Incurable Solid Tumors Research Articles

Primary treatment modification strategies among older adults with advanced cancer.

1512 Background: Primary treatment modification (PTM; any change in dose or agents of the planned chemotherapy regimen from the standard guidelines) is a common therapeutic approach among older adults with advanced cancer due to their geriatric vulnerabilities. However, strategies to employ these modifications are understudied. This study compares a PTM strategy based on Geriatric Assessment (PTM-GA) intervention vs. usual care strategy based on oncologist’s impression (PTM-UC) on treatment tolerability in older adults with advanced cancer starting new chemotherapy regimens. Methods: In this subgroup analysis of the GAP 70+ study (NCT02054741; PI: Mohile), we included patients aged ≥ 70 with incurable solid tumors who initiated a chemotherapy course with PTM (n=298). For the first (PTM-GA) group, PTM was guided by GA results and recommendations while for the second (PTM-UC) group, PTM was guided by the treating oncologist's estimate only. Tolerability outcomes were assessed within 3 months of treatment and included: 1) any grade 3-5 clinician-rated toxicity according to National Cancer Institute Common Toxicity Criteria; 2) subsequent dose reduction; 3) Activity of Daily Living (ADL) decline; 4) unplanned hospitalization. We used multivariable, cluster-weighted generalized estimating equations models to examine the association of PTM-GA vs. PTM-UC and outcomes adjusting for confounders. Results: Mean age was 77 years. The most common cancer types were gastrointestinal (37%) followed by lung cancer (26%). PTM-GA versus PTM-UC was associated with reduced risk of grade 3-5 toxicity (relative risk (RR)= 0.77, 95% CI, 0.61- 0.90) and subsequent dose reduction (RR, 0.46; 95% CI, 0.29-0.73). Point estimates suggest that patients with PTM-GA may have a lower risk of unplanned hospitalization but results did not reach statistical significance (RR, 0.69; 95% CI, 0.46–1.02). PTM-GA vs. PTM-UC was not associated with ADL decline (RR, 1.05; 95% CI, 0.74–1.49). Conclusions: Older patients with advanced cancer who had PTM guided by GA recommendations had improved treatment tolerability compared to those who PTM based on oncologist’s estimate only. Integrating GA into treatment dosing decisions may lead to improved outcomes in this vulnerable population.

Quantification of treatment-related time toxicity in patients with advanced stage cancer.

12137 Background: Treatment-related Time Toxicity (TrTT) in cancer patients is a recently proposed metric to describe the burden of time spent in pursuing medical care, including office/hospital visits, side effect management, lab tests, imaging scans, and travel time. Time toxicity is a valuable concept in patient-centered shared-decision making, especially in the palliative management of end-stage cancer patients with limited life expectancy. Despite tremendous progress in cancer treatment, most of the guideline-recommended treatment options convey short survival benefits of around 3-6 months when compared to supportive care. While medication toxicities are meticulously reviewed with patients, the cumulative burden and impact of time are rarely included in the discussion, partly due to the lack of standardized measurement of TrTT, and the absence of data from clinical trials. Thus, there is a compelling need for the quantification of time toxicity to guide clinical practice and patient preference. Methods: This was an observational analysis of the time toxicity from palliative treatment for patients with incurable solid tumors at a regional safety-net oncology office that focuses on underserved communities. Time toxicity is calculated as the number of days a patient spent with any healthcare-related encounters during a 3-month period from our medical record system. Results: The median age of the total 94 included patients was 57. 54% of the population were Hispanic. The ratios for mild, moderate, and severe time toxicity were 38%, 44%, and 18%, respectively. Immunotherapy was associated with significantly less time toxicity (TrTT = 8.5 days, 95% CI = 6.3-9.7) compared to chemotherapy (26.3 days, 95% CI = 18.3-34.4, P < 0.001), while targeted therapy (13.4, 95% CI = 7.0-19.8, P = 0.01) and hormone therapy (11.9, 95% CI = 4.1-19.7, P < 0.01) also has lower TrTT than chemotherapy. Patients with a worse performance status (ECOG PS 3-4, 30.1 days, 95% CI = 18.3-41.9) experienced higher time toxicity than fitter patients (PS 0-2, 16.7 days, 95% CI = 13.2-20.2, P < 0.05). Among different cancer types, gastrointestinal malignancies were associated with the highest time toxicity with average TrTT of 30.2 days/3 months (95% CI =22.5-37.2). Conclusions: This is the first comprehensive study to quantify real-world Treatment-Related Time Toxicity across multiple cancer and therapy types in an underserved population. We found 18% of patients with incurable solid malignancies experienced severe time toxicity (> 1 in 3 days). Higher TrTT was associated with cytotoxic chemotherapies, GI malignancies, and poor performance status. Time toxicity should be taken into account with other quality-of-life outcomes in treatment pathways and patient-centered oncology care.

Development and Evaluation of a Multisource Approach to Extend Mortality Follow-Up for Older Adults With Advanced Cancer Enrolled in Randomized Trials.

Mortality data can complement primary end points from cancer clinical trials. Yet, identifying deaths after trial completion is challenging, as timely and comprehensive vital status data are unavailable in the United States. We developed and evaluated a multisource approach to capture death data after clinical trial completion. Individuals age 70 years and older with incurable solid tumors or lymphoma and ≥1 aging-related condition were enrolled from October 2014 to March 2019 (ClinicalTrials.gov identifier: NCT02107443 and NCT02054741). Participants provided consent to link trial information to external sources. We developed a stepped approach for extended death capture using (1) active trial follow-up up to 1 year, (2) linkage to the National Death Index (NDI), and (3) obituary searches, thus generating a 5-year survival curve. In a random sample of 50 participants who died during trial follow-up, we estimated sensitivity of death data using NDI and obituary sources and computed survival times by data source. The two trials enrolled 1,169 participants; mean age was 76 years; 46% were female; and gastrointestinal cancer (30%) and lung cancer (26%) were the most common cancer types. Across data sources, maximum follow-up was >7 years; 5-year survival was 18%. In total, there were 841 deaths: 603 identified during trial follow-up; 199 from the NDI; and 39 from obituary searches. The sensitivity for death capture was 92% for the NDI and 94% for the obituary searches compared with the trial data, and computed survival times were similar across data sources. Extending clinical trial mortality follow-up through linkage with external data sources was feasible and accurate. Future cancer clinical trials should collect necessary consent and patient identifiers for vital status linkages that can enhance understanding of longer-term outcomes.

Association of sarcopenia and treatment tolerability in older adults with advanced cancer: Secondary analysis of a nationwide NCI Community Oncology Research Program (NCORP) randomized clinical trial.

12038 Background: Sarcopenia (sarc) is defined by reduced muscle function paired with low muscle mass or quality. Sarc is common in older adults, but the relationship between sarc and treatment tolerability in older patients (pts) with cancer has not been established. This secondary analysis of our nationwide University of Rochester NCORP Research Base randomized trial examines whether pre-treatment sarc was associated with treatment toxicity and survival in older pts with advanced cancers. Methods: Pts aged 70 and older with incurable solid tumors and lymphoma initiating a new high-risk systemic treatment were enrolled in GAP70+ (NCT02054741). GAP70+ was a cluster randomized trial evaluating whether a geriatric assessment intervention can reduce cancer treatment toxicity. This secondary analysis included 161 pts with baseline computed tomography (CT) scans and physical function testing. Sarc was defined as low muscle strength (5-time Chair Stand Test > 16.7 seconds) with reduced muscle mass (BMI and sex-specific cutoffs, cm/m2) or low muscle quality (Hounsfield units [HU] average radiodensity thresholds) utilizing validated cross-sectional CT imaging metrics. Sarc was defined as severe in presence of reduced physical performance (Timed-Up-And-Go > 13.5 seconds). We evaluated if the proportion of pts experiencing any grade 3-5 toxicity in the first 3 months of treatment using Common Terminology Criteria for Adverse Events (CTCAE) V4.0 was higher in those with sarc than those without sarc. Multivariate logistic regression was used to further explore this relationship. Multivariate Cox regression analysis was performed to evaluate the association of sarc and severe sarc with 1-year survival. Results: Mean age of the 161 participants included in this cohort was 76.6 years and 60.9% of were male; over half had gastrointestinal (34.8%) or lung cancer (23.6%). Sarc was found in 91 of 161 (56.5%) pts; 54 had severe sarc. Pts with sarc did not experience significantly more grade 3-5 toxicity compared to those without sarc (79.1% vs. 71.4%, p = 0.26). However, pts with sarc experienced more grade 3-5 non-hematologic toxicity (63.7% vs. 44.3%, p = 0.01) on univariate and multivariate analysis (OR 2.2, CI 1.1-4.5, p = 0.02). The association between sarc and worse survival at 1-year was not statistically significant (OR 1.5, CI 0.9-2.4, p = 0.13). Those with severe sarc did demonstrate significantly worse 1-year survival on multivariate analysis (HR 1.8, CI 1.1-2.9, p = 0.02). Conclusions: Older pts with cancer and sarc were more likely to suffer serious non-hematologic toxicity from cancer treatment. Furthermore, those with severe sarc had significantly worse survival. Evaluation for sarc before initiating treatment in older adults could help oncologists identify pts at higher risk of toxicity and poor survival. Clinical trial information: NCT02054741 .

Peaceful acceptance of illness among older adults with cancer.

12045 Background: Greater illness acceptance is associated with lower levels of psychological distress and higher rates of completion of advance care planning in adults with advanced cancer. However, studies on factors associated with illness acceptance among older adults with advanced cancer are limited and historically have not explored its relationship with caregiver or physician characteristics, despite the important role caregivers and oncologists play in patient illness acceptance. We aimed to evaluate the associations of patient, caregiver, and physician-related factors with illness acceptance among older adults with cancer. Methods: We utilized data from a national geriatric assessment cluster-randomized trial (NCT 02054741; PI: Mohile; funding NCI UG1CA189961). We recruited patients aged 70 years or over with stage III or IV incurable solid tumors or lymphoma and at least one geriatric assessment domain impairment as well as their caregivers. Illness acceptance was assessed using the 5-item Peace, Equanimity, and Acceptance in the Cancer Experience (PEACE) questionnaire (range 5-20). Higher PEACE score indicates greater illness acceptance. Multiple linear regression was used to assess the associations of patient, caregiver, and physician-related variables with PEACE. Variables included patient sociodemographic factors, geriatric assessment variables, and estimated life expectancy; caregiver sociodemographic variables, anxiety, depression, and physical function; and oncologist years in practice and comfort with geriatrics. Results: We included 333 patient-caregiver dyads; mean age (SD) of patients and caregivers, respectively, were 76.8 (5.4) and 66.6 (12.1). Approximately 27%, 26%, and 16% of patients had lung, gastrointestinal, and genitourinary cancers, respectively. Mean PEACE score was 17.4 (2.5), indicating relatively high illness acceptance (Table). On regression analysis, patient psychological impairment domain (including both anxiety and depression) (B=-0.89; p>0.01), patient’s lower estimated life expectancy (≤1 vs. >5 years, B=-1.19, p=0.02), and lower caregiver education attainment (≤high school vs. college; B=-0.86; p<0.01) were associated with a lower illness acceptance. No physician variables were associated with PEACE. Conclusions: A better understanding of illness acceptance and its associated factors can facilitate patient-caregiver dyadic interventions to improve illness acceptance. [Table: see text]

1294TiP Olanzapine for anorexia in cancer cachexia patients: A placebo-controlled randomized trial

Cancer-associated cachexia (CAC) is a complex multifactorial syndrome. Various antipsychotics have been associated with weight gain, especially olanzapine (OLZ) which is suggested to have a role in the management of CAC. It remains unclear whether OLZ has an ameliorating effect on cancer patients’ anorexia, even when those patients exhibit no nausea or vomiting. Given the potential effect of OLZ on CAC and the mixed findings regarding this subject, the current trial aims at evaluating the efficacy of OLZ as a monotherapy in incurable cancer patients with cancer cachexia-associated anorexia. This is a single institution double-blind placebo-controlled randomized clinical trial. One hundred and sixty-four patients are being recruited from December 2021. The trial includes adult patients with incurable solid tumor, CAC, loss of appetite (≥4 score on the 0 to 10 loss of appetite scale of the Edmonton Symptom Assessment System [ESAS]), Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 and a predicted survival >3 months. Causes for exclusion are: highly emetogenic chemotherapy, antipsychotic or appetite stimulant administration, nausea or vomiting score >3 on the 0 to 10 scale of the ESAS, weight gain for a known cause (e.g., oedema) or central nervous system disease. Participants will be 1:1 randomized to the intervention arm (OLZ 5 mg tablet once a night for 28 days) or the control arm (placebo tablet once at night for 28 days). The primary endpoint is the change in the loss of appetite score on the 0 to 10 scale of the ESAS from day 0 to day 7 of treatment. The secondary endpoints include the change in loss of appetite score from day 0 to days 14, 21 and 28 and the change in quality of life, handgrip strength, body mass index, body weight, lean body mass, fatigue and c-reactive protein level from day 0 to day 28. NCT05243251. Cairo University.

Portuguese Consensus Recommendations for Next-Generation Sequencing of Lung Cancer, Rare Tumors, and Cancers of Unknown Primary Origin in Clinical Practice.

Next-generation sequencing (NGS) has been implemented in clinical oncology for diagnosis, prognosis, and therapeutic guidance. Among the various NGS applications in molecular oncology, we focused on the following topics: laboratory standards for targeted gene panels (somatic mutations) and therapeutic guidance based on NGS of lung cancer and rare cancers, namely sarcomas and cancers of unknown primary. Multiple quality control checkpoints should be addressed in the pre-analytical phase for good quality and interpretation of the NGS results. It includes tumor size and cellularity, tissue processing and decalcification, tumor fraction, tumor viability, fixatives, and staining. Communication between clinicians and laboratory support is also essential. In lung cancer, all patients with non-squamous non-small cell lung cancer should be tested with a NGS panel, and it should include not only genes with approved targeted therapies (ALK, BRAF, EGFR, MET, NTRK, RET, and ROS1) but also genes with potentially actionable genomic alterations (HER2 and KRAS). Since there is a lack of extensive knowledge regarding the use of NGS in rare tumors performing comprehensive genomic profiling, NGS panels to better manage the disease are recommended. Moreover, other patients with other incurable solid tumors may benefit from being included in biomarker-driven clinical trials. Multidisciplinary tumor boards with the participation of experts with the ability to integrate genomic profiling data are essential to tailor the best strategy for each patient. Considering that there are no national guidelines, this article aims to guide laboratory and clinical practice for the use of NGS in the context of lung cancer, rare tumors, and cancer of unknown primary in Portugal.

Abstract CT123: A phase 2 study of the MDM2 inhibitor milademetan in patients with TP53-wild type and MDM2-amplified advanced or metastatic solid tumors (MANTRA-2)

Abstract Background: Murine double minute 2 (MDM2) is a potent negative regulator of the tumor suppressor p53. MDM2 induces degradation of p53 and promotes tumorigenesis in solid tumors, and preclinical models have shown that inhibition of MDM2 can restore p53 tumor suppressor activity in TP53-wild type (WT), MDM2-amplified tumors. We performed a mutual exclusivity analysis of patients with solid tumors (n=42,125; AACR Project GENIE) and found that the frequency of co-occurring TP53 mutations decreased with increasing MDM2 copy number. An MDM2 copy number of 12 was chosen as the threshold. An estimated 1.1% of solid tumors meet this molecular criteria, excluding glioblastomas, de-differentiated liposarcomas, and intimal sarcomas where this signature is enriched. Milademetan (RAIN-32), an oral, selective MDM2 inhibitor, inhibits growth of TP53-WT/MDM2-amplified cell lines and patient-derived xenograft models from varying tumor types. Furthermore, tumor regression was observed in 3/3 non-liposarcoma patients with MDM2 copy number >12 in a phase 1 trial of milademetan. MANTRA-2 (RAIN-3202) is a phase 2, multicenter, single-arm, open-label, basket trial designed to evaluate the efficacy or clinical benefit of milademetan in TP53-WT solid tumors with MDM2 amplification (copy number ≥12). Methods: Eligible patients must be ≥18 years of age with histologically and/or cytologically confirmed locally advanced, incurable or metastatic solid tumors refractory to standard therapy. Local testing demonstrating TP53 WT and MDM2 amplification is required, defined as a MDM2 copy number ≥12 or 6-fold increase. Patients with well-differentiated/de-differentiated liposarcomas, intimal sarcomas, or primary central nervous system tumors are excluded. Prior treatment with an MDM2 inhibitor is not permitted. Patients receive milademetan 260 mg orally once daily on Days 1-3 and 15-17 of a 28-day cycle. Tumor response is evaluated by RECIST v1.1 at Weeks 8, 16, 24, and 32, and then every 12 weeks. Primary endpoint: objective response rate. Secondary endpoints include: duration of response; progression-free survival; growth modulation index; disease control rate; overall survival; safety; health-related quality of life scores. Exploratory endpoints include: biomarkers in blood and/or tumor tissue; pharmacodynamics; pharmacokinetics. Enrollment of 65 patients is planned to ensure that 57 patients have centrally confirmed TP53 WT and MDM2 copy number ≥12. The trial opened in November 2021 and is actively enrolling patients. ClinicalTrials.gov: NCT05012397. Citation Format: Ecaterina I. Dumbrava, Glenn J. Hanna, Gregory M. Cote, Thomas E. Stinchcombe, Melissa L. Johnson, Christopher T. Chen, Siddhartha H. Devarakonda, Naisargee Shah, Feng Xu, Robert C. Doebele, Mrinal M. Gounder. A phase 2 study of the MDM2 inhibitor milademetan in patients with TP53-wild type and MDM2-amplified advanced or metastatic solid tumors (MANTRA-2) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT123.

Next-generation sequencing (NGS): How often is testing performed too late?

6575 Background: With the emergence of precision oncology over a decade ago, NGS and the utility of targeted therapies have readily been incorporated into standard-of-care (SOC) practices. Still in many cases, NGS is only done after patients (pts) have failed several lines of treatment and/or their performance status (PS) has declined. We aim to further evaluate the timing of NGS as it pertains to patients’ clinical disease course. Methods: All patients with incurable solid tumor malignancies undergoing NGS testing at our institution from January 2020 to December 2021 were included. Our genomics team (including medical oncologists, bioinformaticians, and a genetic counselor) routinely reviews all NGS results on a biweekly basis to assess for actionable alterations that would be eligible for on-label therapy (tx), clinical trials, and/or off-label consideration for targeted tx that has been FDA approved in another histology. Baseline demographics for pts such as age and gender, in addition to oncologic history, performance status, and date of death were collected via in-depth chart review utilizing the electronic medical record system. Results: We reviewed NGS results for 1767 pts, of which 1455 (82.4%) had genomic tumor board (GTB) recommendations for an actionable alteration. Of the 1767 pts, 33 were deceased at time of results review. The most common histology amongst the deceased were lower gastrointestinal tract (24.2%), genitourinary (18.2%), lung and pancreatic (15.2% each). At time NGS was ordered, 11 (33.3%) had received no prior tx, 8 (24.2%) had received one line of systemic tx, and 14 (42.4%) had received 2 or more lines of systemic tx. The average time from when NGS was ordered to results being reported was 17.9 days. The median time from when NGS was ordered to date of death was 26 days. At time NGS was ordered, 39% of pts had an ECOG PS of 0-1, 34% had an ECOG PS of 2, and 27% had an ECOG PS of 3-4. All 33 of these pts had actionable alterations for which GTB recommendations were made. All of these pts were matched to at least one clinical trial while 21.9% were recommended for an on-label tx as well. 54.5% of these pts were receiving care at regional facilities while 45.5% were receiving care at main campus. Conclusions: In our experience, all patients who were deceased at time of NGS review had an actionable alteration, for which there was a treatment recommendation made. In a rapidly evolving field where novel targeted therapies are on the rise, the rate of actionability is increasing, and NGS is now SOC, we are still seeing pts get testing done only after the receipt of multiple lines of systemic tx and/or once their PS has declined. These pts may benefit from earlier NGS testing, which would have opened up additional therapies earlier on in the course of their disease, when their PS was also likely to be more optimal. Further work is necessary to determine if early NGS testing makes a significant clinical impact on survival.

Association of Prognostic Understanding With Health Care Use Among Older Adults With Advanced Cancer

A poor prognostic understanding regarding curability is associated with lower odds of hospice use among patients with cancer. However, the association between poor prognostic understanding or prognostic discordance and health care use among older adults with advanced incurable cancers is not well characterized. To evaluate the association of poor prognostic understanding and patient-oncologist prognostic discordance with hospitalization and hospice use among older adults with advanced cancers. This was a post hoc secondary analysis of a cluster randomized clinical trial that recruited patients from October 29, 2014, to April 28, 2017. Data were collected from community oncology practices affiliated with the University of Rochester Cancer Center National Cancer Institute Community Oncology Research Program. The parent trial enrolled 541 patients who were aged 70 years or older and were receiving or considering any line of cancer treatment for incurable solid tumors or lymphomas; the patients' oncologists and caregivers (if available) were also enrolled. Patients were followed up for at least 1 year. Data were analyzed from January 3 to 16, 2021. At enrollment, patients and oncologists were asked about their beliefs regarding cancer curability (100%, >50%, 50%, <50%, and 0%; answers other than 0% reflected poor prognostic understanding) and life expectancy (≤6 months, 7-12 months, 1-2 years, 2-5 years, and >5 years; answers of >5 years reflected poor prognostic understanding). Any difference between oncologist and patient in response options was considered discordant. Outcomes were any hospitalization and hospice use at 6 months captured by the clinical research associates. Among the 541 patients, the mean (SD) age was 76.6 (5.2) years, 264 of 540 (49%) were female, and 486 of 540 (90%) were White. Poor prognostic understanding regarding curability was reported for 59% (206 of 348) of patients, and poor prognostic understanding regarding life expectancy estimates was reported for 41% (205 of 496) of patients. Approximately 60% (202 of 336) of patient-oncologist dyads were discordant regarding curability, and 72% (356 of 492) of patient-oncologist dyads were discordant regarding life expectancy estimates. Poor prognostic understanding regarding life expectancy estimates was associated with lower odds of hospice use (adjusted odds ratio, 0.30; 95% CI, 0.16-0.59). Discordance regarding life expectancy estimates was associated with greater odds of hospitalization (adjusted odds ratio, 1.64; 95% CI, 1.01-2.66). This study highlights different constructs of prognostic understanding and the need to better understand the association between prognostic understanding and health care use among older adult patients with advanced cancer. ClinicalTrials.gov Identifier: NCT02107443.

The do-not-resuscitate-like (DNRL) order, a medical directive for limiting life-sustaining treatment in the end-of-life care of children with cancer: experience of major cancer center in Brazil.

In the last few decades, interest in palliative care and advance care planning has grown in Brazil and worldwide. Empirical studies are needed to reduce therapeutic obstinacy and medical futility in the end-of-life care of children with incurable cancer. The aim of this study was to investigate the effects of do-not-resuscitate-like (DNRL) orders on the quality of end-of-life care of children with incurable solid tumors at a cancer center in Brazil. A retrospective observational cohort study of 181 pediatric patients with solid tumors followed at the Pediatric Oncology Department of the Brazilian National Cancer Institute, Rio de Janeiro, Brazil, who died due to disease progression from 2009 to 2013. Medical records were reviewed for indicators of quality of end-of-life care, including overtreatment, care planning, and care at death, in addition to documentation of the diagnosis of life-limiting illness and the presence of a DNRL order. Data were summarized using descriptive statistics. Univariate and multivariate logistic regression analyses were used to examine associations between demographics, disease, treatment, and indicators of end-of-life care with a DNRL order. A documented DNRL order was associated with lower odds of dying in the intensive care unit or emergency room (80%), dying within 30days of endotracheal tube placement (80%), or cardiopulmonary resuscitation (CPR) administration at the time of death (96%). Placement of DNRL orders early in the disease process is critical in reducing futile treatment in pediatric patients with incurable cancer.

Evaluation of geriatric assessment and management on the toxic effects of cancer treatment (GAP70+): a cluster-randomised study

Older adults with advanced cancer are at a high risk for treatment toxic effects. Geriatric assessment evaluates ageing-related domains and guides management. We examined whether a geriatric assessment intervention can reduce serious toxic effects in older patients with advanced cancer who are receiving high risk treatment (eg, chemotherapy). In this cluster-randomised trial, we enrolled patients aged 70 years and older with incurable solid tumours or lymphoma and at least one impaired geriatric assessment domain who were starting a new treatment regimen. 40 community oncology practice clusters across the USA were randomly assigned (1:1) to the intervention (oncologists received a tailored geriatric assessment summary and management recommendations) or usual care (no geriatric assessment summary or management recommendations were provided to oncologists) by means of a computer-generated randomisation table. The primary outcome was the proportion of patients who had any grade 3-5 toxic effect (based on National Cancer Institute Common Terminology Criteria for Adverse Events version 4) over 3 months. Practice staff prospectively captured toxic effects. Masked oncology clinicians reviewed medical records to verify. The study was registered with ClinicalTrials.gov, NCT02054741. Between July 29, 2014, and March 13, 2019, we enrolled 718 patients. Patients had a mean age of 77·2 years (SD 5·4) and 311 (43%) of 718 participants were female. The mean number of geriatric assessment domain impairments was 4·5 (SD 1·6) and was not significantly different between the study groups. More patients in intervention group compared with the usual care group were Black versus other races (40 [11%] of 349 patients vs 12 [3%] of 369 patients; p<0·0001) and had previous chemotherapy (104 [30%] of 349 patients vs 81 [22%] of 369 patients; p=0·016). A lower proportion of patients in the intervention group had grade 3-5 toxic effects (177 [51%] of 349 patients) compared with the usual care group (263 [71%] of 369 patients; relative risk [RR] 0·74 (95% CI 0·64-0·86; p=0·0001). Patients in the intervention group had fewer falls over 3 months (35 [12%] of 298 patients vs 68 [21%] of 329 patients; adjusted RR 0·58, 95% CI 0·40-0·84; p=0·0035) and had more medications discontinued (mean adjusted difference 0·14, 95% CI 0·03-0·25; p=0·015). A geriatric assessment intervention for older patients with advanced cancer reduced serious toxic effects from cancer treatment. Geriatric assessment with management should be integrated into the clinical care of older patients with advanced cancer and ageing-related conditions. National Cancer Institute.

Results from Phase I Extension Study Assessing Pexidartinib Treatment in Six Cohorts with Solid Tumors including TGCT, and Abnormal CSF1 Transcripts in TGCT.

To assess the response to pexidartinib treatment in six cohorts of adult patients with advanced, incurable solid tumors associated with colony-stimulating factor 1 receptor (CSF1R) and/or KIT proto-oncogene receptor tyrosine kinase activity. From this two-part phase I, multicenter study, pexidartinib, a small-molecule tyrosine kinase inhibitor that targets CSF1R, KIT, and FMS-like tyrosine kinase 3 (FLT3), was evaluated in six adult patient cohorts (part 2, extension) with advanced solid tumors associated with dysregulated CSF1R. Adverse events, pharmacokinetics, and tumor responses were assessed for all patients; patients with tenosynovial giant cell tumor (TGCT) were also evaluated for tumor volume score (TVS) and patient-reported outcomes (PRO). CSF1 transcripts and gene expression were explored in TGCT biopsies. Ninety-one patients were treated: TGCT patients (n = 39) had a median treatment duration of 511 days, while other solid tumor patients (n = 52) had a median treatment duration of 56 days. TGCT patients had response rates of 62% (RECIST 1.1) and 56% (TVS) for the full analysis set. PRO assessments for pain showed improvement in patient symptoms, and 76% (19/25) of TGCT tissue biopsy specimens showed evidence of abnormal CSF1 transcripts. Pexidartinib treatment of TGCT resulted in tumor regression and symptomatic benefit in most patients. Pexidartinib toxicity was manageable over the entire study. These results offer insight into outcome patterns in cancers whose biology suggests use of a CSF1R inhibitor. Pexidartinib results in tumor regression in TGCT patients, providing prolonged control with an acceptable safety profile.

Mirtazapine in Cancer-Associated Anorexia and Cachexia: A Double-Blind Placebo-Controlled Randomized Trial

ContextFew pharmacological interventions are available for cancer-associated anorexia and cachexia. Mirtazapine has been suggested for use in cancer-associated anorexia and cachexia. ObjectivesThis study was conducted to assess the efficacy and tolerability of mirtazapine in cancer-associated anorexia and cachexia. MethodsA double-blind placebo-controlled randomized trial. The study included 120 incurable solid tumour patients with anorexia (appetite loss ≥4 on 0 – 10 scale, 10 = maximum appetite loss), cachexia (>5% body weight loss over 6 months or >2% plus body mass index <20) and depression score ≤3 on 0-6 scale (6 = extreme feelings of depression). Patients were 1:1 randomized to receive mirtazapine 15mg daily at night for 8 weeks or placebo. The primary endpoint was change in appetite from baseline to day 28. Other outcomes included changes in quality-of-life, fatigue, depressive symptoms, body weight, lean body mass, handgrip strength, inflammatory markers, adverse events and survival. Results48 (80%) patients in the mirtazapine arm and 52 (87%) in the placebo were assessable for the 1ry endpoint. Appetite score increased significantly with mirtazapine as well as with placebo (P < 0.0001 each). The increase in appetite score did not differ significantly between the two arms in the per-protocol and intention-to-treat analysis (P = 0.472 and 0.462, respectively). Mirtazapine was associated with significantly less increase in depressive symptoms and higher prevalence of somnolence. The change in other outcomes did not differ significantly between mirtazapine and placebo. ConclusionMirtazapine 15mg at night for 28 days is no better than placebo in improving the appetite of incurable solid tumor patients with cancer-associated anorexia and cachexia.

Prognostic understanding, hospitalization, and hospice use among older patients with advanced cancer.

12037 Background: Poor prognostic understanding of curability is associated with lower hospice use in patients with advanced cancer. Little is known if this holds true for older adults specifically. In addition, prognostic understanding are variably assessed and defined in prior studies. We evaluated the associations of poor prognostic understanding and patient-oncologist discordance in both curability and survival estimates with hospitalization and hospice use in older patients with advanced cancer. Methods: We utilized data from a national geriatric assessment cluster-randomized trial (URCC 13070: PI Mohile) that recruited 541 patients aged ≥70 with incurable solid tumor or lymphoma considering any line of cancer treatment and their oncologists. At enrollment, patients and oncologists were asked about their beliefs about cancer curability (options: 100%, &gt; 50%, 50/50, &lt; 50%, 0%, and uncertain) and estimates of patient’s survival (options: 0-6 months, 7-12 months, 1-2 years, 2-5 years, and &gt; 5 years). Non-0% options were considered poor understanding of curability (uncertain was removed from the analysis) and &gt; 5 years was considered poor understanding of survival estimates. Any difference in response options was considered discordant. We used generalized estimating equations to estimate adjusted odds ratios (AOR) assessing associations of poor prognostic understanding and discordance with hospitalization and hospice use at 6 months, adjusting for covariates and practice clusters. Results: Poor prognostic understanding of curability and survival estimates occurred in 59% (206/348) and 41% (205/496) of patients, respectively. Approximately 60% (202/336) and 72% (356/492) of patient-oncologist dyads were discordant in curability and survival estimates, respectively. In the first 6 months after enrollment, 24% were hospitalized and 15% utilized hospice. Poor prognostic understanding of survival estimates was associated with lower odds of hospice use (AOR 0.30, 95% CI 0.16-0.59) (Table). Discordance in survival estimates was associated with greater odds of hospitalization (AOR 1.64, 95% CI 1.01-2.66). Conclusions: Prognostic understanding may be associated with hospitalization or hospice use depending on how patients were queried about their prognosis and whether oncologists’ estimates were considered.[Table: see text]

Phase II trial of the PARP inhibitor, niraparib, in BRCA1-Associated Protein 1 (BAP1) and other DNA damage response (DDR) pathway deficient neoplasms including cholangiocarcinoma.

TPS354 Background: BRCA1-Associated Protein 1 (BAP1) is a critical regulator of the cell cycle, cellular differentiation, cell death, and DNA damage response. It also acts as a tumor suppressor. Preclinical models demonstrate significant synthetic lethality in BAP1 mutant cell lines and patient xenografts when treated with PARP inhibitors, independent of underlying BRCA status, suggesting this mutation confers a BRCA-like phenotype. BAP1 is mutated, leading to a loss of functional protein, in up to 30% of cholangiocarcinomas as well as several other solid tumors. Methods: This phase 2, open-label, single arm multicenter study aims to exploit the concept of synthetic lethality with the use of the PARP inhibitor niraparib in pts with metastatic relapsed or refractory solid tumors. Eligible pts with measurable metastatic and incurable solid tumors are assigned to one of two cohorts: Cohort A (histology-specific): tumors harboring suspected BAP1 mutations including cholangiocarcinoma, uveal melanoma, mesothelioma or clear cell renal cell carcinoma with tissue available for BAP1 mutational assessment via NGS or Cohort B (histology-agnostic): tumors with known DNA damage response (DDR) mutations (Table) confirmed by CLIA-approved NGS. Other key eligibility criteria include age ≥18 years, adequate cardiac, renal, hepatic function and Eastern Cooperative Oncology Group performance status of 0 to 1. Pts with known BRCA1 or BRCA2 mutations or prior PARPi exposure are excluded. Pts receive niraparib 200-300mg daily (depending on weight and/or platelet count) continuously. Primary endpoint is objective response rate with secondary endpoints of PFS, OS, toxicity and exploratory biomarker determinations. Radiographic response by RECIST criteria is measured every 8 weeks while on treatment. Cohort A has fully enrolled. Cohort B enrollment continues to a maximum of 47 total evaluable subjects with expansion cohorts allowable for histologic or molecular subtypes meeting pre-specified responses. NCT03207347 Clinical trial information: NCT03207347. [Table: see text]

Using machine learning to identify older adults at high risk for hospitalization and mortality via the Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE).

169 Background: PRO-CTCAE captures symptomatic adverse events (e.g. pain, fatigue) and may indicate poor treatment tolerability in older patients (pts) with advanced cancer. Using unsupervised machine learning which can detect unknown patterns in data, we aimed to evaluate if clusters identified based on PRO-CTCAE severity were associated with hospitalization and survival. Methods: We included pts randomized to the control arm of GAP 70+ (URCC 13059; PI: Mohile), which enrolled pts aged ≥70, with incurable solid tumors or lymphoma, and ≥1 geriatric assessment (GA) domain impairment starting a new treatment regimen. Measures included 24 PRO-CTCAE items (v1.0) with severity attributes (item 0-4; total score 0-96, higher score = greater severity). The unsupervised algorithm (K-means with Euclidean Distance) clustered pts at baseline based on similarities of severities of the 24 items. We examined if the clusters were associated with treatment-related hospitalization within 3 months and lower survival at 6 months using Logistic and Cox regressions. Results: Of the 369 control pts, 366 completed GA and PRO-CTCAE at baseline (mean age 77.2, 94.3% white, 30.9% with GI and 31.4% with lung cancer; mean number of impaired GA 4.4). By PRO-CTCAE, the most prevalent symptoms were fatigue (82.7%), pain (60.9%), and decreased appetite (58.7%). Greater GA impairment was associated with 20 PRO-CTCAE items (fatigue, pain, and decreased appetite having the strongest associations; all Pearson's r &gt; 0.33). Three clusters were identified: Low Severity (51.4%); Moderate Severity (34.4%), and High Severity (14.2%). Mean total severity score was 6.9 (low), 16.9 (moderate), and 28.7 (high), respectively (p &lt; 0.01). No difference in demographics was found among clusters. Percent of pts hospitalized were 21.3% (low), 36.5% (moderate), and 38.5% (high) (p &lt; 0.01); survival rates were 81.9% (low), 71.4% (moderate), and 55.3% (high) (p &lt; 0.01). Controlling for cancer type and GA, compared to pts in Low Severity cluster, pts in Moderate and High Severity were more likely to be hospitalized (odds ratio = 1.77, p = 0.03); pts in High Severity cluster were more likely to die (hazard ratio = 2.23, p = 0.01). Conclusions: Unsupervised machine learning was able to partition pts into different PRO-CTCAE severity clusters; pts with higher baseline severity were more likely to be hospitalized or die. PRO-CTCAE provides additional information to GA. Funding: R01CA177592, U01CA233167, UG1CA189961.

A geriatric assessment (GA) intervention for older patients with advanced cancer: Secondary outcomes from a University of Rochester cancer center NCI community oncology research program cluster randomized controlled trial (CRCT).

33 Background: GA evaluates aging-related domains (e.g., function) known to be associated with cancer treatment toxicity. We found that providing a GA summary with management recommendations to oncologists reduces clinician-rated toxicity in older patients (pts) with advanced cancer receiving high risk treatment (presented @ASCO2020). Herein, we report secondary outcomes on the effects of the GA intervention on aging-related outcomes. Methods: Pts aged ≥ 70 with incurable solid tumors or lymphoma and ≥ 1 impaired GA domain starting a new treatment regimen were enrolled. Community oncology practices were randomized to intervention (oncologists received GA summary/recommendations) or usual care (none given). Secondary analyses examined effects of the intervention on functional outcomes (patient-reported falls, instrumental activities of daily living (IADL), short physical performance battery (SPPB), geriatric depression scale (GDS), and medications [total and prescription]). Outcomes were analyzed using linear mixed effects model, logistic or Poisson regression adjusted for baseline values, time, and site effects as appropriate. Results: From 2013-19, 718 pts were enrolled from 41 practices. Age (mean 77 yrs), sex (43% women), number of impaired GA domains (median 4/8), and treatment type (chemotherapy 88%) were not different by arm. More pts in intervention were black (12% vs 3%, p&lt;0.01), had GI cancer (38% vs 31%, p&lt;0.01), and had prior chemotherapy (31% vs 23%, p=0.02). Overall, 16.4% of all pts had one new fall over 3 months; patients in the intervention arm were significantly less like to fall over 3 months (11.7% vs 20.7%; Risk Ratio 0.58; 95% CI 0.40-0.84, p=0.004). There was no difference in the total number of medications (mean 5.86 vs 5.79, p=0.80) and prescriptions (mean 4.26 vs 4.20, p=0.70) at baseline. More medications (adjusted mean 0.23 vs 0.09, p=0.03) and prescriptions (0.19 vs 0.07, p=0.05) were discontinued during intervention, although there was no difference at 3 month follow up. There were no significant between-arms differences in IADL, SPPB, and GDS. Conclusions: Providing GA information to oncologists reduces the proportion of older pts who experience a fall over 3 months and improves polypharmacy; both of these endpoints are of clinical importance to older adults with aging-related conditions and advanced cancer undergoing palliative treatment. Funding: R01CA177592, U01CA233167, UG1CA189961. Clinical trial information: NCT02054741 .

Potential insights from population kinetic assessment of progression-free survival curves.

Progression-free survival (PFS) curves follow first order kinetics on exponential decay nonlinear regression analysis (EDNLRA). Some exhibit 1-phase-decay, some have 2-phase-decay, some are convex. We digitized, performed EDNLRA and generated log-linear plots for 887 published PFS curves for incurable solid tumors treated with various systemic therapies. Proportion of curves fitting 2-phase-decay varied by therapy (p < 0.0001). For 13 therapies, >64 % of PFS curves had 2-phase-decay. This included epidermal growth factor receptor inhibitors in unselected lung cancer patients (some with, some without mutations), immune checkpoint inhibitors, interferon, breast cancer hormonal therapies, and selected others, suggesting 2 distinct, potentially identifiable subpopulations with differing progression rates. For 22 other therapies, <25 % of PFS curves had 2-phase-decay. Only 1 therapy was in the mid-range. Small cell lung and colon carcinomas were particularly likely to yield highly convex curves (p < 0.006), probably from discontinuation of effective therapies. PFS curve shape may yield biological and clinical insights.

A geriatric assessment (GA) intervention to reduce treatment toxicity in older patients with advanced cancer: A University of Rochester Cancer Center NCI community oncology research program cluster randomized clinical trial (CRCT).

12009 Background: GA evaluates aging-related domains (e.g., function) known to be associated with cancer treatment toxicity. In this CRCT, we evaluated if providing a GA summary with management recommendations to oncologists can reduce toxicity in older patients (pts) with advanced cancer receiving chemotherapy and/or other agents with a high reported prevalence of grade 3-5 toxicity. Methods: Pts aged &gt; 70 with incurable solid tumors or lymphoma and &gt; 1 impaired GA domain starting a new treatment regimen were enrolled. Community oncology practices were randomized to intervention (oncologists received GA summary/recommendations for impairments) or usual care (none given). The primary outcome was proportion of pts who experienced any grade 3-5 toxicity (CTCAE v.4) within 3 months. Practice staff prospectively captured toxicities; blinded oncology clinicians reviewed medical records to verify. Secondary outcomes included 6 month overall survival (OS) and treatment intensity (standard vs reduced). Outcomes were analyzed using generalized linear mixed/Cox models with Arm as a fixed effect, controlling for practice. Results: From 2013-19, 718 pts were enrolled from 41 practices. Age (mean 77 yrs), sex (43% women), number of impaired GA domains (median 4/8), and treatment type (chemotherapy 88%) were not different by Arm. More pts in intervention were Black (12% vs 3%, p&lt;0.01), had GI cancer (38% vs 31%, p&lt;0.01), and had prior chemotherapy (31% vs 23%, p=0.02). Pts in intervention experienced a lower proportion of grade 3-5 toxicity (175/349; 50%) than pts in usual care (262/369; 71%). The relative risk (RR: intervention vs usual care) of grade 3-5 toxicity was 0.74 (95% CI: 0.63-0.87; p=0.0002); the difference was mostly driven by non-heme toxicities (RR 0.73; 95% CI: 0.53-1.0, p&lt;0.05). OS was not significantly different (71% vs 74%, p=0.3). More pts in intervention received reduced intensity treatment at cycle 1 (49% vs 35%, RR 0.81, p=0.01). Dose modifications due to toxicity were lower in intervention (42% vs 58%, p&lt;0.0001), but results were not significant after controlling for practice (RR 0.85; 95% CI: 0.67-1.08, p=0.2). Conclusions: Providing GA information to oncologists reduces the proportion of older pts who experience grade 3-5 toxicity from high-risk palliative cancer treatment, without compromising OS. Reduced treatment intensity at cycle 1 may explain these results. Funding: R01CA177592, U01CA233167, UG1CA189961. Clinical trial information: NCT02054741 .