Poor Poor Performance Status Research Articles

The Eosinophil Changes, Efficacy and Safety of Pembrolizumab in Advanced Urothelial Carcinoma Patients with an Older Age and a Poor Performance Status.

To evaluate the eosinophil changes, efficacy and safety of pembrolizumab treatment in advanced urothelial carcinoma patients of older age and those with a poor performance status (PS). Consecutive patients with advanced UC who received pembrolizumab after the failure of platinum-based chemotherapy between January 2018 and June 2021 were retrospectively examined. 105 patients (median age, 72 years), 71.4% of whom were men, were enrolled. Patients of ≥75 years of age were considered to be older patients (n=40), and patients with PS ≥2 were considered to have a poor PS (n=10). The objective response and disease control rates were 42.5% and 52.5%, respectively, in older patients and 0% and 10.0%, respectively, in patients with a poor PS. Overall survival (OS) in the older and younger groups did not differ to a statistically significant extent. However, a poor PS was significantly associated with poor survival. Safety analyses demonstrated no significant difference in the occurrence of any immune-related adverse events (irAEs), including grade ≥3, between the older and younger groups. However, a poor PS was significantly associated with the low occurrence of any irAEs. The change of the eosinophil count, the increase of the relative eosinophil count (REC) and the decrease of the neutrophil-to-eosinophil ratio (NER) did not differ to a statistically significant extent between the older and younger groups, but showed significant differences between the poor and good PS (PS 0-1) groups. Pembrolizumab for advanced UC demonstrated similar changes in the eosinophil count, efficacy and toxicity in both older and younger patients. In patients with a poor PS, although toxicity was significantly lower, survival was significantly worse, and neither an increase in REC nor a decrease in NER were observed, but these values showed significant changes in patients with a good PS.

1158P Study of patients’ characteristics associated with osimertinib outcomes upfront or in following lines in EGFR-positive NSCLC

In first line (L1) for EGFR-mutated (mEGFR) advanced NSCLC (aNSCLC), osimertinib (osi) has been the preferred option since 2018. First generation anti-EGFR TKI (1G) alone followed by osi, or 1G + anti-angiogenic or 1G + chemotherapy are other options. We aimed to assess the subgroups of patients (pts) that do not benefit from 1G alone compared with osimertinib L1 in mEGFR aNSCLC. Retrospective international study including pts with mEGFR aNSCLC treated with either osi or the sequence of 1G followed by osi (seq group). Primary endpoint was the PFS of the global strategy (PFSglob) defined as the time between L1 start and progression after L2 treatment or death. Subgroups analyses included pts with high tumour burden (high-TM; > 3 metastatic sites and/or central nervous system (CNS) involvement), poor performance status (PS), and T790M negative (seq subgroup only). A total of 235 pts were included: 104 in the seq group, 118 in the osi L1 group. 15 had T790M negative at PD after 1G, they received osi as a therapeutic test. From these pts, 222 had an exon19 or 21 EGFR mut, 13 had uncommon mEGFR. Mean age was 65 years, 64% were female, and 60% never smokers. Pts from the osi L1 group had poorer PS (23% vs 10%), higher rate of co-mutations (23% vs 19%) and more CNS involvement (47% vs 19%). After a median (m) follow up of 30.6 months in the exon 19 and 21 population, mPFSglob was 27.4 mo (23.0-31.0) and mPFS L1 was 15.5mo (13.7-18.4) Table. The sequence was associated with shorter PFS L1 compared with osi L1 particularly in high-TM (10.5 mo vs 17.1 mo, p<0.0001); PFS was numerically shorter in poor PS (≥2) population (11.0 mo vs 15.6 mo, p=0.1).Table: 1158POsimertinib L1 groupORR L1PFS L1, 18mo rate (95%CI)PFSglob, 36mo rate (95%CI)Exon 19 and 21 mut (n=118)84.3%46.4% (37.0-58.1)36.8% (19.9-68.2)CNS involvement (n=55)92.6%42.2% (28.3-62.7)20.6% (4.7-89.0)Poor PS (n=23)90.5%46.4% (27.7-77.8)55.1% (35.5-85.5)Sequence groupExon 19 and 21 mut (n=104)87.4%41.8% (33.2-52.5)37.8% (29.1-49.1)CNS involvement (n=20)90.0%25% (11.7-53.4)16.6% (5.2-53.0)Poor PS (n=9)88.9%13.9% (2.3-83.6)0%ORR L2PFS L1, 18mo rate (95%CI)PFS L2, mo (95%CI)T790M analysis from the sequence groupT790M positive at L1 PD (n=82)63.2%39.0% (29.8-51.1)10.3 (8.8-14.1)T790M negative at L1 PD (n=9)83.3%44.4% (21.4-92.3)12.8 (6.7-Not Reached) Open table in a new tab 1G TKI followed by osi seemed to be detrimental compared with os L1 for pts with high-TM or poor PS mEGFR aNSCLC. In this population, the intensification of L1 treatment with osimertinib or a combination of 1G with anti-angiogenic or chemotherapy could be the better option in the first-line setting. Updated results will be presented at the congress.

Low-dose weekly decitabine and venetoclax in TP53-mutated myeloid malignancies.

e19005 Background: TP53-mutated ( TP53mut) acute myeloid leukemia (AML) and high-risk myelodysplastic syndromes (MDS) are often treated with hypomethylating agents (HMAs) in combination with Venetoclax (Ven), however, myelosuppression from treatment leads to frequent dose-reductions and/or cycle delays. An approach to decrease HMA-mediated myelosuppression while maintaining S-phase dependent DNMT1-targeting is to administer noncytotoxic doses of Decitabine (Dec) by a frequent-distributed schedule of 1X/week. In pre-clinical studies Ven given as a single dose prior to HMA administration has been shown to inhibit de novo pyrimidine synthesis and counter a major mechanism of resistance to HMAs in MDS/AML, without suppressing normal myelopoiesis. Methods: We conducted a retrospective analysis of all pts with TP53mut MDS/AML at our institution treated with weekly Ven 400mg on D1 and low-dose subcutaneous (subQ) Dec (0.2 mg/kg; ̃5 mg/m2) on D2, administered weekly in 28 day cycles. We analyzed patient characteristics, response to therapy, and outcomes using standard descriptive statistics. Results: Six pts with TP53mut MDS or AML were treated. Two pts with high-risk MDS and 3 pts with adverse risk AML (83%) received treatment frontline, all with poor performance status (PS), and 1 pt (17%) had R/R MDS transformed to adverse risk AML refractory to both standard Aza/Ven and Vyxeos. Median age at diagnosis was 79 years [41-82]. Median TP53mut variant allelic frequency (VAF) was 48% [28-79]. Cytogenetics were complex in all pts. Median follow-up was 10.1 months (mo) [2.9-16.3] and 83% pts were transfusion dependent prior to treatment. Overall response rate (ORR) was 100%: 5/5 frontline pts had complete remissions (CR), and the 1 R/R pt achieved a morphologic leukemia-free state. Median time to best response was 2.5 mo and 60% pts became transfusion independent. 33% pts lost their TP53mut at best response, and another 50% pts had significant reductions (83%, 46% and 38%) in TP53mut VAF. The regimen was well tolerated with no pts stopping therapy due to adverse effects, with a median of 1.5 unplanned hospitalizations per pt during follow-up. Median duration of therapy was 13.8 mo [6.1-27.1] with 2 (33%) pts remaining on therapy and 2 (33%) pts with measurable relapse who have since died. One pt underwent allogeneic stem cell transplantation, however, died 11.4 mo after conditioning due to transplant related mortality. The R/R pt died after being lost to follow-up 2.9 mo after therapy initiation. Conclusions: Combination weekly Ven with low-dose subQ Dec is well tolerated yielding high rates of clinical and molecular response in pts with TP53mut MDS/AML. Although small, this case-series extends proof-of-activity of non-cytotoxic DNMT1-targeting to a high-risk, poor PS, historically chemorefractory patient population allowing frequent, sustained drug exposure often not possible with standard HMA/Ven regimens.

Bevacizumab in first-line chemotherapy to improve the survival outcome for advanced ovarian clear cell carcinoma: A multicenter, retrospective analysis.

5502 Background: Advanced ovarian clear cell carcinoma (ACCC, stage III/IV disease) is a rare tumor characterized by chemoresistance. Bevacizumab (Bev) was approved in November 2013 in Japan and became incorporated in the treatment of advanced ovarian cancer. However, the efficacy of Bev against ACCC remain unknown. We investigated the survival outcomes for ACCC, following first-line chemotherapy with or without Bev. Methods: Patients diagnosed with ACCC at seven institutions between 2008 and 2018 were enrolled in this study. Patients underwent cytoreductive surgery and taxane-carboplatin chemotherapy (78: triweekly regimen; 30: weekly regimen; 25: dose-dense regimen; 12: others) with or without concurrent and maintenance Bev (15 mg/kg/3 weeks). We compared the progression-free survival (PFS) and overall survival (OS) before (group A, n = 102) and after (group B, n = 43) Bev approval, using Kaplan–Meier method and Cox regression model. We excluded patients with poor performance status (PS) in group A, and patients who did not receive Bev due to poor PS or thrombosis in group B. Results: There was no significant difference between two groups in terms of age (p = 0.135) and initial CA125 level (p = 0.674). Thirteen (13%) and 11 (26%) patients had stage IV disease (p = 0.058) and 2 (3%) and 7 (16%) patients were of poor PS (PS ≥2) (p = 0.004) in group A and B, respectively (p = 0.058). More patients (29/43, 67%) in group B were achieved complete resection than in A group (52/102, 51%) (p = 0.068). The median cycle of Bev in B group was 16 (interquartile range: 6-21). The median follow-up time was 36 months. The median PFS increased from 12.5months in A group to 29.7 months in B group (log-rank test: p = 0.023, Wilcoxon test: p = 0.006). The median OS increased from 34.7 months in A group to 51.4 months in B group (log-rank test: p = 0.085, Wilcoxon test: p = 0.027). Multivariate analysis revealed that Bev use (Hazard ratio (HR): 0.54, p = 0.011; HR: 0.54, p = 0.019), PS &lt;2 (HR: 0.33, p = 0.013; HR: 0.29, p = 0.006) and completeness of resection (HR: 0.38, p &lt; 0.001; HR: 0.37, p &lt;0.001) were independent prognostic factors for PFS and OS. Conclusions: Incorporating Bev in first-line chemotherapy may improve PFS in patients with ACCC. [Table: see text]

PD-9 Three-arm phase II/III randomized controlled trial in patients with unresectable/metastatic gall bladder cancer with poor performance status: Erlotinib or capecitabine v/s best supportive care

Currently there is no standard of care for Eastern Cooperative Oncology Group (ECOG) poor performance status (PS) patients (PS-III) with unresectable/metastatic Gall Bladder Cancer (GBC). Being unfit for chemotherapy, these patients receive only best supportive care (BSC) resulting in a very dismal outcome. A report published from M.D. Anderson Cancer Centre stated median overall survival (OS) of only one month in patients with poor PS with GBC. This single centre, prospective randomized controlled phase II/III, open label trial was done at a tertiary health care centre in India. Patients (above 18 years) with histologically confirmed unresectable/ metastatic GBC with adequate organ function and ECOG PS-III were included. Patients with prior adjuvant chemotherapy/erlotinib/capecitabine in last 6 months, active malignancy other than GBC, lactating and pregnant women, and HIV-positive status were excluded. Random allocation (1:1:1) was done to one of the three arms - Erlotinib (150 mg OD) + BSC, Capecitabine + BSC or BSC alone using computer-generated sequence. The primary end point was median OS, defined as time from randomisation to death, in the intention-to-treat population. A sample size of 105 was estimated, assuming median OS in BSC, Erlotinib+BSC and Capecitabine+BSC as 2, 4 and 5 months respectively (taking two-sided alpha error as 0.05 and power as 80%). Between Dec 27, 2017 and January 18, 2021, 201 patients were screened, of which 105 were randomized to Erlotinib +BSC (n = 36), Capecitabine +BSC (n = 36) or BSC alone arm (n = 33). After a median follow up of 10 months (IQR 3.9- 11.5), there were 82 deaths in the whole cohort. The median OS in Erlotinib arm was significantly higher at 3.84 months (2.33- 4.67) compared to 1.77 months (1.18- 2.73) in BSC only arm, with hazard ratio (HR) of 0.50 (95% CI - 0.26 -0.95), p = 0.02. However, there was no statistically significant difference observed in survival between Capecitabine +BSC over BSC alone - median OS 2.46 months (1.67-3.58), HR - 0.70 (95% CI - 0.38- 1.2), p = 0.30. Compared to only 15.1% (5/33) in BSC arm, the disease control rate (complete response + partial response + stable disease) at 6-8 weeks was 58.3% (21/36) in Erlotinib arm (p = 0.004) and 47.2% (17/36) in Capecitabine arm (p = 0.04). Grade III/IV toxicities were reported in 12 patients (33.3%) in Erlotinib arm (skin rash and diarrhea being most common at 8% each) and in 5 patients (13.8%) in Capecitabine arm (anemia and fatigue most common at 6 % each). No treatment related deaths were reported in either group. Addition of Erlotinib to BSC significantly improves OS in patients with unresectable/metastatic GBC, otherwise unfit to receive chemotherapy, with acceptable toxicity profile.

Real-world effectiveness of immunotherapies in pre-treated, advanced non-small cell lung cancer Patients: A systematic literature review

BackgroundClinical trials have shown immunotherapy (IO) to be more effective than chemotherapy in pre-treated, advanced non-small cell lung cancer (NSCLC). However, there is a lack of understanding of its effectiveness in clinical practice, and among patient groups that are often underrepresented in trials. We aimed to summarize the existing real-world evidence (RWE) on the survival outcomes of IO in second- or higher line in advanced NSCLC. MethodsWe conducted a systematic review of real-world observational studies that reported overall survival (OS) estimates with IO, primarily nivolumab, pembrolizumab or atezolizumab, in adult, previously treated advanced or recurrent NSCLC patients. Meta-analysis was conducted using random-effect models to pool 1- and 2-year OS rates across studies. Additional subgroups were examined among patients treated with IO, including the elderly, those with poor performance status (PS) and those exhibiting metastasis. ResultsIn total, 66 studies were included, of which 46 (70%) included a nivolumab-specific study arm. Pooled 1-year and 2-year OS rates with nivolumab monotherapy were 45.6% (95% CI; 43.4–47.8) and 28.0% (95% CI; 24.8–31.4), respectively, compared to 43.9% (95% CI; 39.1–48.8) and 20.4% (95% CI; 14.7–27.6) in the mixed immune checkpoint inhibitors (ICI) group. OS rates with nivolumab were slightly lower in elderly compared to non-elderly populations. Poor PS was associated with worse survival rates, with a pooled one-year OS estimate of 27.1% in PS ≥ 2 vs 51.6% in PS < 2. The pooled 2-year OS rate with nivolumab in patients with and without brain metastases was 22.1% and 26.1% respectively, and this difference was significant in 36% of individual studies. ConclusionsWhile the OS benefits of IO seen in real-world studies among pre-treated, advanced NSCLC patients are consistent with pivotal clinical trials, these tend to vary for the more vulnerable patient groups, such as patients with poor PS, which are often excluded from trials. Further research is needed to investigate findings in patients with brain and liver metastases.

Efficacy of first-line combination therapy in metastatic renal cell carcinoma (mRCC) patients (pts) with poor performance status (PS).

320 Background: Immune checkpoint combination therapy (ICI-combo) is the new standard of care for mRCC in first-line setting. However, pts with poor PS (≥2) were excluded from pivotal trials. Hence, the activity and safety of ICI-combo in this group of pts is still unknown. Methods: We performed a multicentre retrospective study of PS≥2 mRCC pts who received ICI-combo, either nivolumab-ipilimumab (NI) or pembrolizumab-axitinib (PA) as first-line treatment between 2017-2021. Patient’s characteristics, clinical outcomes and toxicity were retrospectively reviewed. We analysed overall response rate (ORR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS) and grade ≥3 treatment-related adverse events (G≥3 AEs) in pts treated with NI or PA. The association between LIPI (Lung Immune Prognostic Index) and ORR, PFS and OS was also evaluated. Results: We identified 56 mRCC pts with PS≥2 treated with ICI-combo across 13 institutions. Thirty-six and 20 pts were treated with NI and PA respectively. Median age at diagnosis was 64 (31-83) years, 38 (68%) were male, 16 (29%) had prior nephrectomy and 40 (71%) had synchronous metastatic disease at diagnosis. Respectively, 19 (34%) and 37 (66%) pts were intermediate and poor risk according to IMDC. Fifty pts (89%) were clear cell RCC, and only 4 pts had sarcomatoid features reported. At the time of analysis (median follow-up 11.1 months(mo)) 45% pts were dead. The ORR for the entire cohort was 27%; ORR was numerically higher with PA (42%) than with NI (20%) but did not reach statistical significancy (p=0.157). Median PFS (mPFS) and mOS in the entire cohort were 4.4 mo and 15.9 mo respectively. No significant differences in PFS, OS or the rate of G≥3AEs were seen between the NI and PA groups. Efficacy and toxicity outcomes are described in the table below. No significant differences in OS or PFS according to the IMDC risk score were observed (p=0.818). However, LIPI was significantly associated with OS (poor LIPI: HR=8.18; p=0.004) and PFS (Intermediate LIPI: HR=2.4; p=0.048 and poor LIPI: HR=8.59; p&lt;0.001). LIPI was predictive of response in patients treated with NI (p=0.024). Conclusions: We report the first cohort of PS≥2 mRCC pts treated with ICI-combo in first-line setting. No significant differences in ORR, PFS or OS were seen between NI and PA. LIPI was significantly associated with both OS and PFS, and was predictive of ORR in the NI group. Prospective real-world studies are needed to confirm these results.[Table: see text]

Profile of metastatic lung cancer patients susceptible to development of thromboembolism during immunotherapy

BackgroundThromboembolism (TE) is a serious complication in lung cancer patients; however, risk factors for developing TE during treatment with immuno-oncology (IO) drugs are unclear. Materials and methodsA retrospective study of lung cancer patients hospitalized in Tokyo Medical and Dental University was performed to clarify the association between TE and systemic therapy, especially IOs. Patients were divided into an IO cohort, a chemotherapy cohort (CT cohort), and a control cohort (patients without recurrence after surgery). Association studies of variables relevant to TE were performed. ResultsA total of 592 patients were enrolled (IO cohort, 120; CT cohort, 294; control cohort, 178). Eight patients (6.7%) in the IO cohort, seven (2.4%) in the CT cohort, and three (1.7%) in the control cohort developed TE. Least Absolute Shrinkage and Selection Operator (LASSO) regression analysis identified IO, a history of TE, poor performance status (PS), and prior anticoagulation therapy as being associated with TE. Subsequent multivariate logistic regression analysis identified a history of TE (odds ratio (OR), 6.03; 95% confidence interval (CI), 2.09–17.40; P = 0.01) and poor PS (OR, 3.84; 95% CI, 1.34–11.00; P < 0.001) as potential risk factors for developing TE. The incidence of TE in the IO cohort patients with both of these characteristics was significantly higher (OR, 52.82; 95% CI, 6.72–506.37; P < 0.001) than that in the control cohort. ConclusionLung cancer patients with a history of TE and poor PS are at increased risk of TE during treatment with IOs. Micro abstractThe profiles of lung cancer patients susceptible to development of thromboembolism (TE) during immunotherapy are unclear, even though TE is associated with a worse prognosis. Here, association studies of variables relevant to TE revealed that patients with a history of TE and poor performance status are at higher risk of developing TE during immunotherapy.

First-line osimertinib for poor performance status patients with EGFR mutation-positive non-small cell lung cancer: A prospective observational study.

The clinical outcomes of poor performance status (PS) patients with epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC) who are treated with osimertinib as a first-line treatment have not been sufficiently evaluated. This study aimed to assess the efficacy and safety of osimertinib in chemotherapy-naive and poor PS (2 or more) patients with NSCLC harboring sensitive EGFR mutations. We assessed the clinical effects of osimertinib as a first-line treatment for patients with poor PS NSCLC with an exon 19 deletion or exon 21 L858R mutation in EGFR. All patients were administered osimertinib (80mg/day) as the initial treatment. Sixteen patients (nine women and seven men) who were treated between August 2018 and July 2021 were included in this study; their median age was 78years. The overall objective response rate was 56.3%. The median progression-free survival (PFS) of the entire patient population was 10.5months and the PS score improved in 8 of 16 patients (50%). The most common adverse event was acneiform rash (42%), followed by diarrhea (36%) and paronychia (36%); none of these were of grade ≥ 3. Interstitial lung disease occurred in 2 patients (12.5%); however, no treatment-related deaths occurred. Considering the findings of this study, osimertinib appears to be an effective and safe treatment option for patients with poor PS and advanced NSCLC harboring sensitive EGFR mutations. To obtain conclusive results, further studies with larger cohorts are warranted.

Clinical Effectiveness of Immune Checkpoint Inhibitors in Non-Small-Cell Lung Cancer with a Poor Performance Status.

Immune checkpoint inhibitors (ICIs) are standard treatments for patients with lung cancer. PD-1/PD-L1 or CTLA4 antibodies are chosen as the first-line therapy, contributing to the long-term survival and tolerability. Unlike molecular targeting agents, such as gefitinib, lung cancer patients with a poor performance status (PS) display unsatisfactory clinical improvements after ICI treatment. Several previous reports also demonstrated that the PS is identified as one of the most probable prognostic factors for predicting poor outcomes after ICI treatment. However, first-line pembrolizumab seemed to be effective for lung cancer patients with a PS of 2 if PD-L1 expression was greater than 50%. Currently, the induction of ICIs in patients with lung cancer with a poor PS is controversial. These problems are discussed in this review.

Low-Dose Weekly Decitabine and Venetoclax in TP53-Mutated Myeloid Malignancies

Decitabine (Dec) and Azacitidine (Aza) that target DNA methyltransferase 1 (DNMT1) are hypomethylating agents (HMAs) approved to treat acute myeloid leukemia (AML) in combination with Venetoclax (Ven). The combination is also used to treat high-risk myelodysplastic syndromes, especially TP53-mutated (TP53mut) cases in which responses to HMA alone are short-lived. In most patients (pts), however, myelosuppression from treatment leads to frequent Ven duration and/or dose-reductions, and/or cycle delays. An approach to decrease HMA-mediated myelosuppression but maintain S-phase dependent DNMT1-targeting, evaluated in a previous clinical trial (https://doi.org/10.1111/bjh.16281), is to administer noncytotoxic doses/concentrations of Dec (0.2 mg/kg; ~5 mg/m 2) by a frequent-distributed schedule of 1X/week. An approach to decrease Ven mediated myelosuppression but maintain cooperation with HMA, shown in pre-clinical studies, is to administer a single-dose prior to HMA. Ven can depolarize mitochondrial membranes; mitochondrial membrane-potential is essential to function of the mitochondrial enzyme DHODH that produces cytidine/deoxycytidine that competes with HMA in cells. Thus, Ven prior to HMA dosing temporarily inhibits de novo pyrimidine synthesis, to counter a major mechanism of resistance to HMA in MDS/AML, without suppressing normal myelopoiesis (https://doi.org/10.1182/blood-2020-143200). We conducted a retrospective analysis of all pts with TP53mut MDS or AML treated with weekly Ven and low-dose subcutaneous Dec at our institution. We analyzed the characteristics of these pts, response to therapy, and outcomes using standard descriptive statistics. Mutational testing was performed using a commercial next-generation sequencing (NGS) panel.Five pts, 3 male and 2 female, with TP53mut MDS or AML were treated with weekly Ven 400 mg on D1 and subcutaneous Dec 0.2 mg/kg on D2, administered weekly in 28 day cycles. Two pts had MDS (1 de novo, 1 treatment related) and 3 pts had AML (1 de novo, 2 secondary from prior MDS). Four pts (80%) received the treatment in frontline, all with poor performance status (PS), and 1 pt (20%) had R/R disease. Median age at diagnosis was 79 years [41-82]. The only young pt had prolonged severe cytopenias after 1 cycle Dec standard dosing during the peak of COVID-19 pandemic so was switched to this regimen. Of the 4 frontline treated pts, 2 pts had high-risk MDS, and 2 pts had adverse risk AML. The R/R pt had high-risk MDS transformed to AML that was refractory to 2 prior lines of therapy: standard Aza/Ven x5 cycles, then standard Vyxeos. Disease cytogenetics were complex in all pts. 60% (3/5) pts had sole TP53mut on NGS, with median variant allelic frequency (VAF) 48% [28-79]. 80% (4/5) pts were transfusion dependent prior to treatment. Median time to initiating therapy was 7 days from initial or refractory diagnosis [3-59] and median follow-up was 7.8 months (mo) [2.9-11.4]. The overall response rate (ORR) was 100%: 4/4 frontline pts had complete remissions (CR), and the 1 R/R pt achieved morphologic leukemia-free state (MLFS). Median time to best response was 2.9 mo. 50% (2/4) pts became transfusion independent. 40% (2/5) pts lost their TP53mut at best response, and another 40% (2/5) pts had significant reductions (83% and 38%) in TP53 mut VAF. The regimen was well tolerated with no pts stopping therapy due to adverse effects (AE) . AE included G3/G4 neutropenia (80%), G1 thrombocytopenia (40%), nausea (20%), fatigue (20%), lower extremity edema (20%), pneumonia (60%), and neutropenic fever (20%) with a median of 1 unplanned hospitalization per pt during follow-up. 60% (3/5) pts remain in CR on continued therapy for a median of 7.8 mo [7.2-9.4] thus far. One pt underwent allogeneic stem cell transplantation, however, died 11.4 mo after conditioning due to transplant related mortality. The R/R pt died after being lost to follow-up 2.9 mo after therapy initiation. No pt had measurable relapse during follow-up.Combination weekly Ven with subcutaneous low-dose Dec is well tolerated yielding high rates of clinical and molecular response in pts with TP53mut MDS/AML. Although small, this case-series extends previous clinical trial proof-of-activity of non-cytotoxic DNMT1-targeting to a high-risk, poor PS, historically chemorefractory patient population. The regimen allowed frequent, sustained exposure to therapy often not possible with standard HMA/Ven regimens. [Display omitted] DisclosuresShastri: Kymera Therapeutics: Research Funding; Guidepoint: Consultancy; GLC: Consultancy; Onclive: Honoraria. Gritsman: iOnctura: Research Funding. Feldman: Glycomimetics: Current Employment, Current holder of stock options in a privately-held company. Verma: Celgene: Consultancy; Acceleron: Consultancy; Novartis: Consultancy; Stelexis: Consultancy, Current equity holder in publicly-traded company; Eli Lilly: Research Funding; Curis: Research Funding; Medpacto: Research Funding; Incyte: Research Funding; GSK: Research Funding; BMS: Research Funding; Stelexis: Current equity holder in publicly-traded company; Throws Exception: Current equity holder in publicly-traded company. Saunthararajah: EpiDestiny: Consultancy, Current holder of individual stocks in a privately-held company, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties.

Osimertinib in poor performance status patients with T790M-positive advanced non-small-cell lung cancer after progression of first- and second-generation EGFR-TKI treatments (NEJ032B)

BackgroundOsimertinib is effective in patients with T790M mutation-positive advanced non-small-cell lung cancer (NSCLC) resistant to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs). However, its effectiveness and safety in patients with poor performance status (PS) are unknown.MethodsEnrolled patients showed disease progression after treatment with gefitinib, erlotinib, or afatinib; T790M mutation; stage IIIB, IV, or recurrent disease; and PS of 2–4. Osimertinib was orally administered at a dose of 80 mg/day. The primary endpoint of this phase II study (registration, jRCTs061180018) was response rate and the secondary endpoints were progression-free survival (PFS), overall survival (OS), disease control rate, and safety.ResultsThirty-three patients were enrolled, of which 69.7% and 24.2% had PS of 2 and 3, respectively. One patient was excluded due to protocol violation; in the remaining 32 patients, the response rate was 53.1%; disease control rate was 75.0%; PFS was 5.1 months; and OS was 10.0 months. The most frequent adverse event of grade 3 or higher severity was lymphopenia (12.1%). Interstitial lung disease (ILD) was observed at all grades and at grades 3–5 in 15.2% (5/33) and 6.1% (2/33) of patients, respectively. Treatment-related death due to ILD occurred in one patient. Patients negative for activating EGFR mutations after osimertinib administration had longer median PFS than those positive for these mutations.ConclusionOsimertinib was sufficiently effective in EGFR-TKI-resistant, poor PS patients with T790M mutation-positive advanced NSCLC. Plasma EGFR mutation clearance after TKI treatment could predict the response to EGFR-TKIs.

Treatment Patterns and Outcomes of Patients With Advanced Pleural Mesothelioma at an Academic Referral Centre

BackgroundOverall survival (OS) for malignant pleural mesothelioma (MPM) in vulnerable subgroups remains poorly understood with scarce data available to guide treatment decisions. The study describes real-world detailed treatment patterns and outcomes of patients with advanced MPM overall and specifically in elderly and poor performance status (PS) patients. MethodsRetrospective chart review was performed for all patients with histologically confirmed MPM seen at University Health Network/Princess Margaret Cancer Centre (UHN-PM). ResultsA total of 667 patients with MPM were identified and 304 advanced-disease MPM (aMPM) patients had continuing care at UHN-PM (UP-cohort). In the UP-cohort, 77% of patients received ≥ one line of systemic treatment. Systemic therapy trial participation was 39%. Patients not treated with systemic therapy (29%) were more likely to be ≥ 75 years and PS ≥ 2. Median OS was 15.3 months (95%CI 13.6-18.3), with longer survival in treated vs. untreated patients (17.4 vs. 10.6 months; P = .01). Longer survival with systemic treatment was seen in patients ≥75 years (12.7 vs. 6.6 months) and patients with poor PS (9.1 vs. 5.9 months). Median progression-free-survival (PFS) and OS for patients treated with second-line therapy was poor (3.0 and 8.9 months, respectively). DiscussionIn our real-world analysis of patients with aMPM treated at an academic referral centre, systemic treatment was given to the majority of patients and benefit was seen even in the elderly and poor PS patients frequently underrepresented in clinical trials. Trial participation was potentially facilitated by the formation of a dedicated multidisciplinary MPM clinic.

Are clinical trial eligibility criteria representative of older patients with lung cancer? A population-based data linkage study

ObjectivesOlder adults constitute the majority of patients with lung cancer. However, they are under-represented in clinical trials as eligibility criteria often restrict enrolment based on comorbidities that are common with aging. We aimed to describe comorbidities relating to trial exclusion criteria in older adults with lung cancer, determine the proportion that would typically be excluded from trials, and examine the impact on treatment uptake. Materials and MethodsWe conducted a population-based study of people aged ≥65 years diagnosed with metastatic lung cancer using linked data for clients of the Australian Government Department of Veterans' Affairs (2005–2015). We defined trial-typical patients based on the absence of comorbidities related to the following: inadequate organ (cardiac, renal, hepatic, marrow) function; cognitive dysfunction; poor performance status (PS); prior malignancy within 5 years. We report systemic therapy uptake within 3 months of diagnosis. ResultsOur study included 677 patients (median age 84). Over half (53.4%) were not trial-typical, with the most common reasons being poor PS (37.5%), cardiac disease (19.2%), and prior cancer (12.9%). Eighty-two (12.1%) received systemic therapy. Patients with poor PS, cardiac disease, and dementia had lower treatment uptake rates. However, there was no significant difference in treatment uptake between trial-typical and non-trial-typical patients (13.4 vs 11.0%). ConclusionMore than half of older adults with advanced lung cancer would be typically excluded from trial participation. Future clinical trials of older adults need to consider broader eligibility criteria to better reflect this population to gain the best evidence for their care.

Effectiveness and safety of immunotherapy in NSCLC patients with ECOG PS score ≥2 – Systematic review and meta-analysis

BackgroundImmune checkpoint inhibitors (ICIs) are standard of care in advanced non-small cell lung cancer (NSCLC), however their status in patients with poor performance status (PS) is poorly defined. We aimed to evaluate the efficacy and safety of ICIs in NSCLC patients with PS ≥ 2. MethodsWe conducted a systematic review and meta-analysis of interventional and observational studies, which reported efficacy and safety data on ICIs in PS ≥ 2 comparing to PS ≤ 1 NSCLC patients. Efficacy endpoints included: Objective Response Rate (ORR), Disease-Control Rate (DCR), Overall Survival (OS), Progression-Free Survival (PFS). Safety endpoint was the incidence of severe (grade≥3) Adverse Events (AE). Random-effects model was applied for meta-analysis. Heterogeneity was assessed using I2. The review is registered on PROSPERO (CRD42020162668). FindingsSixty-seven studies (n = 26,442 patients) were included. In PS ≥ 2 vs. PS ≤ 1 patients, the pooled odds ratios were: for ORR 0.46 (95 %CI: 0.39−0.54, I2:0 %); for DCR 0.39 (95 %CI: 0.33−0.48, I2:50 %) and for AEs 1.12 (95 %CI: 0.84–1.48, I2:39 %). The pooled hazard ratio for PFS was 2.17 (95 %CI: 1.96–2.39, I2:65 %) and for OS was 2.76 (95 %CI: 2.43–3.14, I2:76 %). The safety profile was comparable regardless of the PS status. InterpretationPatients with impaired PS status are, on average, twice less likely to achieve a response when exposed to ICIs when compared with representative PS ≤ 1 population. For lung cancer patients treated with ICIs, the impaired PS is not only prognostic, but also predictive for response, while the safety profile is not affected. Prospective randomized studies are indispensable to determine whether poor PS patients derive benefit from ICIs.

Randomized phase III study comparing the first-line chemotherapy regimens in patients with driver mutation-negative advanced non-small cell lung cancer and poor performance status complicated with chronic obstructive pulmonary disease.

BackgroundPatients with non-small cell lung cancer (NSCLC) complicated with chronic obstructive pulmonary disease (COPD) with poor performance status (PS) are common in clinical practice with few related studies. Present studies have found that weekly low-dose docetaxel or gemcitabine combined with platinum is suitable for elderly or poor PS patients with advanced NSCLC.MethodsUntreated advanced driver mutation-negative NSCLC patients with COPD and PS ≥2 were enrolled in this double-blind randomized trial. Both groups controlled their COPD symptoms according to the GOLD guidelines. The anti-tumor regimens included docetaxel (37.5 mg/m2, D1, D8)/carboplatin (AUC 5.0) (DC group) and gemcitabine (1,000 mg/m2, D1, D8)/carboplatin (AUC 5.0) (GC group) were used every 3 weeks with continuous chemotherapy for 4–6 cycles or until disease progression. The primary endpoints were progression-free survival (PFS), and overall survival (OS).ResultsAmong the 52 patients (DC, n=25; GC, n=27), the median follow-up time was 12.3 months. There was no significant difference in tumor overall response rate (ORR; DC, 20.0% vs. GC, 22.2%, P=0.845) and disease control rate (DCR; DC, 72.0% vs. GC, 74.1%, P=0.064) between the 2 groups. The median PFS (GC, 6.5 vs. DC, 5.5 months; P=0.296) and the median OS (GC, 14.9 vs. DC, 12.3 months; P=0.548) of the GC group was slightly longer than the DC group. The main adverse reactions were myelosuppression and there were few adverse reactions of grade 3–4. Compared with the anti-tumor therapy only group in previous literature, the median PFS in this study was longer (6.2 months, 95% CI: 3.533–6.733 vs. 3.5 months, 95% CI: 2.432–4.568; P=0.589). There was also no significant difference in median OS and median PFS between the 2 groups (14.0 vs. 15.0 months, P=0.718). Chemotherapy cycle (P<0.001) was an independent prognostic factor for PFS, while chemotherapy cycle (P=0.011) and PS (P=0.041) were independent prognostic factors for OS.ConclusionsWeekly low-dose docetaxel or gemcitabine combined with carboplatin chemotherapy regimens can yield survival benefits and a tolerable safety profile in patients with driver mutation-negative advanced NSCLC and poor PS complicated with COPD, with no significant difference between the two regimens.Trial RegistrationChinese Clinical Trial Registry ChiCTR-IPR-15006164.

Predictors of hypomethylating agent discontinuation among patients with higher-risk myelodysplastic syndromes.

7043 Background: Real-world studies have shown that persistence with intravenous (IV) and subcutaneous (SC) hypomethylating agents (HMAs) among patients (pts) with higher-risk myelodysplastic syndromes (MDS) is poor, with over one-third of treated pts receiving &lt;4 cycles or having a ≥90-day gap in therapy, despite recommendations for at least 4-6 cycles to elicit response in absence of progression/unacceptable toxicity. Survival outcomes have also been shown to be worse, and direct medical costs higher, among HMA non-persistent vs persistent pts. We explored factors associated with early discontinuation of HMA therapy in this population. Methods: This was a retrospective cohort study among pts from the 2010-2016 SEER-Medicare linked database with a diagnosis of refractory anemia with excess blasts (RAEB; a surrogate for higher-risk MDS) from 2011-2015. Included pts had to have received HMA therapy and have ≥12 months’ continuous follow-up after diagnosis. Discontinuation was defined as stopping HMA therapy before 4 cycles. Multivariable logistic regression was used to assess predictors of HMA discontinuation. Results: In total, 664 pts with RAEB and treated with HMAs were included. Overall, 193 (29%) discontinued before 4 cycles; of these, 91 (47%) discontinued after 1 cycle, 57 (30%) 2 cycles, and 45 (23%) 3 cycles. Compared with pts continuing for ≥4 cycles, pts discontinuing before 4 cycles were generally older and more likely to be single/separated/divorced/widowed, have more comorbidities, and have poor performance status (PS) (Table). These trends were most pronounced among pts discontinuing HMA therapy after only 1 cycle vs ≥4 cycles (Table). In multivariable analysis, age 71-75 vs ≥80 y (odds ratio [OR] 0.556, p=0.017) and poor PS (OR 1.585, p=0.019) remained significant predictors of HMA discontinuation. Among treatment-related factors, the most statistically significant association with HMA discontinuation was observed for GCSF use (OR 0.453, p&lt;0.001). Number of pills/day was not a predictor of HMA discontinuation (OR 1.009, p=NS). Conclusions: In this real-world study, almost one-third of RAEB pts treated with IV/SC HMAs discontinued before 4 cycles, with almost half of these pts discontinuing after only 1 cycle. Predictors of HMA discontinuation included older age and poor PS. Novel approaches are needed to improve persistence with HMA therapy, particularly among these higher-risk groups.[Table: see text]

Immune checkpoint inhibitors in patients with solid tumors and poor performance status: A prospective data from the real-world settings.

Immune checkpoint inhibitors (ICIs) are rapidly being incorporated as treatment option either alone or in combination with chemotherapy in most of the solid tumors. Since there is very limited data of ICI in patients with poor performance status (PS) from the real world settings, we performed a retrospective audit of patients who received ICI and report the analysis based on ECOG PS of these patients.This study is a retrospective audit of a prospectively collected database of patients receiving ICIs for advanced solid tumors in any line between August 2015 and November 2018 at Tata Memorial Hospital, Mumbai, India. All statistical calculations were performed using SPSS statistical software for windows version 20.0.A total of 155 patients who received ICIs during the specified period were evaluated for this study. Baseline ECOG PS 0–1 (n = 103, 66.4%) patients was associated with median OS 9.1 (95% CI [confidence interval], 4.4-NR) months when compared to ECOG 2–4 (n = 52, 33.5%) which had a median OS of 2.9 (95% CI; 1.8–5.5) months (HR, 1.7, 95% CI, 1.1–2.7, log rank P = .017). The disease control rate for the poor PS group was 34.6%. However, 27.3% patients (95% CI: 20.3–34.3) were still alive at 1 year. Median OS in patients with PS 2 was 3.7 months (95% CI: 0–11.6) as compared to 1.8 months (95% CI: 0.2–3.4) for those with PS 3–4 (HR-2.0; 95% CI: 1.0–3.9, P = .041). The tolerance to ICIs was good with no grade 3/4 toxicities in 44 (84.6%) patients.Immune checkpoint inhibitors are a safe and effective therapeutic option even in solid tumor patients with poor performance status.

Clinical factors associated with shorter durable response, and patterns of acquired resistance to first-line pembrolizumab monotherapy in PD-L1-positive non-small-cell lung cancer patients: a retrospective multicenter study

BackgroundDespite the wide-spread use of immune checkpoint inhibitors (ICIs) in cancer chemotherapy, reports on patients developing acquired resistance (AR) to ICI therapy are scarce. Therefore, we first investigated the characteristics associated with shorter durable responses of ICI treatment and revealed the clinical patterns of AR and prognosis of the patients involved.MethodsWe conducted a retrospective multi-center cohort study that included NSCLC patients with PD-L1 tumor proportion scores of ≥50% who received first-line pembrolizumab and showed response to the therapy. Among patients showing response, progression-free survival (PFS) was investigated based on different clinically relevant factors. AR was defined as disease progression after partial or complete response based on Response Evaluation Criteria in Solid Tumors. Among patients with AR, patterns of AR and post-progression survival (PPS) were investigated. Oligoprogression was defined as disease progression in up to 5 individual progressive lesions.ResultsAmong 174 patients who received first-line pembrolizumab, 88 showed response and were included in the study. Among these patients, 46 (52%) developed AR. Patients with old age, poor performance status (PS), at least 3 metastatic organs, or bone metastasis showed significantly shorter PFS. Among 46 patients with AR, 32 (70%) developed AR as oligoprogression and showed significantly longer PPS than those with non-oligoprogressive AR.ConclusionsPatients with old age, poor PS, at least 3 metastatic organs, or bone metastasis showed shorter durable responses to pembrolizumab monotherapy. Oligoprogressive AR was relatively common and associated with better prognosis. Further research is required to develop optimal approaches for the treatment of these patients.

Anti-PD-1 Monotherapy for Advanced NSCLC Patients with Older Age or Those with Poor Performance Status.

PurposeAnti-programmed death 1 (PD-1) antibodies have emerged as frontline treatments for patients with advanced non-small cell lung cancer (NSCLC) on the basis of global Phase III trials. However, current data regarding responses to anti–PD-1 therapy in older patients with NSCLC or those with poor performance status (PS) are limited. Therefore, we examined the therapeutic effect of anti PD-1 antibody in these patients.PatientsWe retrospectively examined consecutive patients treated with anti–PD-1 monotherapy (pembrolizumab or nivolumab) from January 2016 to September 2018.ResultsWe enrolled 125 patients (median age, 60 years), 80.8% of whom were men. Patients aged ≥75 years were considered older patients (n = 15), and those with PS 2–3 were regarded as having poor PS (n = 11). The objective response and disease control rates were 15.4% and 46.2%, respectively, in older patients and 9.1% and 27.3%, respectively, in those with poor PS. Progression-free survival (PFS) and overall survival (OS) did not significantly differ between older and younger patients. However, poor PS was significantly associated with poor survival. High programmed death ligand 1 (PD-L1) expression in tumor specimens (≥50%) was associated with favorable survival in the entire cohort as well as patients with poor PS. Safety analyses demonstrated no significant difference in the occurrence of any adverse event, including grade ≥3 adverse events, between patients with poor PS or older age and the remaining patients.ConclusionAnti–PD-1 therapy had similar efficacy in older and younger patients with NSCLC, whereas survival was significantly worse in patients with poor PS. However, immune checkpoint inhibitors may be considered for patients with poor PS harboring positive PD-L1 expression.