Chris Ryan

Some patients with kidney cancer may have an increased risk for heart-related events such as heart attacks and strokes, and more research into the link between clonal hematopoiesis and heart health may improve outcomes for these patients, an expert discussed.

Maxine Sun, a research scientist in the Lank Center for Genitourinary Oncology at Dana-Farber Cancer Institute in Boston, presented on this topic at the 2023 International Kidney Cancer Symposium.

"Cardiovascular health is becoming increasingly important for patients diagnosed with kidney cancer as we are increasing the number of therapies that are available in the first line and subsequent lines,” Sun said during the presentation. “Clonal hematopoiesis appears to have an influence on the risk of cardiovascular outcomes in patients diagnosed with kidney cancers. Therefore, there is a definite interest in trying to (further) investigate (its) role and to try to understand and characterize the specific biological pathways (of) this potential association.”

Clonal hematopoiesis refers to when a patient has too many blood cells that originate from one group, which can happen even if a person doesn't have cancer. People with clonal hematopoiesis often have TET2 mutations in their blood cells, and this can raise the chances of getting heart failure. Moreover, if there is not enough TET2 in certain immune cells called macrophages, it might make the body more prone to inflammation by increasing the levels of a molecule called interleukin 1β, which causes inflammation.

“As people age, their tissues accumulate an increasing number of somatic mutations (an alteration in DNA that occurs after conception), most of which are inconsequential. Occasionally, there will be a mutation that will arise and will confer this fitness advantage on a cell,” Sun said. “When this process happens in the hematopoietic system, a large proportion of circulating blood cells end up derived from this single mutated stem cell, and this particular outgrowth is what is termed as clonal hematopoiesis.”

Clonal hematopoiesis is a known biomarker in hematologic cancer for its development and progression, Sun noted. Additionally, findings from a 2014 study showed an increase in all-cause mortality (death from any cause) with clonal hematopoiesis in the general population as well an increased risk of incident coronary heart disease (narrowing or blockage of the coronary arteries) and ischemic stroke (when a blood clot blocks an artery that leads to the brain).

"What was surprising and unexpected about that study was that when they dug a little bit deeper, they found that the cause of death driving that increased risk of all-cause mortality wasn't actually caused by somatological cancer; it was mostly driven by incident coronary heart disease, as well as ischemic stroke,” Sun said.

Sun also delved into mosaic chromosomal alterations, which refers to changes or abnormalities in a person’s chromosomes that are not the same in all cells of the body. She noted the mosaic loss of chromosome Y has been associated with an increase in all-cause mortality, Alzheimer’s, autoimmune disease, diabetes, cancer and cardiovascular events.

In addition, autosomal (or related to the 22 pairs of numbered chromosomes found in most human cells) mosaic chromosomal alterations have been linked with an increase in hematologic cancers and all-cause mortality.

Specifically for patients with renal cell carcinoma, findings from a 2023 study published in 

Cancer Epidemiology, Biomarkers & Prevention

 by Sun and colleagues showed that those harboring mosaic chromosomal alterations had an increased risk of death due to cardiovascular disease causes and coronary artery disease causes.

Based on the current literature and data surrounding the association between clonal hematopoiesis and cardiovascular health, Sun said future research is being designed to better understand this correlation and identify patients with kidney cancer who may be at higher risk for worse cardiovascular outcomes.

"We're going to propose looking at associations of clonal hematopoiesis, whether it be clonal hematopoiesis of indeterminate potential (CHIP) or (other biomarkers), on cardiovascular outcomes in patients diagnosed with kidney cancer using institutional data, such as a Dana-Farber Cancer Institute cohort, and likely a bigger population–based cohort with genomic data. If we're able to replicate the effect across these different cohorts, it (would) strengthen the robustness of this marker,” Sun concluded.

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Although research has delved into the potential link between clonal hematopoiesis and heart-related events such as heart attacks and strokes in patients with kidney cancer, more research is needed to further understand this association. 

Genetic Mutations May Explain Heart Events in Some Patients With Kidney Cancer

Patients with extensive-stage small cell lung cancer (ES-SCLC) benefited from receiving Trodelvy (sacituzumab govitecan-hziy) as second-line treatment, according to results from a phase 2 trial presented at the 

Trodelvy is a drug that contain the monoclonal antibody sacituzumab, which binds to TROP2, a protein that can be found on some cancer cells. The drug also contains the anti-cancer drug SN-38, which could help kill cancer cells, according to National Cancer Institute.

In the 30 patients treated prior to the data cutoff date, the median age was 67 years, and 60% of patients were female. Ninety percent of patients were White, and 97% were current or former smokers.

The majority of patients had stage 4 disease at initial diagnosis (93%). Fifty percent of patients experienced a complete response or partial response to their last prior anticancer therapy and 33% had stable disease or progressive disease on their last prior therapy.

At a median follow-up of 5.1 months, the overall response rate (ORR; percentage of patients in a study who had a complete or partial response to treatment) was 37%. 

All responders experienced a confirmed partial response, and the rates of stable disease and progressive disease were 50% and 10%, respectively. The median duration of response (DOR; length of time when a tumor responds to treatment without progressing) was 6.3 months and the six-month DOR rate was 63%.

“Seventy-seven percent of patients (who underwent) post-baseline tumor assessment (experienced) some kind of tumor reduction, and 43% had a reduction of greater than 30%,” lead study author Dr. Afshin Dowlati said in a presentation of the data. “Very few patients had up-front (disease) progression on their first imaging.”

Dowlati is a professor in the department of medicine division of hematology and oncology in the school of medicine, associate director for clinical research and a member of the developmental therapeutics program at Case Comprehensive Cancer Center in Cleveland, Ohio.

Trodelvy previously received full approval from the FDA 

for the treatment of adults with unresectable locally advanced or metastatic hormone receptor-positive, HER2-negative breast cancer

 who have received endocrine-based therapy and at least two additional systemic therapies in the metastatic setting in February 2023 and 

for patients with unresectable locally advanced or metastatic triple-negative breast cancer

 who have previously received two or more systemic therapies, at least one of them for metastatic disease, in April 2021.

granted accelerated approval to the for the treatment of patients with locally advanced or metastatic urothelial cancer

 who previously received a platinum-containing chemotherapy and either PD-1 or PD-L1 inhibitor.

The ongoing, open-label, multicohort TROPiCS-03 study is evaluating Trodelvy in patients with locally advanced or metastatic solid tumors, including ES-SCLC.

To enroll in the ES-SCLC cohort, patients are required to have histologically confirmed ES-SCLC that progressed after no more than one prior line of platinum-based chemotherapy and anti-PD-1 or -PD-L1 therapy. Patients with active central nervous system metastases and/or carcinomatous meningitis are not permitted.

Investigators plan to enroll approximately 40 patients in the ES-SCLC cohort. Treatment consists of 10 mg/kg of intravenous Trodelvy on days 1 and 8 of each 21-day cycle until progressive disease or unacceptable toxicity.

Investigator-assessed ORR serves as the trial’s primary endpoint. Secondary endpoints include investigator-assessed DOR and progression-free survival (length of time during and after treatment when a patient lives with cancer but it does not worsen), overall survival (length of time from diagnosis or the beginning of treatment when patients are still alive) and safety.

Regarding safety, all patients experienced any grade treatment-emergent side effects, and 93% had treatment-emergent side effects deemed related to study treatment. Grade 3 or higher treatment-emergent side effects occurred in 60% of patients, 50% of which were related to treatment. The rates of serious treatment-emergent side effects and those related to treatment were 30% and 13%, respectively.

Twenty-seven percent of patients experienced treatment-emergent side effects that led to dose reductions. However, treatment-emergent side effects did not lead to treatment discontinuation or death in any patients.

The most common treatment-emergent side effects reported in at least 15% of patients included diarrhea, neutropenia (lower levels of white blood cells), constipation, fatigue, nausea, alopecia (hair loss), anemia, decreased appetite, vomiting, abdominal pain and hypomagnesemia (electrolyte disturbance due to low serum magnesium levels).

“These results are encouraging in (patients with) ES-SCLC. The trial is ongoing, and we will hopefully have full results early (in 2024) with a full cohort. We believe that further investigation of (Trodelvy) in SCLC is warranted,” Dowlati concluded.

Patients with extensive-stage small cell lung cancer responded well to the treatment of Trodelvy, according to preliminary results from a phase 2 trial. 

Trodelvy May Provide Benefits in Extensive-Stage Small Cell Lung Cancer

Platinum-based chemotherapy, given before chemoradiation, improved outcomes for patients with advanced cervical cancer. 

Patients with locally advanced cervical cancer saw an improvement in survival when they added platinum-based chemotherapy before chemoradiation, compared to those who had chemoradiation alone, according to findings from the phase 3 INTERLACE clinical trial.

, showed that induction (given before the main treatment to shrink cancer) chemotherapy followed by chemoradiation reduced the risk of progression or death by 35% vs chemoradiation alone. Patients treated in the experimental arm (250 patients) experienced three- and five-year progression-free survival (PFS; time from treatment until disease progression or death) rates of 75% and 73%, respectively. Those rates were 72% and 64%, respectively, for patients given chemoradiation alone (250 patients).

Furthermore, induction chemotherapy prior to chemoradiation reduced the risk of death by 39% vs chemoradiation alone. Patients in the experimental arm achieved three- and five-year overall survival (OS; time from treatment until death of any cause) rates of 86% and 80%, respectively, vs 80% and 72%, respectively, for those given chemoradiation alone.

“Induction chemotherapy with weekly paclitaxel and carboplatin delivered immediately before chemoradiation should be considered the new standard in locally advanced cervical cancer and is feasible across diverse health care settings,” lead study author Mary McCormack, of University College London in the United Kingdom, said in a presentation of the data.

For more than 20 years, chemoradiation has served as the standard of care for patients with locally advanced cervical cancer; however, up to 30% of patients still relapse and die from metastatic disease.

INTERLACE enrolled newly diagnosed patients with stage IB1 (node positive), 1B2, 2, 3B or 4A squamous, adeno, or adenosquamous cervical cancer. Patients needed to be fit for chemotherapy and radical radiotherapy and have adequate renal, liver and bone marrow function.

Patients were not allowed to have nodes above aortic bifurcation on imaging and prior pelvic radiation was not permitted.

Investigators randomly assigned patients to receive induction chemotherapy followed by chemoradiation or chemoradiation alone. In the experimental arm, patients received induction therapy once per week for six weeks before beginning chemoradiation in week 7. In both arms, chemoradiation consisted of 40 mg/m2 of cisplatin once every week for five weeks plus external beam radiation (EBRT) ranging from 40 Gy to 50.4 Gy given in 20 to 28 fractions. Patients also received brachytherapy at a minimum total of biologically equivalent doses of 78 Gy. It was recommended that patients receive image-guided adaptive brachytherapy.

The overall treatment time of chemoradiation was not to exceed 50 days and all participating centers were required to undergo radiotherapy quality assurance.

Patients were stratified by site; stage; nodal status; 3D-conformal vs intensity-modulated radiotherapy (IMRT); 2D vs 3D brachytherapy; tumor size; and squamous cell carcinoma vs other.

PFS and OS served as the trial’s co-primary end points. Key secondary end points included side effects, pattern of relapse, quality of life and time to subsequent treatment.

Baseline characteristics showed that the median age was 46 years (range, 26-78) in the experimental arm and 46 years (range, 24-78) in the control arm. The majority of patients had an ECOG performance status of 0, meaning that they could perform all of their daily tasks with no assistance (86% and 88% for the experimental and control arms, respectively), were from the United Kingdom (76% and 76%), had FIGO (2008) stage 2B disease (71% and 70%), had squamous histology (82% and 82%) and were node negative (58% and 57%). The median longest tumor diameter was 4.8 cm (range, 1.3-13.5) and 4.9 cm (range, 1.8-12.8), respectively.

In the experimental arm, 84% of patients completed six cycles of induction chemotherapy and 92% completed at least five cycles. The primary reasons for receiving less than six cycles were side effects (11%; 29 patients), including blood-related side effects (nine patients), non-hematologic side effects (17 patients) and both (three patients); and patient withdrawal or other (4%; 10 patients). The median interval between induction chemotherapy and radiotherapy was seven days (range, 5-53).

During chemoradiation, 68% of patients in the experimental arm completed all five cycles of cisplatin and 85% completed at least four cycles. Those rates were 79% and 90%, respectively, in the control arm. In the experimental arm, the primary reasons for receiving less than five cycles of cisplatin were side effects leading to discontinuation (27%), including hematologic side effects (34 patients), non-hematologic side effects (20 patient) and both (14 patients); and other (5%). For the chemoradiation alone arm, the main reasons for not completing five cycles of cisplatin were side effects leading to discontinuation (13%), including hematologic side effects (four patients), non-hematologic side effects (25 patients) or both (four patients); and other (8%).

Ninety-seven percent of patients in the experimental arm and 92% of patients in the control arm received EBRT. In the experimental arm, the rates of IMRT and 3D-conformal radiation were 42% and 58%, respectively; those rates were 40% and 60%, respectively, for the control arm. The majority of patients in the experimental arm (98%) and control arm (97%) received brachytherapy consisting of 2D point A (19% and 22% for the experimental and control arms, respectively), 3D point A (51% and 48%) and 3D HRCTV D90 (30% and 30%).

“Adherence to standard chemoradiation was high in both arms and reflected best clinical practice,” McCormack noted.

The median overall treatment time was 45 days (range, 36-70) in the experimental arm and 45 days (range, 37-88) in the control arm.

In the induction chemotherapy/chemoradiation arm, the rates of total local/pelvic relapses and total distant relapses were 16% and 12%, respectively; 10% of patients had local/pelvic relapses, 6% had distant relapses and 6% had both local/pelvic and distant relapses. In the chemoradiation alone arm, the rates of total local/pelvic relapses and total distant relapses were 16% and 20%, respectively; 8% of patients had local/pelvic relapses, 12% had distant relapses and 8% had both.

Regarding safety, any-grade side effects occurred in 99% of patients in the induction chemotherapy/chemoradiation arm and 95% of patients in the chemoradiation arm. The rates of grade 3/4 side effects were 59% and 48%, respectively.

Any-grade hematologic side effects were reported in 30% of patients in the experimental arm and 13% of patients in the control arm. The most common any-grade hematologic side effect included neutropenia (19% and 5% for the experimental and control arms, respectively), anemia (5% and 4%) and thrombocytopenia (5% and 2%). The rates of any-grade non-hematologic side effects were 44% and 43%, respectively, and the most common included abdominal/pelvic pain (5% and 7%); diarrhea (8% and 12%); fatigue, muscle weakness, or joint pain (11% and 6%); and infection (6% and 5%).

“As anticipated, hematologic toxicity was greater in the experimental arm, but this did not compromise the delivery of chemotherapy,” McCormack concluded.

Platinum-based chemotherapy, when administered before chemoradiotherapy, improved progression-free and overall survival for patients with locally advanced cervical cancer. 

Chemo Before Chemoradiation Boosts Cervical Cancer Outcomes

Patients with newly diagnosed, high-risk multiple myeloma experienced high rates of minimal residual disease (MRD) negativity with treatment with the combination of Sarclisa (isatuximab-irfc), Kyprolis (carfilzomib), Revlimid (lenalidomide) and Isa-KRd (dexamethasone), irrespective of transplant status, according to data from an interim analysis of the phase 2 GMMG-CONCEPT trial.

Findings presented at the 2023 International Myeloma Society Annual Meeting showed that among the 93 evaluable transplant-eligible patients treated in arm A, 67.7% (63 patients) were MRD negative at the end of consolidation. Additionally, 3.2% (3 patients) were MRD positive, MRD assessment was not done or missing for 2.2% (2 patients) and 27% (25 patients) had not reached the end of consolidation.

MRD is an assessment of malignant cells remaining in a patient’s body following treatment. When a patient reaches MRD negative status, that means the number of malignant cells in their body is below the threshold of detection.

In the 24 evaluable transplant-ineligible patients in arm B, the MRD-negativity rate at the end of consolidation was 54.2% (13 patients). No patients were MRD positive, and no patients had MRD data status missing or not completed. Notably, 45.8% (11 patients) had not reached the end of consolidation.

Regarding MRD negativity, 81.8% (81) of transplant-eligible patients and 69.2% (18) of transplant-ineligible patients achieved MRD negativity at any point. MRD negativity was sustained for at least one year in 62.6% (62) and 46.2% (12) of transplant-eligible and -ineligible patients, respectively. Sustained MRD negativity for at least six months was observed in 72.7% (72) and 53.8% (14) of transplant-eligible and -ineligible patients, respectively.

“Isa-KRd induces high rates of MRD-negative remissions in these (patients with) high-risk, newly diagnosed myeloma, (including those who are) transplant eligible and ineligible,” Dr. Lisa Leypoldt said in a presentation of the data. Leypoldt is a clinician scientist and research fellow at University Medical Center Hamburg-Eppendorf in Germany. She is also a member of the department of medical oncology at Dana-Farber Cancer Institute and the department of medicine at Harvard Medical School, both in Boston.

The nonrandomized, open-label, investigator-initiated GMMG-CONCEPT trial enrolled patients with newly diagnosed, high-risk multiple myeloma. Patients in arm A were required to be transplant eligible and no older than 70. Patients in arm B could be transplant ineligible or older than 70.

In arm A, patients underwent six 28-day cycles of Isa-KRd induction therapy, consisting of 10 mg/kg of Sarclisa on days one, eight, 15 and 22 in cycle one, then on days one and 15 in cycle two and beyond; 20 mg/m of Kyprolis on days one and two of cycle one, then 36 mg/m on days eight, nine, 15 and 16 of cycle one, then 36 mg/m on days one, two, eight, nine, 15 and 16 in cycle two and beyond; 25 mg of Revlimid on days one to 21 of all cycles; and 40 mg of dexamethasone on days one, eight, 15 and 22 of all cycles. Stem cell mobilization occurred after the third cycle, and following the completion of induction, patients proceeded to high-dose therapy and autologous stem cell transplant (ASCT). Patients then received four cycles of Isa-KRd as consolidation, then 26 cycles of Isa-KRd as maintenance.

In arm B, patients received eight cycles of Isa-KRd induction, followed by four cycles of Isa-KRd consolidation and 26 cycles of Isa-KR maintenance.

The rate of MRD negativity following consolidation served as the primary end point. Progression-free survival (PFS, the time following treatment that a patent’s disease does not spread or get worse) was a key secondary end point. Key tertiary end points included overall response rate (patients whose disease responded partially or completely to treatment), overall survival (OS) and safety.

The median age was 58 in arm A (99 patients) and 74 in arm B (26 patients). Among all patients in both arms, the majority were female (52.8%), had an ECOG performance status of 0 or 1 (82.4%), had ISS stage 2 disease (52.8%) and had Second Revision ISS stage 3/4 disease (52.8%).

Among all patients, 61.6% had one high-risk characteristic, and 30.4% had at least two high-risk characteristics. Additionally, 25.6% of patients had elevated lactate dehydrogenase (LDH) above the upper limit of normal and 33.6% of patients received one prior cycle of therapy before enrollment. The median plasma cell infiltration was 60%.

Additional data from arm A showed that at the end of induction, the complete response (CR, meaning no traces of disease were found after treatment) or better rate was 48%. The CR or better rates at the end of ASCT and end of consolidation were 65% and 73%, respectively. A best response of CR or better was observed in 72.7% of patients.

In arm B, the CR or better rates at the end of induction, intensification and consolidation were 38%, 38% and 58%, respectively. A best response of CR or better was reported in 57.7% of patients.

The median PFS and OS were not met in either arm and the study met its PFS end point in both arms. In arm A, the one-, two- and three-year PFS rates were 84.5%, 77.2% and 68.8%, respectively. The one-, two- and three-year OS rates were 90.7%, 84.4% and 72.8%, respectively.

In arm B, patients experienced a one-year PFS rate of 75.1%, a two-year PFS rate of 62.6% and a three-year PFS rate of 58.4%. The one-, two- and three-year OS rates were 83.5%, 71.0% and 71.0%, respectively.

Findings also showed that elevated LDH, the presence of at least two high-risk characteristics, and 17p deletions were associated with impaired survival.

“Most strikingly, an elevated baseline LDH did show very significantly impaired survival,” Leypoldt said.

Investigators also conducted an analysis of PFS by MRD status for patients in arm A, and showed that achievement of MRD negativity conferred a prognostic PFS benefit.

“We could clearly see that the achievement of MRD negativity did confer a significant prognostic PFS benefit,” Leypoldt concluded.

Treatment with the combination of Sarclisa, Kyprolis, Revlimid and Isa-KRd generated high rates of minimal residual disease negativity in patients with newly diagnosed, high-risk multiple myeloma, irrespective of transplant status.

Chris Ryan

Genetic Mutations May Explain Heart Events in Some Patients With Kidney Cancer

Trodelvy May Provide Benefits in Extensive-Stage Small Cell Lung Cancer

Chemo Before Chemoradiation Boosts Cervical Cancer Outcomes

Patients With Newly Diagnosed, High-Risk Myeloma See High MRD Negative Rates With Isa-KRd

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