Improvement In Median Overall Survival Research Articles

The Basis and Advances in Clinical Application of Cytomegalovirus-Specific Cytotoxic T Cell Immunotherapy for Glioblastoma Multiforme.

A high percentage of malignant gliomas are infected by human cytomegalovirus (HCMV), and the endogenous expression of HCMV genes and their products are found in these tumors. HCMV antigen expression and its implications in gliomagenesis have emerged as a promising target for adoptive cellular immunotherapy (ACT) strategies in glioblastoma multiforme (GB) patients. Since antigen-specific T cells in the tumor microenvironments lack efficient anti-tumor immune response due to the immunosuppressive nature of glioblastoma, CMV-specific ACT relies on in vitro expansion of CMV-specific CD8+ T cells employing immunodominant HCMV antigens. Given the fact that several hurdles remain to be conquered, recent clinical trials have outlined the feasibility of CMV-specific ACT prior to tumor recurrence with minimal adverse effects and a substantial improvement in median overall survival and progression-free survival. This review discusses the role of HCMV in gliomagenesis, disease prognosis, and recent breakthroughs in harnessing HCMV-induced immunogenicity in the GB tumor microenvironment to develop effective CMV-specific ACT.

Comparative Effectiveness and Safety of Pertuzumab and Trastuzumab Plus Chemotherapy vs Trastuzumab Plus Chemotherapy for Treatment of Metastatic Breast Cancer

To date, limited studies have examined the comparative outcomes of pertuzumab treatment in the real-world setting. End-of-study analyses of the CLEOPATRA trial found median overall survival (OS) of 57.1 months in patients receiving pertuzumab compared with 40.8 months in control patients, a benefit of 16.3 months. However, studies examining the real-world use of pertuzumab have found conflicting results. To assess the real-world comparative effectiveness and safety of pertuzumab, trastuzumab, and chemotherapy for patients with metastatic breast cancer in Ontario, Canada. A population-based retrospective comparative effectiveness research study was conducted. Patients receiving first-line treatments for metastatic breast cancer from January 1, 2008, to March 31, 2018, in Ontario were identified. Data analysis was performed from November 13, 2019, to August 1, 2021. Thirteen patients had received treatment before diagnosis or were not Ontario residents and were excluded from the analysis. Of the remaining 1823 patients identified, 912 received pertuzumab and 911 were control patients. Using propensity-score methods, 579 pairs of patients receiving pertuzumab were matched to those in the control group, resulting in a total of 1158 patients in the final cohort. Patients in the case group received pertuzumab with trastuzumab and chemotherapy and those in the control group received trastuzumab and chemotherapy. Overall survival (the primary outcome) and hazard ratios (HRs) were calculated using Kaplan-Meier and Cox proportional hazards regression methods. Secondary outcomes included cumulative incidence of safety end points including resource use and adverse events. Follow-up duration was up to 5 years from the start of therapy, with maximum follow-up to March 31, 2019. Of the 1158 matched patients (579 pairs) receiving pertuzumab and controls, 1151 (99%) were women (mean [SD] age, 58.2 [12.97] years). The median OS was higher in patients receiving pertuzumab (40.2; 95% CI, 35.6-47.8 months) than in the control patients (25.3; 95% CI, 22.8-27.6 months), a median OS improvement of 14.9 months. Pertuzumab was associated with reduced mortality (HR, 0.66; 95% CI, 0.57-0.79). The cumulative incidence of direct hospitalization at 1 year was lower among patients receiving pertuzumab (11.7%) compared with the control patients (19.0%) (P < .001). Although the median OS in both the pertuzumab and control groups were shorter in this study than those observed in the CLEOPATRA trial, there appears to be a similar significant OS benefit with pertuzumab in the real-world setting.

REVERCEII (ACCRU-GI-1809): A randomized phase II study of regorafenib followed by anti-EGFR monoclonal antibody therapy versus the reverse sequencing for metastatic colorectal cancer patients previously treated with fluoropyrimidine, oxaliplatin and irinotecan.

TPS213 Background: Regorafenib (R) is an oral multikinase inhibitor that blocks several protein kinases involved in angiogenesis and oncogenesis; it has a survival benefit in refractory metastatic colorectal cancer (mCRC). The current standard (std) treatment in patients (pts) with RAS wildtype (WT) mCRC is sequential treatment with an anti-EGFR antibody (AEA) followed by R. However, R, which is orally administered once daily, may be more convenient and thus preferable for pts than AEA. REVERCE, a Japanese trial, demonstrated a significant 5.8 month (mo.) survival benefit with regorafenib administered prior to AEA compared to the std sequence. Based off these findings, the proposed phase II trial is to confirm the observed survival benefit from regorafenib sequencing prior to anti-EGFR monoclonal antibody therapy in REVERCE in a US patient population. Methods: REVERCEII is an Academic and Community Cancer Research United (ACCRU) network-led randomized phase II study of R (dose escalation from 80mg to 160mg based on tolerance) prior to AEA (R+AEA) compared to standard sequencing (AEA+R) in pts with refractory RAS WT mCRC. Patients are randomized 1:1 to receive R (Arm A) vs. AEA (with or without irinotecan per investigator choice) (Arm B). At the time of disease progression or intolerance, patients will receive sequential treatment until disease progression. Eligibility criteria include histologically confirmed mCRC, ECOG ≤ 2, acceptable organ function, and patients must have had prior fluoropyrimidine, oxaliplatin and irinotecan, and no prior AEA nor R. The primary objective is to compare the overall survival (OS), the primary endpoint, between evaluable patients (eligible, consented, started protocol treatment) who were randomized to R+AEA (arm A) and AEA+R (arm B). With 83 OS events, we have 87% power to detect an improvement in median OS from 9 months to 14.5 mo., assuming 1-sided significance level of 0.15, and exponential distribution. The total sample size is 124 patients. Secondary endpoints include progression-free survival, objective response, and adverse events. The total study duration is expected to be 3 years. Clinical trial information: NCT04117945. Clinical trial information: 04117945.

Smoking cessation after lung cancer diagnosis improves disease prognosis

Abstract: The presented clinical and epidemiological study is the world»s first large prospective study of the effect of smoking cessation after lung cancer (LC) diagnosis on the prognosis. Follow‑up of 517 patients with NSCLC for 7 years in average showed that continued smoking after diagnosis is a serious negative prognostic factor. At the same time smoking cessation improves OS and PFS by 22,6 months and specific cancer mortality by 22,8 months; reduces the risk of all‑cause mortality by 33 %, the risk of progression by 30 % and the risk of specific cancer mortality by 25 %. Almost 60 % of patients in our study continued smoking after diagnosis. Consequently, they had avoidable excess mortality which eventually reduced their life by 2 years.The positive effect of smoking cessation after diagnosis found in our study significantly exceeds the «meaningful benefit» (improvement in median overall survival by 2,5–6 months) for antineoplastic agents proposed by the American Society of Clinical Oncology (ASCO). Moreover, the study suggests that the benefits of smoking cessation after LC diagnosis are at least equal or superior to the significant results obtained in clinical studies of the effectiveness of innovative treatments.We hope that the results of our study will contribute to the inclusion of smoking cessation in clinical guidelines for the treatment of NSCLC and other cancers. The treatment program for cancer patients should include evidence‑based methods of smoking cessation presented in the form of «Clinical Guidelines for Smoking Cessation for Cancer Patients».Treating smoking in cancer patients is cost‑effective for the health care system, especially when compared to other treat‑ments. Conversely, continuing smoking after diagnosis significantly increases treatment costs.The introduction of recommendations on smoking cessation and treatment of nicotine addiction into the practice will improve the overall mortality rate by 30–35 % in more than 60,000 patients annually diagnosed with lung cancer in Russia. The clinical value of this method is obvious, since it has been proven to be highly efficient in improving the life expectancy of patients, and, ultimately, in reducing cancer mortality in Russia.

Current and future landscape of targeted therapy in HER2-positive advanced breast cancer: redrawing the lines.

Background:Evidence to date supports continued human epidermal growth factor receptor 2 (HER2) suppression beyond progression on HER2-directed therapy for advanced HER2-positive breast cancer. Data from several phase II and III trials evaluating HER2-directed therapy following second-line T-DM1 have recently become available.Methods:We performed a systematic search of the published and presented literature to identify phase II and phase III trials assessing novel HER2-targeted agents as third-line therapy or beyond for HER2-positive advanced breast cancer using search terms ‘breast cancer’ AND ‘HER2’ AND ‘advanced’ AND (‘phase II’ OR ‘phase III’).Results:Eight clinical trials reporting efficacy outcomes on third-line or greater HER2-directed therapy for HER2-positive advanced breast cancer were identified. In phase III trials, margetuximab and neratinib combinations demonstrated significant 1.3-month (hazard ratio, HR = 0.71, p < 0.001) and 0.1-month (HR = 0.76, p = 0.006) net improvements in median progression-free survival (PFS), respectively, with no significant improvements in overall survival (OS). Tucatinib added to trastuzumab and capecitabine demonstrated a significant 2.7-month improvement in median PFS (HR = 0.57, p < 0.00001) and a 5.5-month improvement in median OS (HR = 0.73, p = 0.004) in a randomized phase II trial, including significant clinical benefit for patients with brain metastases. Finally, trastuzumab-deruxtecan, zenocutuzumab, and poziotinib demonstrated benefit in phase II trials with the most robust overall response rate (62.0%) and median duration of response (18.2 months) observed for trastuzumab-deruxtecan among heavily pretreated patients.Conclusion:Tucatinib plus trastuzumab and capecitabine significantly prolongs OS, and promising preliminary response outcomes for trastuzumab-deruxtecan suggest that sequencing of these regimens following second-line therapy is reasonable.

O-OGC09 PD-1 inhibitors in Oesophageal Cancer: A systematic review of the oncological outcomes associated with PD-1 blockade and the evolving therapeutic landscape

Abstract Background Patients with oesophageal or gastro-oesophageal junction (GOJ) cancer that fail to respond to chemoradiotherapy have a poor clinical prognosis. Recent clinical trials have investigated the use of immune checkpoint inhibitors in these patients. The use of programmed cell death protein 1 (PD-1) inhibitors have emerged as exciting therapeutic options in other solid tumors, such as non-small cell lung cancer, renal cell carcinoma and melanoma. We assessed the efficacy and safety of PD-1 inhibitors in oesophageal and GOJ cancers. Methods This systematic review was performed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. A comprehensive electronic literature search from the EMBASE, Pubmed, Scopus, MEDLINE and Google Scholar databases was conducted up to April 1st 2021. Results This review identified nine eligible studies reporting outcomes of 2149 patients treated with PD-1 blockade compared with 1244 patients treated with either a placebo or the standard regimen of chemotherapy for oesophageal and GOJ cancer. Clinically significant improvements in median overall survival have been demonstrated in advanced and metastatic oesophageal and GOJ cancer while maintaining acceptable safety profiles. Promising survival data has also recently emerged from PD-1 blockade in the adjuvant setting. Conclusions PD-1 blockade in oesophageal and GOJ cancer has delivered impressive survival benefit whilst remaining well tolerated. Its use in the adjuvant setting may further advance our treatment options for this difficult-to-treat tumour, and more advancements in the immunotherapy landscape are highly anticipated. However, further characterization of the PD-1/PD-L1 pathway is required to optimise patient selection.

Real World Outcomes in Patients with Advanced Melanoma Treated in Alberta, Canada: A Time-Era Based Analysis.

Immune checkpoint and MAP kinase pathway inhibitors can significantly improve long-term survival for patients with melanoma. There is limited real-world data of these regimens’ effectiveness. We retrospectively analyzed 402 patients with unresectable and metastatic melanoma between August 2013 and July 2020 treated with immune checkpoint inhibitors and MAP kinase pathway targeted therapy in Alberta, Canada. Overall survival (OS) was compared using Kaplan–Meier and Cox regression analyses. Subgroup survival outcomes were analyzed by first-line treatment regime and BRAF mutation status. Three treatment eras were defined based on drug access: prior to August 2013, August 2013 to November 2016, and November 2016 to July 2020. Across each era, there were improvements in median OS: 11.7 months, 15.9 months, and 33.6 months, respectively. Patients with BRAF mutant melanoma had improved median OS when they were treated with immunotherapy in the first line as opposed to targeted therapy (median OS not reached for immunotherapy versus 17.4 months with targeted treatment). Patients with BRAF wild-type melanomas had improved survival with ipilimumab and nivolumab versus those treated with a single-agent PD-1 inhibitor (median OS not reached and 21.2 months). Our real-world analysis confirms significant survival improvements with each subsequent introduction of novel therapies for advanced melanoma.

Association Between Overall Survival and the Tendency for Cancer Programs to Administer Neoadjuvant Chemotherapy for Patients With Advanced Ovarian Cancer

Randomized clinical trials have found that, in patients with advanced-stage epithelial ovarian cancer, neoadjuvant chemotherapy has similar long-term survival and improved perioperative outcomes compared with primary cytoreductive surgery. Despite this, considerable controversy remains about the appropriate use of neoadjuvant chemotherapy, and the proportion of patients who receive this treatment varies considerably among cancer programs in the US. To evaluate the association between high levels of neoadjuvant chemotherapy administration and overall survival in patients with advanced ovarian cancer. This difference-in-differences comparative effectiveness analysis leveraged differential adoption of neoadjuvant chemotherapy in Commission on Cancer-accredited cancer programs in the US and included women with a diagnosis of stage IIIC and IV epithelial ovarian cancer between January 2004 and December 2015 who were followed up through the end of 2018. The data were analyzed between September 2020 and January 2021. Treatment in a cancer program with high levels of neoadjuvant chemotherapy administration (more often than expected based on case mix) or in a program that continued to restrict its use after the 2010 publication of a clinical trial demonstrating the noninferiority of neoadjuvant chemotherapy compared with primary surgery for the treatment of patients with advanced ovarian cancer. Case mix-standardized median overall survival time and 1-year all-cause mortality assessed with a flexible parametric survival model. We identified 19 562 patients (mean [SD] age, 63.9 [12.6] years; 3.2% Asian, 8.0% Black, 4.8% Hispanic, 82.5% White individuals) who were treated in 332 cancer programs that increased use of neoadjuvant chemotherapy from 21.7% in 2004 to 2009 to 42.2% in 2010 to 2015 and 19 737 patients (mean [SD] age, 63.5 [12.6] years; 3.1% Asian, 7.7% Black, 6.5% Hispanic, 81.8% White individuals) who were treated in 332 programs that marginally increased use of neoadjuvant chemotherapy (20.1% to 22.5%) over these periods. The standardized median overall survival times improved by similar magnitudes in programs with high (from 31.6 [IQR, 12.3-70.1] to 37.9 [IQR, 17.0-84.9] months; 6.3-month difference; 95% CI, 4.2-8.3) and low (from 31.4 [IQR, 12.1-67.2] to 36.8 [IQR, 15.0-80.3] months; 5.4-month difference, 95% CI, 3.5-7.3) use of neoadjuvant chemotherapy after 2010 (difference-in-differences, 0.9 months; 95% CI, -1.9 to 3.7). One-year mortality declined more in programs with high (from 25.6% to 19.3%; risk difference, -5.2%; 95% CI, -6.4 to -4.1) than with low (from 24.9% to 21.8%; risk difference, -3.2%, 95% CI, -4.3 to -2.0) use of neoadjuvant chemotherapy (difference-in-differences, -2.1%; 95% CI, -3.7 to -0.5). In this comparative effectiveness research study, compared with cancer programs with low use of neoadjuvant chemotherapy, those with high use had similar improvements in median overall survival and larger declines in short-term mortality.

PD-1 inhibitors in esophageal cancer: a systematic review of the oncological outcomes associated with PD-1 blockade and the evolving therapeutic paradigm.

Patients with esophageal or gastroesophageal junction (GEJ) cancer who fail to respond to chemoradiotherapy have a poor clinical prognosis. Recent clinical trials have investigated the use of immune checkpoint inhibitors in these patients. The use of programmed cell death protein 1 (PD-1) inhibitors has emerged as exciting therapeutic options in the curative and palliative setting of other solid tumors. We assessed the efficacy and safety of PD-1 inhibitors in esophageal and GEJ cancers. This systematic review was performed in accordance with the PRISMA guidelines. A comprehensive electronic literature search from the EMBASE, Pubmed, Scopus, MEDLINE, and Google Scholar databases was conducted up to 25 July 2021. This review identified 11 eligible studies reporting outcomes of 3451 patients treated with PD-1 blockade compared with 2286 patients treated with either a placebo or the standard regimen of chemotherapy. Clinically significant improvements in median overall survival have been demonstrated in advanced and metastatic esophageal and GEJ cancer while maintaining acceptable safety profiles. Promising survival data have also recently emerged from PD-1 blockade in the adjuvant setting. PD-1 blockade in esophageal and GEJ cancer has delivered impressive survival benefit while remaining well tolerated. Its use in the adjuvant setting will further advance treatment options, and more advancements in this area of therapy are highly anticipated. However, further characterization of the PD-1/programmed death ligand-1 pathway and elucidation of biomarkers to predict response are required to optimize patient selection.

1540P Ripretinib as ≥4th-line treatment in patients with advanced gastrointestinal stromal tumor: Long-term update from the phase III INVICTUS study

Ripretinib is an approved switch-control tyrosine kinase inhibitor (TKI) that broadly inhibits mutant KIT and PDGFRA kinase signaling. In INVICTUS, a randomized, double-blind, placebo-controlled trial in ≥4th-line advanced GIST, ripretinib compared with placebo (PBO) significantly improved median progression-free survival (mPFS; 6.3 vs 1.0 months), reducing the risk of disease progression or death by 85%, and showed a clinically meaningful improvement in median overall survival (mOS; 15.1 vs 6.6 months); data as of May 31, 2019 (ESMO 2019).

LBA17 Overall survival (OS) results from the phase III MONALEESA-2 (ML-2) trial of postmenopausal patients (pts) with hormone receptor positive/human epidermal growth factor receptor 2 negative (HR+/HER2−) advanced breast cancer (ABC) treated with endocrine therapy (ET) ± ribociclib (RIB)

ML-2 (NCT01958021) is a randomized phase III clinical trial investigating first-line (1L) RIB, a cyclin-dependent kinase 4/6 inhibitor (CDK4/6i), + letrozole (LET) vs placebo (PBO) + LET in postmenopausal pts with HR+/HER2− ABC. ML-2 previously reported a statistically significant improvement in progression-free survival (PFS; primary endpoint) with RIB + LET vs PBO + LET (HR, 0.56; 95% CI, 0.43-0.72). We report the protocol-specified final analysis of OS (key secondary endpoint). Postmenopausal pts with HR+/HER2− ABC were randomized 1:1 to receive RIB + LET or PBO + LET. Pts were excluded if they received a prior CDK4/6i, chemotherapy (CT), or ET in the advanced setting. OS was evaluated with a stratified log-rank test and summarized using Kaplan–Meier methods. This protocol-specified analysis was planned after 400 deaths. The intention-to-treat population included 668 pts (RIB: 334; PBO: 334). At data cutoff (10 June 2021), 47 pts were still on treatment (RIB: 30 [9.0%]; PBO: 17 [5.1%]) and the median follow-up was 79.7 mo (min, 74.6 mo). Final OS was evaluated after 400 deaths (RIB: 181 [54.2%]; PBO: 219 [65.6%]). RIB + LET showed a significant OS benefit vs PBO + LET (median, 63.9 vs 51.4 mo; HR, 0.76; 95% CI, 0.63-0.93; P=.004) and met the boundary of statistical significance. Estimated 6-year OS rate was 44.2% for RIB vs 32.0% for PBO. Time to first CT (median, 50.6 vs 38.9 mo; HR, 0.74; 95% CI, 0.61-0.91) and CT-free survival (median, 39.9 vs 30.1 mo; HR, 0.74; 95% CI, 0.62-0.89) showed a consistent benefit for RIB vs PBO. Among pts who discontinued study treatment, 87.8% vs 90.2% received a subsequent antineoplastic therapy for RIB vs PBO, respectively, and 21.7% and 34.4% received a subsequent CDK4/6i. No new safety signals were observed. To date, this is the first report of a statistically significant and clinically meaningful OS benefit with a 1L CDK4/6i in postmenopausal pts with HR+/HER2– ABC. After a median follow-up of >6.5 y, median OS improvement was >12 mo for 1L RIB + LET vs PBO + LET.

MM-130: Updates from ICARIA-MM, a Phase 3 Study of Isatuximab (Isa) Plus Pomalidomide and Low-Dose Dexamethasone (Pd) vs Pd in Relapsed and Refractory Multiple Myeloma (RRMM)

Background Isa is an approved monoclonal antibody that binds to a specific epitope on the CD38 receptor. Phase 3 ICARIA-MM study (NCT02990338) demonstrated improved progression-free survival (PFS) with Isa-Pd vs Pd (P=0.001) and manageable safety profile. Here, we report updated ICARIA results. Methods Patients with RRMM (N=307) who received ≥2 prior therapies, including lenalidomide (Len) and a proteasome inhibitor (PI), were randomized to Isa-Pd (n=154) or Pd (n=153). Isa was administered intravenously at 10 mg/kg weekly for 4 weeks and every other week thereafter. This pre-planned second interim analysis assessed time to next treatment (TTNT), overall survival (OS), time from randomization to disease progression on first subsequent therapy or death (PFS2), and safety. Results Patients had median 3 prior lines of therapy. As of Oct 1, 2020 (median follow-up, 35.3 months), 27 Isa-Pd patients (18%) vs 12 Pd patients (8%) were still on treatment; 60% vs 72% proceeded to subsequent therapy. Median TTNT: 15.5 months Isa-Pd vs 8.9 months Pd (HR 0.56; 95% CI 0.42–0.74; P Conclusions Isa-Pd demonstrates significant improvement in TTNT and PFS2 vs Pd. A strong trend in OS benefit was seen in the Isa-Pd arm, with approximately 7 months improvement in median OS. The OS profile remains unchanged from prior analyses.

Survival Trends in Young Patients with Multiple Myeloma: Focus on Racial-Ethnic Minorities

Background: Population-based studies have shown outcome disparities in multiple myeloma (MM) patients by race-ethnicity. A definite improvement in overall survival (OS) as well as a trend towards younger age at diagnosis has been seen in MM over recent years. Hispanics and African-Americans (AA) have younger median age at MM diagnosis and while overall MM patients have had improving OS, a focus on younger patients, especially racial-ethnic minorities has been missing.Methods: The Surveillance Epidemiology and End Results (SEER) 18 Registry data (1973-2014) was utilized for patients with a confirmed diagnosis of MM. Young MM patients were defined as being diagnosed at <40 years of age. Cases that received a diagnosis at death certificate or autopsy, no follow-up records, no documented age at diagnosis were excluded. OS was estimated using the Kaplan-Meier method. Survival curves were compared using log-rank tests. Expected survival was estimated using the age and sex specific death rates from the US population. Relative survival rate (RSR) was provided as the ratio of the observed to expected survival at individual time points. 5-year and 10-year RSR were calculated for patients diagnosed in 1995 or earlier (no novel agents or stem cell transplant; SCT), between 1996-2002 (SCT but no novel agents) and 2003 or later (SCT and novel agents) was calculated.Results: A total of 89,451 MM patients with MM were available in the SEER database, of which 1,460 were diagnosed at ≤40 years of age (young MM) and met study inclusion. These included 59% males and 41% females with a median age at diagnosis 37 years (range 18-40) for the whole group. Median follow up for the whole cohort was 44 months (range: 0-419 months). Mutually exclusive racial subgroups included non-Hispanic Whites (NHW; 46.8%), non-Hispanic Blacks (NHB; 28.2%), Hispanic (18.4%), Asian (5.5%), Native American (<1%) and other (<1%). No significant differences were noted between the racial subgroups for median age at diagnosis, gender distribution or listed cause of death. Survival analyses were done between NHW, NHB and Hispanics, the 3 largest subgroups in the selected cohort. 5-year and 10-year RSR improved for patients age >40 years diagnosed in the 3 time periods for NHW, NHB and Hispanics (all p<.0001) as well as both genders (p<.0001). For the young MM patients there was a significant improvement in RSR noted over time for both genders (p<.0001) and among racial subgroups for NHW (p<.0001) and NHB (p<.0001) but not for Hispanics. Change in 5-year RSR for Hispanic young MM patients for the 3 time periods was 39%, 48% and 56% (p=.08) and for 10-year RSR was 21%, 35% and 33% (p=.13) (Figure 1).Conclusions: There has been a significant improvement in median OS of MM patients over time due to availability of novel therapeutics including access to SCT. Racial disparities exist in outcomes and we show that young Hispanic MM patients have not yet realized a benefit in outcomes over time possibly due to variability in disease biology, response to therapy or access/utilization of the effective novel therapeutics. These factors need to be explored further to improve outcomes in all MM patients and eliminate disparities, especially the youngest subgroup of patients where survival, productivity and well-being carry different implications. [Display omitted] DisclosuresAilawadhi:Pharmacyclics: Research Funding; Amgen: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Takeda: Consultancy, Honoraria. Sher:LAM Therapeutics, Inc: Research Funding.

Trial in progress: A phase 3, randomized, double-blind trial of trilaciclib versus placebo in patients receiving first- or second-line gemcitabine and carboplatin for locally advanced unresectable or metastatic triple-negative breast cancer (PRESERVE 2).

TPS1107 Background: Trilaciclib is an intravenous (IV), highly potent and selective, reversible cyclin-dependent kinase (CDK) 4/6 inhibitor that protects hematopoietic stem and progenitor cells during chemotherapy (myeloprotection) and may directly enhance antitumor immunity (anticancer efficacy). In a randomized phase 2 trial of trilaciclib administered prior to gemcitabine and carboplatin (GC) versus GC alone in advanced/metastatic triple-negative breast cancer (mTNBC), although the primary endpoint of myeloprotection was not met, the addition of trilaciclib resulted in a substantial improvement in median overall survival (OS; 19.8 months with trilaciclib vs 12.6 months with placebo, hazard ratio [95% CI] = 0.37 [0.21–0.63]; O’Shaughnessy et al. SABCS 2020 [PD1-06]). Clinically meaningful improvements in OS and progression-free survival (PFS) were also observed in both programmed death ligand-1 (PD-L1)–positive and –negative subsets. Methods: The PRESERVE 2 trial (EudraCT: 2020-004930-39) is a randomized, double-blind, placebo-controlled, international phase 3 trial evaluating the efficacy of trilaciclib administered prior to GC in patients with mTNBC. Two mTNBC patient populations will be studied and analyzed separately: cohort 1 (N = 170) will evaluate first-line, PD-1/PD-L1 inhibitor–naïve patients with ≥6 months between completion of last curative treatment and first recurrence; cohort 2 (N = 80) will evaluate second-line PD-L1–positive patients following ≥4 months of PD-1/PD-L1 inhibitor therapy in the advanced setting. Key eligibility criteria for both cohorts include age ≥18 years, Eastern Cooperative Oncology Group performance status of 0/1, and available tumor tissue. Patients will be randomized (1:1) to trilaciclib 240 mg/m2 or placebo prior to gemcitabine 1000 mg/m2 and carboplatin area under the curve 2 IV on days 1 and 8, every 21 days. Stratification factors (cohort 1 only) include tumor PD-L1 status by Ventana SP-142 IVD assay, disease-free interval, and country. Study treatment will continue until progressive disease per RECIST v1.1, unacceptable toxicity, or investigator/patient decision, after which, patients will be followed every 3 months for survival. Up to 80 patients will be consented for optional paired baseline and on-treatment biopsies. Archival tissue and serial peripheral blood will be collected from all patients. The primary endpoint is OS, and the key secondary endpoint is time to confirmed deterioration in fatigue. Other secondary endpoints include PFS, myeloprotection, and safety/tolerability. Exploratory endpoints will assess pharmacodynamic parameters, including those related to immune-based mechanisms, and efficacy by CDK4/6-dependence signatures. Study enrollment is open. Clinical trial information: 2020-004930-39 .

Masitinib plus gemcitabine as first-line treatment of pancreatic cancer with pain: Results from phase 3 study AB12005.

4018 Background: Masitinib (MAS) is a small molecule drug targeting mast cell and macrophage activity, innate immune cells that are critical components of the tumor microenvironment. Proof of concept that MAS in combination with gemcitabine (GEM) improved overall survival (OS) in pancreatic cancer (PC) patients (pts) with pain, was previously shown [doi 10.1093/annonc/mdv133]. The presence of pain in PC is thought to identify pts whose disease is driven in part by a pro-tumoral immune response. Methods: AB12005 was a prospective, placebo (PBO) controlled, double blind, randomized (2:1 MAS:PBO, stratified by disease stage, ECOG and geographic region) phase 3 trial, evaluating oral MAS (6.0 mg/kg/d) in combination with GEM (1000 mg/m²) against PBO plus GEM for the treatment of unresectable locally advanced PC (LAPC) and/or metastatic PC (mPC) pts with pain criteria; i.e. baseline visual analog scale of pain intensity (VAS) &gt; 20 and/or pt treated with an opioid analgesics dose ≥1 mg/kg/d at baseline. Eligible pts were chemo-naïve with histologically or cytologically confirmed inoperable LAPC or mPC and an ECOG status ≤2. The estimated sample size was ̃330 pts to detect an OS hazard ratio (HR) of 0.68 (80% power, 2-sided α = 0.025) after 310 deaths. The study was successful if improvement in median OS (primary endpoint) relative to control reached a 2.5% level of statistical significance for either a targeted subgroup of LAPC with pain criteria, or the overall study cohort. Results: A total of 384 pts were enrolled (safety population n = 383; mITT n = 379; target subgroup n = 92). In the predefined subgroup of unresectable LAPC with pain, MAS-GEM (n = 62) showed significant benefit over PBO-GEM (n = 30) with median OS of 13.0 months (97.5% CI [11.0;18.0]) vs 11.2 months (97.5% CI [7.4;13.0]); p = 0.007. The HR was 0.46 (97.5% CI [0.2;0.9], p = 0.0047), corresponding to a significant 54% reduction in risk of death for MAS-GEM pts relative to control. Secondary analyses in the same subgroup were convergent with this primary outcome. Median PFS showed a 1.8 month between group difference in favor of MAS-GEM (p = 0.039), with a HR of 0.47 (97.5% CI [0.3;0.9], p = 0.014). The 12-month and 18-month OS rates showed a 1.3 fold and 3.4 fold improvement, respectively, in favor of MAS-GEM (53.2% and 33.9% for MAS-GEM vs 40.0% and 10% for PBO-GEM, respectively). In the overall population, comprising LAPC and mPC pts with pain, no survival benefit was observed; median OS for MAS-GEM (n = 244) was 6.9 months vs 8.0 months for PBO-GEM (n = 135); p = 0.461. The MAS-GEM combination was well tolerated with no sign of add-on toxicity. The proportion of patients presenting at least one adverse event (AE) or serious AE was respectively, 96.3% and 19.1% for MAS-GEM (n = 246) vs 99.3% and 21.3% for PBO-GEM (n = 136). Conclusions: The combination MAS (6.0 mg/kg/d) plus GEM may provide a new first line treatment option for unresectable LAPC pts with associated pain. Clinical trial information: NCT03766295.

Updates from ICARIA-MM, a phase 3 study of isatuximab (Isa) plus pomalidomide and low-dose dexamethasone (Pd) versus Pd in relapsed and refractory multiple myeloma (RRMM).

8017 Background: Isa is an approved monoclonal antibody that binds to a specific epitope on the CD38 receptor. The Phase 3 ICARIA-MM study (NCT02990338) demonstrated significantly improved progression-free survival (PFS) with Isa-Pd vs Pd ( P= 0.001) and a manageable safety profile (Attal M, et al. Lancet 2019;394:2096-2107). Here we report updated ICARIA results. Methods: Pts with RRMM (N = 307) who have received ≥2 prior therapies, including lenalidomide (Len) and a proteasome inhibitor (PI), were randomized to Isa-Pd (n = 154) or Pd (n = 153). Isa was administered intravenously at 10 mg/kg weekly for 4 weeks, and every other week thereafter. This preplanned second interim analysis assessed longer term outcomes, including time to next treatment (TTNT), overall survival (OS), time from randomization to disease progression on first subsequent therapy or death (PFS2), and safety. Results: Pts had a median of 3 prior lines of therapy (IQR 2–4; table). As of Oct 1, 2020 (median follow-up, 35.3 months [mo]), 27 Isa-Pd pts (18%) vs 12 Pd pts (8%) were still on treatment; 60% vs 72% had proceeded to subsequent therapy. Median TTNT was 15.5 mo with Isa-Pd vs 8.9 mo with Pd (hazard ratio [HR] 0.56; 95% confidence interval [CI] 0.42–0.74; P&lt; 0.0001); 24% vs 58% of pts with subsequent therapy received daratumumab (dara). Overall response rate (ORR) in subsequent treatment with dara monotherapy was higher after Pd (38%) than Isa-Pd (14%), but was similar (32% vs 31%) with dara combination therapy (table). Median PFS2 in the intent-to-treat population was 17.5 mo with Isa-Pd vs 12.9 mo with Pd (HR 0.76; 95% CI 0.58–0.99; P= 0.0202). Median OS was 24.6 mo with Isa-Pd vs 17.7 mo with Pd (HR 0.76; 95% CI 0.58–1.01; one-sided P= 0.0280). Median treatment duration was 47.6 weeks (range 1.3–171.6) with Isa-Pd vs 24.0 weeks (range 1.0–168.6) with Pd. Serious treatment-emergent adverse event (TEAEs) were seen in 73% of Isa-Pd pts vs 60% of Pd pts. Most frequent non-hematologic TEAEs (any grade) with Isa-Pd were infusion reaction (38%), upper respiratory tract infection (34%), and diarrhea (30%). Grade 3–4 neutropenia (85% vs 71%) and thrombocytopenia (34% vs 25%) were more frequent with Isa-Pd than with Pd. Conclusions: Isa-Pd demonstrates a significant improvement in TTNT and PFS2 compared with Pd. A strong trend in OS benefit was also seen in the Isa-Pd arm, with approximately 7 mo improvement in median OS. The overall safety profile remains unchanged from prior analyses. Funding: Sanofi. Clinical trial information: NCT02990338. [Table: see text]

Final overall survival in the phase 3 NETTER-1 study of lutetium-177-DOTATATE in patients with midgut neuroendocrine tumors.

4112 Background: As demonstrated in the primary analysis of the phase 3 NETTER-1 trial, 177Lu-DOTATATE significantly prolonged progression-free survival (PFS) versus high-dose long-acting octreotide, with a HR of 0.18 (95% CI: 0.11, 0.29; p &lt; 0.0001), in patients with advanced, progressive, well-differentiated, somatostatin receptor-positive midgut neuroendocrine tumors (NETs). Here we report final overall survival (OS) for NETTER-1. Methods: In this international open-label trial, eligible patients were randomized to receive either four cycles of 177Lu-DOTATATE 7.4 GBq (200 mCi) every 8 ± 1 weeks plus long-acting octreotide 30 mg or high-dose long-acting octreotide 60 mg every 4 weeks (control arm), both on top of best supportive care. After disease progression on randomized treatment or completion of an 18-month treatment period, patients in both arms entered long-term follow-up and could receive further anti-cancer treatment as recommended by their physicians. The primary endpoint was PFS per RECIST 1.1 and OS was a key secondary endpoint. Primary intention-to-treat analysis of OS was prespecified to take place after 158 deaths or 5 years after the last patient was randomized, whichever occurred first. Results: Of 231 randomized patients, 101/117 (86.3%) in the 177Lu-DOTATATE arm and 99/114 (86.8%) in the control arm entered long-term follow-up. Final analysis occurred 5 years after the last patient was randomized, following 142 deaths, with a median follow-up of more than 76 months. During long-term follow-up, 41/114 (36%) of patients in the control arm received subsequent radioligand therapy (“cross-over”), the majority (22.8%) within 24 months. Median OS was 48.0 months (95% CI: 37.4, 55.2) in the 177Lu-DOTATATE arm and 36.3 months (95% CI: 25.9, 51.7) in the control arm. HR was 0.84 (95% CI: 0.60, 1.17) with p = 0.30 (unstratified 2-sided log-rank test). A total of 2/112 (1.8%) 177Lu-DOTATATE treated patients in the study developed myelodysplastic syndrome (MDS). No new cases of MDS or acute leukemia were reported in the long-term follow-up. Overall, no new safety signals emerged during long-term follow-up. Conclusions: Median OS was 48.0 months in the 177Lu-DOTATATE arm of the NETTER-1 trial and 36.3 months in the control arm. This difference was not statistically significant, potentially impacted by a high rate (36%) of cross-over of patients in the control arm to radioligand therapy after progression. In overall conclusion, the NETTER-1 study demonstrated that 177Lu-DOTATATE yielded a clinically and statistically significant improvement in PFS as a primary endpoint (HR: 0.18, p &lt; 0.0001) as well as a clinically meaningful trend towards improvement in median OS of 11.7 months. No new safety signals emerged during the 5-year long-term follow-up. Clinical trial information: NCT01578239.

ROCSAN trial (GINECO-EN203b/ENGOT-EN8): A multicentric randomized phase II/III evaluating dostarlimab in combination with niraparib versus niraparib alone compared to chemotherapy in the treatment of endometrial/ovarian carcinosarcoma after at least one line of platinum based chemotherapy.

TPS5604 Background: Gynecological carcinosarcomas (CS) are rare and highly aggressive tumors with a 5-year overall survival (OS) &lt; 10%. After initial treatment majority of patients (pts) relapse and receive diverse chemotherapies (CT) producing modest benefits. The median PFS in relapse after platinum based CT is less than 4 months and median OS less than 1 year. New innovative strategies are urgently needed. Since CS showed high DNA damage response activity and potentially a high tumor mutation load resulting in neo-antigens, a synergy between PARPi and anti-PD1 is expected. Methods: ROCSAN is a multicentric, randomized, open-label, integrated Phase II/III study. In the Phase II, 63 pts with recurrent or progressing endometrial or ovarian CS after at least a first line of platinum-based CT will be randomized (2:2:1) to receive either niraparib in monotherapy, niraparib in combination with dostarlimab or standard CT (paclitaxel, doxorubicine, gemcitabine, topotecan). Stratification factors include the number of previous CT lines (1 vs 2-3), FIGO stage at diagnosis (I-II vs III-IV), CS localisation (ovarian vs endometrial), and performance status (0-1 vs 2). The primary objective of the Phase II is to select the best experimental strategy between niraparib and dostarlimab/niraparib combination based on Response Rate at 4 months (RR-4M by RECIST1.1). A single stage design with a 10% unacceptable RR-4M and a 30% targeted RR-4M was used to determine Phase II sample size, assuming a 10% one sided alpha for each comparison and more than 90% power. A pick-the-winner selection design could be used in case of promising efficacy in each experimental arm. At the interim analysis, an Independent Data Monitoring Committee will make recommendation for the selection of the optimal experimental arm. The Steering committee could then support to continue enrolment for the international Phase III which is calibrated to detect an improvement in median OS from 7 months (Standard CT) to 11.7 months (best experimental arm). Assuming a 5% alpha level and 80% power, 133 additional pts could be randomized (2:1). Secondary endpoints include safety, PFS, PFS2, TTST, ORR, duration of response, patient report outcomes (assessed via EORTC QLQ-C30 OV28, HADS, PRO-CTCAE). A translational program supported by European Community is associated to the clinical study to identify predictive biomarkers of response/resistance to study treatments, to correlate with immune environment, a special focus on genetic instability and the EMT process will be included. Trial is currently recruiting only in France for the phase II part, the first pt was randomized in July 2020. Clinical trial information: NCT 03651206.

Pharmacotherapy for liposarcoma: current and emerging synthetic treatments.

Liposarcomas are rare tumors arising from adipocytic tissue and accounting for approximately 15-20% of all soft tissue sarcomas. Liposarcoma can be further classified into histopathological subtypes with variable chemosensitivity according to subtype. Decisions regarding management should be made on an individual basis, but surgery for localized disease and systemic chemotherapy remain the mainstay of treatment. Currently, only doxorubicin and trabectedin have robust Phase III data to support their use in the management of advanced liposarcoma. However, in the subgroup analysis of a Phase III trial comparing eribulin with dacarbazine, there was a greater than 7-month improvement in median overall survival in those treated witheribulin. There are alsopromising results from emerging studies in novel and targeted agents for the treatment ofliposarcoma.

Impact of a Thoracic Multidisciplinary Conference on Lung Cancer Outcomes

BackgroundWith the complexity of cancer treatment rising, the role of multidisciplinary conferences (MDCs) in making diagnostic and treatment decisions has become critical. This study evaluated the impact of a thoracic MDC (T-MDC) on lung cancer care quality and survival. MethodsLung cancer cases over 7 years were identified from the Roswell Park cancer registry system. The survival rates and treatment plans of 300 patients presented at the MDC were compared with 300 matched patients. The National Comprehensive Cancer Network (NCCN) guidelines were used to define the standard of care. The compliance of care plans with NCCN guidelines was summarized using counts and percentages, with comparisons made using the Fisher exact test. Survival outcomes were summarized using Kaplan-Meier methods. ResultsThere was improvement in median overall survival (36.9 vs 19.3 months; P < .001) and cancer-specific survival (48 vs 28.1 months; P < .001) for lung cancer patients discussed at the T-MDC compared with controls. These differences were statistically significant in patients with stages III/IV disease but not in patients with stages I/II disease. The NCCN guidelines compliance rate of treatment plans improved from 80% to 94% (P < .001) after MDC discussion. MDC recommendations resulted in treatment plan changes in 123 of 300 patients (41%). ConclusionsOur results suggest that lung cancer patients have a survival benefit from MDC discussion compared with controls. Patients with advanced disease (stages III and IV) benefited the most. Further research is necessary to understand the precise mechanisms that drive these results.