discovered incidentally is rising, and some of these tumors can or must be treated less aggressively, according to lead investigator Marcos Vinicius O. Ferrari, MD, urology division, A.C. Camargo Cancer Center, São Paulo, and coinvestigators. “Thus, it is important to identify molecular markers that have prognostic value that can assist physicians in therapeutic strategies.”

The investigators studied 575 consecutive patients who underwent radical or partial nephrectomy for clear cell RCC during 1985-2016. A single pathologist reclassified all cases and determined the most representative tumor areas for tissue immunohistochemistry for ezrin and moesin, proteins that link the actin cytoskeleton to the cell membrane and that play roles in cell adhesion, migration, and growth.

Results reported in Urologic Oncology showed that 18.3% of tumors were negative for ezrin and 2.8% were negative for moesin.

Compared with counterparts who had ezrin-positive tumors, patients with ezrin-negative tumors had higher pathologic T stage (P less than .001); were less likely to have incidentally discovered tumors (P = .007); and were more likely to have clinical stage III or IV disease (P = .012), synchronous metastasis (P less than .001), and an International Society of Urological Pathology histologic grade of 3 or 4 (P = .025).

Similarly, compared with counterparts who had moesin-positive tumors, patients with moesin-negative tumors had higher pathologic T stage (P = .025) and pathologic N stage (P = .007), and were more likely to have clinical stage III or IV disease (P = .027).

The 10-year rate of disease-specific survival was poorer for patients with ezrin-negative vs. ezrin-positive tumors (70% vs. 88%; P less than .001) and for patients with moesin-negative vs. moesin-positive tumors (68% vs. 86%; P = .065). Similarly, the 10-year rate of overall survival was poorer for patients with ezrin-negative vs. ezrin-positive tumors (68% vs. 86%; P = .001) and for patients with moesin-negative vs. moesin-positive tumors (68% vs. 84%; P = .142).

In multivariate analyses, ezrin negativity was associated with a near doubling of the risk of disease-specific survival events (hazard ratio, 1.89; 95% confidence interval, 1.11-3.20) and with a trend toward poorer overall survival. Moesin negativity was not independently associated with either outcome.

“Negative expression of ezrin was associated with major prognostic factors in renal cancer and significantly influenced tumor-related death,” Dr. Ferrari and coinvestigators summarize, noting that this aligns with the pattern seen in bladder and ovarian cancers, but contrasts with the pattern seen in head and neck, colorectal, cervical, and breast cancers.

“The exact mechanism by which negative ezrin expression influences tumor progression and survival rates is unknown,” they conclude. “We encourage further prospective studies to analyze ezrin to determine its value in the prognosis of clear cell RCC.”

Dr. Ferrari disclosed that he had no relevant conflicts of interest. The study did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sector.

SOURCE: Ferrari MVO et al. Urol Oncol. 2019 Oct 22. doi: 10.1016/j.urolonc.2019.09.011.
 

Patients whose clear cell renal cell carcinoma (RCC) tumors lack the cytoskeleton linker protein ezrin have a poorer prognosis, finds a single-center retrospective cohort study.

The number of small renal masses discovered incidentally is rising, and some of these tumors can or must be treated less aggressively, according to lead investigator Marcos Vinicius O. Ferrari, MD, urology division, A.C. Camargo Cancer Center, São Paulo, and coinvestigators. “Thus, it is important to identify molecular markers that have prognostic value that can assist physicians in therapeutic strategies.”

The investigators studied 575 consecutive patients who underwent radical or partial nephrectomy for clear cell RCC during 1985-2016. A single pathologist reclassified all cases and determined the most representative tumor areas for tissue immunohistochemistry for ezrin and moesin, proteins that link the actin cytoskeleton to the cell membrane and that play roles in cell adhesion, migration, and growth.

Results reported in Urologic Oncology showed that 18.3% of tumors were negative for ezrin and 2.8% were negative for moesin.

Compared with counterparts who had ezrin-positive tumors, patients with ezrin-negative tumors had higher pathologic T stage (P less than .001); were less likely to have incidentally discovered tumors (P = .007); and were more likely to have clinical stage III or IV disease (P = .012), synchronous metastasis (P less than .001), and an International Society of Urological Pathology histologic grade of 3 or 4 (P = .025).

Similarly, compared with counterparts who had moesin-positive tumors, patients with moesin-negative tumors had higher pathologic T stage (P = .025) and pathologic N stage (P = .007), and were more likely to have clinical stage III or IV disease (P = .027).

The 10-year rate of disease-specific survival was poorer for patients with ezrin-negative vs. ezrin-positive tumors (70% vs. 88%; P less than .001) and for patients with moesin-negative vs. moesin-positive tumors (68% vs. 86%; P = .065). Similarly, the 10-year rate of overall survival was poorer for patients with ezrin-negative vs. ezrin-positive tumors (68% vs. 86%; P = .001) and for patients with moesin-negative vs. moesin-positive tumors (68% vs. 84%; P = .142).

In multivariate analyses, ezrin negativity was associated with a near doubling of the risk of disease-specific survival events (hazard ratio, 1.89; 95% confidence interval, 1.11-3.20) and with a trend toward poorer overall survival. Moesin negativity was not independently associated with either outcome.

“Negative expression of ezrin was associated with major prognostic factors in renal cancer and significantly influenced tumor-related death,” Dr. Ferrari and coinvestigators summarize, noting that this aligns with the pattern seen in bladder and ovarian cancers, but contrasts with the pattern seen in head and neck, colorectal, cervical, and breast cancers.

“The exact mechanism by which negative ezrin expression influences tumor progression and survival rates is unknown,” they conclude. “We encourage further prospective studies to analyze ezrin to determine its value in the prognosis of clear cell RCC.”

Dr. Ferrari disclosed that he had no relevant conflicts of interest. The study did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sector.

SOURCE: Ferrari MVO et al. Urol Oncol. 2019 Oct 22. doi: 10.1016/j.urolonc.2019.09.011.
 

Patients whose clear cell renal cell carcinoma (RCC) tumors lack the cytoskeleton linker protein ezrin have a poorer prognosis, finds a single-center retrospective cohort study.

The number of small renal masses discovered incidentally is rising, and some of these tumors can or must be treated less aggressively, according to lead investigator Marcos Vinicius O. Ferrari, MD, urology division, A.C. Camargo Cancer Center, São Paulo, and coinvestigators. “Thus, it is important to identify molecular markers that have prognostic value that can assist physicians in therapeutic strategies.”

The investigators studied 575 consecutive patients who underwent radical or partial nephrectomy for clear cell RCC during 1985-2016. A single pathologist reclassified all cases and determined the most representative tumor areas for tissue immunohistochemistry for ezrin and moesin, proteins that link the actin cytoskeleton to the cell membrane and that play roles in cell adhesion, migration, and growth.

Results reported in Urologic Oncology showed that 18.3% of tumors were negative for ezrin and 2.8% were negative for moesin.

Compared with counterparts who had ezrin-positive tumors, patients with ezrin-negative tumors had higher pathologic T stage (P less than .001); were less likely to have incidentally discovered tumors (P = .007); and were more likely to have clinical stage III or IV disease (P = .012), synchronous metastasis (P less than .001), and an International Society of Urological Pathology histologic grade of 3 or 4 (P = .025).

Similarly, compared with counterparts who had moesin-positive tumors, patients with moesin-negative tumors had higher pathologic T stage (P = .025) and pathologic N stage (P = .007), and were more likely to have clinical stage III or IV disease (P = .027).

The 10-year rate of disease-specific survival was poorer for patients with ezrin-negative vs. ezrin-positive tumors (70% vs. 88%; P less than .001) and for patients with moesin-negative vs. moesin-positive tumors (68% vs. 86%; P = .065). Similarly, the 10-year rate of overall survival was poorer for patients with ezrin-negative vs. ezrin-positive tumors (68% vs. 86%; P = .001) and for patients with moesin-negative vs. moesin-positive tumors (68% vs. 84%; P = .142).

In multivariate analyses, ezrin negativity was associated with a near doubling of the risk of disease-specific survival events (hazard ratio, 1.89; 95% confidence interval, 1.11-3.20) and with a trend toward poorer overall survival. Moesin negativity was not independently associated with either outcome.

“Negative expression of ezrin was associated with major prognostic factors in renal cancer and significantly influenced tumor-related death,” Dr. Ferrari and coinvestigators summarize, noting that this aligns with the pattern seen in bladder and ovarian cancers, but contrasts with the pattern seen in head and neck, colorectal, cervical, and breast cancers.

“The exact mechanism by which negative ezrin expression influences tumor progression and survival rates is unknown,” they conclude. “We encourage further prospective studies to analyze ezrin to determine its value in the prognosis of clear cell RCC.”

Dr. Ferrari disclosed that he had no relevant conflicts of interest. The study did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sector.

SOURCE: Ferrari MVO et al. Urol Oncol. 2019 Oct 22. doi: 10.1016/j.urolonc.2019.09.011.