Significant Progression-free Survival Benefit Research Articles

Effect of Favorable Pathologic Response After Neoadjuvant Radiation Therapy Alone in Soft-tissue Sarcoma

PurposeWhether the therapeutic response of soft-tissue sarcoma to neoadjuvant treatment is predictive for clinical outcomes is unclear. Given the rarity of this disease and the confounding effects of chemotherapy, this study analyzes whether a favorable pathologic response (fPR) after neoadjuvant radiation therapy (RT) alone is associated with clinical benefits. Methods and MaterialsAn institutional review board-approved retrospective review was conducted on a database of patients with primary soft-tissue sarcoma treated at our institution between 1987 and 2015 with neoadjuvant RT alone followed by surgical resection. Time-to-event outcomes estimated with a Kaplan–Meier analysis included overall survival, progression-free survival (PFS), locoregional control, and distant control (DC). Cox regression analyses were performed to determine prognostic variables associated with clinical outcomes. ResultsOf the overall cohort of 315 patients, 181 patients (57%) were included in the primary analysis with documented pathologic necrosis (PN) rates (mean: 59%) and a median follow up from diagnosis of 48 months (range, 4-170 months). The median neoadjuvant RT dose was 50 Gy (range, 40-60 Gy), and the majority of patients had negative surgical margins (79%). Only 35 patients (19%) achieved a fPR (PN ≥95%), which was associated with a higher R0 resection rate (94% vs. 75%; P = .013), a significant 5-year PFS benefit (74% vs. 43%; P = .014), and a nonsignificant 5-year DC benefit (76% vs. 62%; P = .12) compared with PN <95%. On multivariable analysis, fPR was an independent predictor for PFS (hazard ratio: 0.47; 95% confidence interval, 0.25-0.90; P = .022). ConclusionsAchieving fPR with neoadjuvant RT alone is associated with a higher R0 resection rate and possible DC benefit, translating into a significant improvement in PFS. Further studies to improve pathologic response rates and prospectively validate this endpoint are warranted.

No obvious advantage of hyperthermic intraperitoneal chemotherapy after interval debulking surgery in the treatment of advanced ovarian cancer: A retrospective study.

ObjectiveTo study the efficacy of interval debulking surgery (IDS) plus hyperthermic intraperitoneal chemotherapy (HIPEC) compared to IDS alone for the treatment of ovarian cancer after neoadjuvant chemotherapy (NACT).MethodsWe conducted a retrospective study of patients with stage IIIC/IV high-grade serous ovarian carcinoma who underwent surgery at our center from January 2018 to December 2019. Patients who underwent IDS after NACT with (N = 20) or without (N = 42) HIPEC were included. HIPEC was administered after surgery and was combined with 1–2 courses of intraperitoneal hyperthermic perfusion with normal saline only. We analyzed clinical information and outcomes for the two groups.ResultsThe median progression-free survival (PFS) was 14.05 months in the IDS plus HIPEC group and 12.97 months in the IDS group (P = 0.597). The median overall survival (OS) was not reached. After adjustment for age between the two groups, the differences in PFS and OS remained nonsignificant. The change ratio of postoperative CA-125 to preoperative CA-125 was 0.66 in the IDS plus HIPEC group and 0.53 in the IDS group (P = 0.341). The difference in human epididymis protein 4 (HE-4) change ratio between the two groups was nonsignificant (P = 0.225). No significant difference was observed in the occurrence of grade 3 and 4 adverse events between the two groups (P = 0.201).ConclusionAfter NACT, IDS plus HIPEC did not show significant PFS and tumor index change ratio benefits over IDS alone in patients with primary ovarian cancer. Further investigations are needed to assess the role of HIPEC in the treatment of ovarian cancer.

Maintenance olaparib plus bevacizumab in patients with newly diagnosed advanced high-grade ovarian cancer: Main analysis of second progression-free survival in the phase III PAOLA-1/ENGOT-ov25 trial

BackgroundPAOLA-1/ENGOT-ov25 (NCT02477644) demonstrated a significant progression-free survival (PFS) benefit with maintenance olaparib plus bevacizumab versus placebo plus bevacizumab in newly diagnosed, advanced ovarian cancer. We report the prespecified main second progression-free survival (PFS2) analysis for PAOLA-1. MethodsThis randomised, double-blind, phase III trial was conducted in 11 countries. Eligible patients had newly diagnosed, advanced, high-grade ovarian cancer and were in response after first-line platinum-based chemotherapy plus bevacizumab. Patients were randomised 2:1 to olaparib (300 mg twice daily) or placebo for up to 24 months; all patients received bevacizumab (15 mg/kg every 3 weeks) for up to 15 months. Primary PFS end-point was reported previously. Time from randomisation to second disease progression or death was a key secondary end-point included in the hierarchical-testing procedure. ResultsAfter a median follow-up of 35.5 months and 36.5 months, respectively, median PFS2 was 36.5 months (olaparib plus bevacizumab) and 32.6 months (placebo plus bevacizumab), hazard ratio 0.78; 95% confidence interval (CI) 0.64–0.95; P = 0.0125. Median time to second subsequent therapy or death was 38.2 months (olaparib plus bevacizumab) and 31.5 months (placebo plus bevacizumab), hazard ratio 0.78; 95% CI 0.64–0.95; P = 0.0115. Seventy-two (27%) patients in the placebo plus bevacizumab group received a poly(ADP-ribose) polymerase inhibitor as first subsequent therapy. No new safety signals were observed for olaparib plus bevacizumab. ConclusionIn newly diagnosed, advanced ovarian cancer, maintenance olaparib plus bevacizumab provided continued benefit beyond first progression, with a significant PFS2 improvement and a time to second subsequent therapy or death delay versus placebo plus bevacizumab.

369P Irinotecan is superior to oxaliplatin in KRAS-G12C-mutated (K-G12C-m) colorectal cancer (CRC) and should be preferred in combination strategies with K-G12C inhibitors. A multicenter propensity score-matched (PSM) retrospective analysis

K-G12C inhibitors have recently become available, yet limited activity has been observed when used as monotherapy in CRC. Given their good safety profile, combination strategies with other targeted agents or chemotherapy (CT) are being considered to increase efficacy. A multicenter analysis was conducted to assess the efficacy of standard first-line CT in K-G12C-m metastatic CRC patients(pts). K-G12D-m pts were used as control group. Only pts treated with first-line FOLFIRI or FOLFOX +/- bevacizumab (bev) were included. Primary and secondary outcome measures were progression free survival (PFS) and objective response rate (ORR), respectively. Both an unmatched and a PSM analysis were conducted. 86 pts were included: 51 K-G12C-, 35 K-G12D-m. Median age was 63 yrs (range 34-83), 49 were male, 37 female. Liver mets were present in 71% of pts, 51% had 2 or more metastatic sites. FOLFIRI, FOLFIRI-bev, FOLFOX and FOLFOX-bev was the first-line for 15, 36, 10 and 25 pts, respectively. In K-G12C-m pts a statistically significant benefit in PFS was demonstrated for FOLFIRI+/-bev vs FOLFOX+/-bev: HR 0.52 (95%CI 0.28-0.98), p 0.04. The benefit was even more pronounced in the PSM analysis based on age, gender, receipt of bev, grading, KPS, metachronous vs synchronous mets, number of metastatic sites, presence of peritoneal mets: HR 0.24 (95%CI 0.08-0.71), p 0.01. No difference in ORR was seen: 48% vs 47%, p 0.87, respectively. Also median PFS was not numerically different: 11.7 vs 11.6 months, however 12-, 18-, 24-month PFS rates were 48%, 43%, 32% and 46%, 18%, 5% for FOLFIRI+/-bev and FOLFOX+/-bev, respectively. In the K-G12D-m group, no significant differences were observed between FOLFIRI+/-bev vs FOLFOX+/-bev for both PFS and ORR, p 0.09 and 0.45, respectively. Irinotecan (i.e. FOLFIRI+/-bev) was significantly superior to oxaliplatin (i.e. FOLFOX+/-bev) in K-G12C-m CRC pts, with a subset of pts (32%) achieving a long-lasting (> 2 yrs) PFS. Irinotecan should be the preferred chemotherapy to be used in combination strategies with K-G12C inhibitors.

LBA76 Overall survival (OS) results from the phase III TROPiCS-02 study of sacituzumab govitecan (SG) vs treatment of physician's choice (TPC) in patients (pts) with HR+/HER2- metastatic breast cancer (mBC)

Pts with HR+/HER2- mBC are treated with endocrine-based therapy (ET), followed by single-agent chemotherapy (CT), with increasingly shorter durations of benefit. SG is an anti–Trop-2 antibody-drug conjugate approved for triple-negative mBC with ≥2 prior therapies (≥1 in the metastatic setting). In TROPiCS-02 (NCT03901339), SG showed significant progression-free survival (PFS) benefit vs TPC in ET resistant HR+/HER2- mBC (HR, 0.66; P<0.001; median 5.5 vs 4.0 mo; Rugo, et al. ASCO 2022). Here, we report the planned TROPiCS-02 OS 2nd interim analysis.

LBA29 Final overall survival (OS) results from the phase III PAOLA-1/ENGOT-ov25 trial evaluating maintenance olaparib (ola) plus bevacizumab (bev) in patients (pts) with newly diagnosed advanced ovarian cancer (AOC)

In the PAOLA-1/ENGOT-ov25 (NCT02477644) primary analysis, adding ola to maintenance bev after first-line (1L) platinum-based chemotherapy (PBC) + bev led to a significant progression-free survival (PFS) benefit in AOC (HR 0.59, 95% CI 0.49–0.72; P<0.001), particularly in pts with homologous recombination deficiency (HRD+; BRCA1/2 mutation [BRCAm] and/or genomic instability; Ray-Coquard et al NEJM 2019). Here, we report the prespecified final OS analysis.

205P Pooled exploratory analysis of survival in patients (pts) with HR+/HER2- advanced breast cancer (ABC) and visceral metastases (mets) treated with ribociclib (RIB) + endocrine therapy (ET) in the MONALEESA (ML) trials

RIB + ET demonstrated statistically significant progression-free survival (PFS) and overall survival (OS) benefits in the ML-2, -3, and -7 trials in pts with HR+/HER2− ABC. The presence of visceral mets indicates a worse prognosis, with a particularly poor survival observed in pts with liver mets. Here we report a pooled survival analysis of the ML-2, -3, and -7 trials in pts with visceral mets, including those with liver mets. In ML-2, postmenopausal pts were randomized 1:1 to receive first-line (1L) RIB or placebo (PBO) with letrozole. In ML-3, postmenopausal pts were randomized 2:1 to receive RIB or PBO with fulvestrant in the 1L or second-line (2L) setting. In ML-7, premenopausal pts were randomized 1:1 to receive 1L RIB or PBO and goserelin with nonsteroidal aromatase inhibitor (NSAI)/tamoxifen (only pts in the NSAI arm were included in this analysis). A significant PFS and OS benefit was observed with RIB in pts with visceral mets (Table), among which were pts with liver mets or ≥3 met disease sites across the pooled population of 1L/2L. This significant benefit persisted in the 1L subgroup, including in the subgroups of pts with a worse prognosis, such as those with liver mets or ≥3 met sites who achieved a median OS of ≈4-5 y with RIB. No new safety signals, including liver enzyme elevations, even in pts with baseline liver mets, were observed. This large, pooled analysis of the ML trials confirms the consistent survival benefit of RIB + ET in pts with visceral mets who historically have a poor prognosis. This analysis also demonstrates the substantial benefit of RIB in those with poorer outcomes within the visceral mets subgroup, ie, pts with liver mets and those with multiple met disease sites, especially in the 1L population.Table: 205PVisceral metsLiver metsVisceral mets and ≥3 metsET+Overall1LOverall1LOverall1LRIBPBORIBPBORIBPBORIBPBORIBPBORIBPBOn640484395319276222140116334263253195mPFS, mo22.112.729.614.713.45.716.79.821.311.024.814.5HR (95% CI), P0.61 (0.53-0.70), <.00010.57 (0.48-0.68), <.0010.52 (0.42-0.65), <.00010.55 (0.41-0.74), <.00010.55 (0.46-0.67), <.00010.59 (0.47-0.74), <.001mOS, mo49.046.562.752.139.635.444.238.149.040.457.749.3HR (95% CI), P0.81(0.69-0.94), .0030.79(0.65-0.97), .0230.71(0.57-0.89), .0020.77(0.55-1.07), .120.73 (0.59-0.90), .0020.81 (0.63-1.03), .09 Open table in a new tab

Sacituzumab Govitecan in Hormone Receptor-Positive/Human Epidermal Growth Factor Receptor 2-Negative Metastatic Breast Cancer.

Hormone receptor-positive (HR+) human epidermal growth factor receptor 2-negative (HER2-) endocrine-resistant metastatic breast cancer is treated with sequential single-agent chemotherapy with poor outcomes. Sacituzumab govitecan (SG) is a first-in-class antibody-drug conjugate with an SN-38 payload targeting trophoblast cell-surface antigen 2, an epithelial antigen expressed in breast cancer. In this global, randomized, phase III study, SG was compared with physician's choice chemotherapy (eribulin, vinorelbine, capecitabine, or gemcitabine) in endocrine-resistant, chemotherapy-treated HR+/HER2- locally recurrent inoperable or metastatic breast cancer. The primary end point was progression-free survival (PFS) by blinded independent central review. Patients were randomly assigned to receive SG (n = 272) or chemotherapy (n = 271). The median age was 56 years, 95% had visceral metastases, and 99% had a prior cyclin-dependent kinase 4/6 inhibitor, with three median lines of chemotherapy for advanced disease. Primary end point was met with a 34% reduction in risk of progression or death (hazard ratio, 0.66 [95% CI, 0.53 to 0.83; P = .0003]). The median PFS was 5.5 months (95% CI, 4.2 to 7.0) with SG and 4.0 months (95% CI, 3.1 to 4.4) with chemotherapy; the PFS at 6 and 12 months was 46% (95% CI, 39 to 53) v 30% (95% CI, 24 to 37) and 21% (95% CI, 15 to 28) v 7% (95% CI, 3 to 14), respectively. Median overall survival (first planned interim analysis) was not yet mature (hazard ratio, 0.84; P = .14). Key grade ≥ 3 treatment-related adverse events (SG v chemotherapy) were neutropenia (51% v 38%) and diarrhea (9% v 1%). SG demonstrated statistically significant PFS benefit over chemotherapy, with a manageable safety profile in patients with heavily pretreated, endocrine-resistant HR+/HER2- advanced breast cancer and limited treatment options.

A randomized Phase III trial of durvalumab with chemotherapy and bevacizumab, followed by maintenance durvalumab, bevacizumab and olaparib in newly diagnosed advanced ovarian cancer (DUO-O): Updated trial endpoint and inclusion of China cohort (329)

Objectives: Maintenance therapy with the PARP inhibitor olaparib (with or without the antiangiogenic agent bevacizumab) leads to significant progression-free survival (PFS) benefits in patients with newly diagnosed advanced ovarian cancer (OC) (with or without a BRCA’ and/or BRCA2 mutation [BRCAm]) (Moore et al. N Eng J Med 2018; Ray-Coquard et al. N Eng J Med 2019). Preclinical data have shown a potential synergistic antitumor effect when combining an immune checkpoint inhibitor with an antiangiogenic agent and a PARP inhibitor. The combination has shown promise as a treatment in platinum-sensitive relapsed non-germline BRCAm OC patients (Drew et al. ESMO 2020). The Phase III DUO-O trial (NCT03737643) began global enrollment in January 2019 and will evaluate the efficacy and safety of combinations of the standard of care platinumbased chemotherapy, bevacizumab, and the anti-PD-L1 antibody durvalumab, followed by maintenance bevacizumab, durvalumab, and olaparib in patients with newly diagnosed advanced OC (Harter et al. ASCO 2019). The China cohort will evaluate these combinations in a standalone analysis of patients with non-BRCAm tumors. Methods: Eligible patients must have newly diagnosed stage III or IV high-grade ovarian, epithelial, fallopian, or primary peritoneal cancer and have undergone upfront primary surgery or be planned to have interval debulking surgery. From sites in China, ~120 patients with a non-BRCAm tumor (using a China-based central laboratory to determine BRCAm status) will be randomized 1:1:1 to: chemotherapy + bevacizumab + durvalumab, followed by bevacizumab + durvalumab + olaparib maintenance; chemotherapy + bevacizumab + durvalumab, followed by bevacizumab + durvalumab + placebo maintenance; or chemotherapy + bevacizumab + placebo, followed by bevacizumab + placebo. Olaparib (300 mg bid) and durvalumab (1120 mg q3w) will be administered for up to 24 months, and bevacizumab (15 mg/kg q3w) for up to 15 months, or until disease progression. The primary endpoints are investigator-assessed PFS (modified RECIST v1.1) in all patients with a non-BRCA tumor and patients with a non-BRCA, homologous recombination deficiency-positive tumor. A key secondary efficacy endpoint is overall survival, and safety will be summarized descriptively. Local China protocol amendments are in progress, and relevant updates will be presented. Enrollment in China began in April 2021. Objectives: Maintenance therapy with the PARP inhibitor olaparib (with or without the antiangiogenic agent bevacizumab) leads to significant progression-free survival (PFS) benefits in patients with newly diagnosed advanced ovarian cancer (OC) (with or without a BRCA’ and/or BRCA2 mutation [BRCAm]) (Moore et al. N Eng J Med 2018; Ray-Coquard et al. N Eng J Med 2019). Preclinical data have shown a potential synergistic antitumor effect when combining an immune checkpoint inhibitor with an antiangiogenic agent and a PARP inhibitor. The combination has shown promise as a treatment in platinum-sensitive relapsed non-germline BRCAm OC patients (Drew et al. ESMO 2020). The Phase III DUO-O trial (NCT03737643) began global enrollment in January 2019 and will evaluate the efficacy and safety of combinations of the standard of care platinumbased chemotherapy, bevacizumab, and the anti-PD-L1 antibody durvalumab, followed by maintenance bevacizumab, durvalumab, and olaparib in patients with newly diagnosed advanced OC (Harter et al. ASCO 2019). The China cohort will evaluate these combinations in a standalone analysis of patients with non-BRCAm tumors. Methods: Eligible patients must have newly diagnosed stage III or IV high-grade ovarian, epithelial, fallopian, or primary peritoneal cancer and have undergone upfront primary surgery or be planned to have interval debulking surgery. From sites in China, ~120 patients with a non-BRCAm tumor (using a China-based central laboratory to determine BRCAm status) will be randomized 1:1:1 to: chemotherapy + bevacizumab + durvalumab, followed by bevacizumab + durvalumab + olaparib maintenance; chemotherapy + bevacizumab + durvalumab, followed by bevacizumab + durvalumab + placebo maintenance; or chemotherapy + bevacizumab + placebo, followed by bevacizumab + placebo. Olaparib (300 mg bid) and durvalumab (1120 mg q3w) will be administered for up to 24 months, and bevacizumab (15 mg/kg q3w) for up to 15 months, or until disease progression. The primary endpoints are investigator-assessed PFS (modified RECIST v1.1) in all patients with a non-BRCA tumor and patients with a non-BRCA, homologous recombination deficiency-positive tumor. A key secondary efficacy endpoint is overall survival, and safety will be summarized descriptively. Local China protocol amendments are in progress, and relevant updates will be presented. Enrollment in China began in April 2021.

Comparison of autologous and allogeneic hematopoietic cell transplantation strategies in patients with primary plasma cell leukemia, with dynamic prediction modeling.

Primary plasma cell leukemia (pPCL) is a rare and challenging malignancy. There are limited data regarding optimum transplant approaches. We therefore undertook a retrospective analysis from 1998-2014 of 751 patients with pPCL undergoing one of four transplant strategies; single autologous transplant (single auto), single allogeneic transplant (allo-first) or a combined tandem approach with an allogeneic transplant following an autologous transplant (auto-allo) or a tandem autologous transplant (auto-auto). To avoid time bias, multiple analytic approaches were employed including Cox models with time-dependent covariates and dynamic prediction by landmarking. Initial comparisons were made between patients undergoing allo-first (n=70) versus auto-first (n=681), regardless of a subsequent second transplant. The allo-first group had a lower relapse rate (45.9%, 95% confidence interval [95% CI]: 33.2-58.6 vs. 68.4%, 64.4-72.4) but higher non-relapse mortality (27%, 95% CI: 15.9-38.1 vs. 7.3%, 5.2-9.4) at 36 months. Patients who underwent allo-first had a remarkably higher risk in the first 100 days for both overall survival and progression-free survival. Patients undergoing auto-allo (n=122) had no increased risk in the short term and a significant benefit in progression-free survival after 100 days compared to those undergoing single auto (hazard ratio [HR]=0.69, 95% CI: 0.52- 0.92; P=0.012). Auto-auto (n=117) was an effective option for patients achieving complete remission prior to their first transplant, whereas in patients who did not achieve complete remission prior to transplantation our modeling predicted that auto-allo was superior. This is the largest retrospective study reporting on transplantation in pPCL to date. We confirm a significant mortality risk within the first 100 days for allo-first and suggest that tandem transplant strategies are superior. Disease status at time of transplant influences outcome. This knowledge may help to guide clinical decisions on transplant strategy.

A randomized, phase II trial of fulvestrant or exemestane with or without ribociclib after progression on anti-estrogen therapy plus cyclin-dependent kinase 4/6 inhibition (CDK 4/6i) in patients (pts) with unresectable or hormone receptor–positive (HR+), HER2-negative metastatic breast cancer (MBC): MAINTAIN trial.

LBA1004 Background: CDK 4/6i has demonstrated benefit in progression free survival (PFS) and overall survival (OS) in pts with HR+, HER2- MBC when combined with endocrine therapy (ET). While observational data demonstrate a potential benefit of continuing CDK 4/6i and switching ET at progression, no prospective trials have evaluated this approach. We conducted a phase II, multi-center, randomized, trial to evaluate the efficacy of fulvestrant or exemestane +/- ribociclib in pts with HR+HER2- MBC whose cancer previously progressed on any CDK 4/6i + any ET. Methods: In this investigator-initiated, phase II, double-blind, placebo-controlled trial, men or women with measurable or non-measurable HR+/HER2- MBC whose cancer progressed during CDK 4/6i and ET were randomized 1:1 to fulvestrant or exemestane +/- ribociclib. Pts treated with prior fulvestrant received exemestane as ET in the randomization; if prior exemestane fulvestrant was the ET; if neither, fulvestrant or exemestane was per investigator discretion, though fulvestrant was encouraged. PFS was the primary endpoint, defined as time from randomization to progression of disease or death. A one-sided log-rank test with a sample size of 120 randomized and evaluable pts with a significance level alpha of 2.5%, achieves 80% power to detect an effect size (difference in PFS) of 3 months. Results: Of the 120 randomized evaluable pts, 1 pt was removed due to not taking ET along with ribociclib/placebo. All but 1 pt was female, the median age was 57.0 years, 88 pts (74%) were white, and 21 (17.6%) were Hispanic. For ET, 99 pts received fulvestrant (83%) and 20 pts exemestane (17%). In terms of prior CDK 4/6i, 100 pts previously received palbociclib (84%), 13 pribociclib (11%), 2 abemaciclib (2%), and 4 palbociclib and another CDK 4/6i (3%). There was a statistically significant PFS improvement for pts randomized to fulvestrant or exemestane + ribociclib [median: 5.33 months, 95% CI (Confidence Interval): 3.25–8.12 months] vs. placebo (median: 2.76 months, 95% CI: 2.66–3.25 months): Hazard Ratio (HR) = 0.56 (95% CI: 0.37-0.83), p = 0.004. Similar results were seen in the subset of pts treated with fulvestrant, with a median PFS for those randomized to ribociclib (5.29 months) vs. placebo (2.76 months), HR = 0.59 (95% CI: 0.38-0.91), p = 0.02. At 6 months, 42% were progression-free on the ribociclib arm vs. 24% on placebo. At 12 months, 25% were progression-free on the ribociclib arm vs. 7% on placebo. Additional endpoints will be reported, including overall response rate and safety. Conclusions: In this randomized, placebo-controlled trial, there was a significant PFS benefit for pts with HR+/HER2- MBC to switch ET and receive ribociclib after progression on CDK 4/6i. Clinical trial information: NCT02632045.

Quality of life in patients with advanced high-grade ovarian cancer (HGOC) receiving maintenance therapies after first-line (1L) chemotherapy in the randomized phase III PAOLA-1/ENGOT-ov25 trial (NCT02477644).

5560 Background: In the Phase III PAOLA-1/ENGOT-ov25 trial, maintenance olaparib + bevacizumab (bev) provided a significant progression-free survival (PFS) benefit vs placebo (pbo) + bev in patients (pts) with newly diagnosed advanced ovarian cancer in response to platinum-based chemotherapy. Subgroup analyses revealed a substantial PFS benefit in homologous recombination deficiency (HRD)-positive (including BRCA1/2 mutation) pts, leading to US/EU labels for this combination. Preliminary analyses reported that olaparib did not alter global health-related quality of life (G-HQoL; Ray-Coquard I et al. NEJM 2019). We analyzed HQoL by domains and molecular subgroups and explored the impact of disease progression (DP) on HQoL in the 1L setting. Methods: Eligible pts with newly diagnosed advanced (FIGO stage III–IV) HGOC were randomized 2:1 to maintenance olaparib + bev or pbo + bev. Pts completed European Organisation for Research and Treatment of Cancer QLQ-C30 and QLQ-OV28 HQoL questionnaires at baseline and every 12 weeks for 2 years’ follow-up, irrespective of DP. The minimal important difference for clinically relevant change was fixed at 10 points. Longitudinal data were analyzed by mixed model for repeated measures (MMRM) and time until definitive deterioration (TUDD). Analyses were in the intent-to-treat population and HRD-positive subgroup. HQoL analyses at DP (± 60 days) were explored. Results: 806 pts were randomized to olaparib + bev (n=537) or pbo + bev (n=269). 465 pts had DP over 2 years’ follow-up. Compliance to HQoL questionnaires was high at baseline (95%) and over time (&gt;70%). MMRM models by HQoL domain did not reveal a clinically relevant difference between treatment arms over time. TUDD of G-HQoL did not differ between arms (hazard ratio [HR] 0.88, 95% confidence interval [CI] 0.72–1.07). In the HRD-positive subgroup (n=372), we observed no difference by HQoL domain between treatment arms. Interestingly, TUDD of G-HQoL was statistically significantly in favor of olaparib + bev compared with pbo + bev (HR 0.70, 95% CI 0.52–0.93). We also observed a clinically significant deterioration in emotional (mean change −12.30 points, 95% CI −16.46 to −8.13) and social (−11.17 points, 95% CI −16.21 to −6.12) functioning in both treatment arms at DP, among 103 pts with HQoL questionnaires at DP. Conclusions: The substantial PFS benefit provided by maintenance olaparib + bev in the newly diagnosed setting was achieved without detrimental effect on HQoL domains, even with longer TUDD of G-HQoL in the HRD-positive subgroup. Use of an effective maintenance therapy (ie one with a significant PFS benefit) in HGOC patients in the 1L setting is likely to delay the clinically significant deterioration in emotional and social functioning we identified in patients at DP across PAOLA-1 treatments arms. Clinical trial information: NCT02477644.

Identifying genetic factors of response and resistance to CDK4/6 inhibitors in metastatic HR+/HER2-breast cancer using real-world data.

1064 Background: CDK4/6 inhibitors plus endocrine therapy are approved for treatment of HR+/HER2- metastatic breast cancer (MBC) and have shown to provide a significant progression free survival benefit over endocrine therapy alone. But not all patients benefit from this treatment and some develop resistance over time. The molecular mechanisms governing this resistance are poorly understood. We have developed a real world dataset that includes data elements from structured EMR tables as well as deeply curated unstructured data from BC patients (ConcertAI Genome360 BC Dataset) who have been treated with CDK4/6 inhibitors and have undergone DNA sequencing to identify somatic mutations. We have leveraged this linked clinical-genomics dataset to identify genetic drivers of resistance and response to CDK4/6 inhibitors. Methods: This retrospective study uses the Genome360 BC Dataset (N = 1249). The patient’s eligibility to be included in this study (N = 456) was HR+/HER2- MBC patients with age &gt; 18 years treated with at least one of the CDK4/6 inhibitors and have response data based on RECIST criteria (responders = 231, non-responders = 225). For each patient in both cohorts, all pathogenic gene mutations and copy number changes were identified and enrichment analysis was performed. Biomarkers with Z value &gt; 1.96 (p value &lt; 0.05) were considered for further analysis. Pathway analysis was performed using these biomarkers and the CDK4/6 pathway to identify pathways and genes that can potentially be targeted to overcome resistance based on the mutational landscape of the patients receiving therapy. Results: We identified 7 potential segments (similar groups of genes) which predicted response or resistance to CDK4/6 inhibitors. Here we present data on 3 such segments which are closely related. Loss of function mutations in RB1 were enriched in the non-responder population (Z value = 2.33; p value = 0.026; N = 31). This is consistent with previously reported findings. In addition, amplifications and gain of function mutations in MYC and associated genes were also significantly enriched in the non-responder population (Z value = 2.71; P value = 0.01; N = 44). Interestingly, loss of function mutations in TSC1/2 genes which are downstream of MYC were predictors of good response to CDK4/6 inhibitors (Z value = 2.19; P value = 0.036; N = 30), strengthening the role of the parallel MYC signaling pathway in resistance to CDK4/6 inhibitors. Conclusions: Using our Genome360 BC Dataset, we have identified genetic markers affecting response to CDK4/6 inhibitors. In addition to the known role of RB1 in resistance to CDK4/6 inhibitors, the MYC signaling pathway emerged as a strong candidate. Based on these results, patients with mutations in these pathways may benefit from addition of mTOR or PKL1 inhibitors to CDK4/6 inhibitors to overcome resistance and prolong their effect.

Case for More Autologous Transplants in Myeloma in Resource-Constrained Settings

AbstractMultiple myeloma is characterized by a near universal risk of relapse. Autologous stem cell transplantation provides a significant progression free survival benefit but is under utilized worldwide. We provide a small snapshot of why ASCT assumes greater importance in resource-constrained settings.

The correlation of homologous recombination deficiency status with and Olaparib efficacy in Chinese ovarian cancer patients.

e17556 Background: Homologous recombination and DNA repair are important for genome maintenance. Genetic variations in essential homologous recombination genes, including BRCA1 and BRCA2, results in homologous recombination deficiency (HRD) can be a target for therapeutic strategies of ovarian cancer (OC) including poly (ADP-ribose) polymerase inhibitors (PARPi). Here, we proposed an emerging method based on ADx-GSS algorithm to predict HRD status and explore the correlation between HRD status and first-line maintenance therapy of Olaparib in OC patients or Olaparib maintenance therapy in platinum-sensitive relapsed (PSR) OC patients. Methods: Formalin-fixed, paraffin-embedded tissues of 38 consented OC patients between January 2016 and March 2021 were retrospectively collected. Genomic DNA was extracted and subjected to AmoyDx HRD Focus Panel (Amoy Diagnostics Co., Ltd) covering HRD score and BRCA1/2. The HRD score was calculated as the weighted sum of different types of copy number variation (CNV) trained through BRCAness events. Tumors were defined as genomic instability with an HRD score of ≥ 50 (i.e. HRD-positive). The primary endpoint was progression-free survival (PFS), and was assessed by Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1). Results: Histology of collected samples were mostly serous OC (84.2%). All samples were at stage III-IV (80.84%). The fractions of HRD-positive (n = 26) and HRD-negative (n = 12) group were 68.4%, and 31.6%, respectively. 65.8% (n = 25) of the OC patients had received Olaparib first-line maintenance therapy and 34.2% (n = 13) of PSR patients had received Olaparib maintenance therapy. In December 2021, 34.2% (n = 13) of the whole patients had relapsed. A significant PFS benefit was seen in HRD-positive patients compared with HRD-negative ones (P = 0.0017) or in the first-line maintenance treated population (P = 0.0068). In patients with HRD-positive tumors that did not have BRCA mutations, the PFS benefit was improved versus HRD-negative patients without BRCA mutations. However, Olaparib showed no efficacy difference between HRD-positive and HRD-negative tumor in PSR OC patients. Conclusions: HRD status tested by AmoyDx HRD Focus Panel is significantly correlated with the efficacy of Olaparib, and our results demonstrated a significant PFS benefit for HRD-positive patients compared with HRD-negative patients, especially for patients received Olaparib first-line maintenance therapy.

Dabrafenib (D) and trametinib (T) plus spartalizumab (S) in patients (pts) with previously untreated BRAF V600–mutant unresectable or metastatic melanoma: Three-year overall survival (OS) data from the randomized part 3 of the phase III COMBI-i trial.

9527 Background: Combination of immune checkpoint inhibitors and targeted therapy may produce durable and deep response in a higher proportion of pts with BRAF V600–mutant unresectable or metastatic melanoma. A recent report from the randomized, double-blind, placebo (PBO)-controlled Part 3 of the Phase 3 COMBI-i trial (NCT02967692) failed to show a statistically significant progression-free survival (PFS) benefit (hazard ratio (HR) of 0.82 (95% CI, 0.66‒1.03, p=.042)). Here, we report 3-year OS data from COMBI-i part 3. Methods: Eligible pts were randomized 1:1 to receive either S+D+T (n = 267; S 400 mg IV Q4W + D 150 mg orally BID + T 2 mg orally QD) or PBO+D+T (n = 265), until progression or unacceptable toxicity. Although the primary endpoint of PFS was not met, exploratory OS and safety analyses were performed. OS was summarized descriptively using Kaplan–Meier methods and HR was estimated using a stratified cox regression model. Results: As of October 19, 2021 (median follow-up, 42.8 months), the median OS was not reached in S+D+T arm and was 40.4 months with PBO+D+T (HR 0.796; 95% CI, 0.615‒1.029). There were 113 (42.3%) deaths in the S+D+T and 126 (47.5%) in the PBO+D+T. Estimated 2-year and 3-year OS rates were 67.7% (95% CI 61.6‒73.1) and 60.1% (95% CI 53.8‒65.8) with S+D+T vs 61.9% (95% CI 55.6‒67.5) and 52.9% (95% CI 46.6‒58.9) with PBO+D+T, respectively. An OS benefit was observed with S+D+T in these prespecified subgroups – Eastern Cooperative Oncology Group Performance Status (ECOG PS) 1 (HR 0.50; 95% CI, 0.32‒0.8), age ≥65 years (HR 0.58; 95% CI, 0.36‒0.94), PD-L1 negative ( &lt; 1%) (HR 0.62; 95% CI, 0.42‒0.91), sum of lesion diameters ≥ 66 mm at baseline (HR 0.63; 95% CI, 0.43‒0.91) and metastatic sites ≥ 3 (HR 0.66; 95% CI, 0.47‒0.94). Adverse events (AEs) irrespective of study treatment relationship were observed in 99.3% of pts in S+D+T vs 97.3% in PBO+D+T. The most common AEs (in &gt; 30%; all grades) were pyrexia, diarrhea, and nausea. Grade ≥3 treatment-related AEs (TRAEs) occurred in 56.9% vs 35.2% of pts treated with S+D+T vs PBO+D+T, respectively. Dose reductions of D and T due to AEs were more frequent in the S+D+T arm than PBO+D+T arm (47.2% vs 25.4% and 45.7% vs 25.4%, respectively), contributing to a lower relative dose intensity; the TRAEs leading to discontinuation of all 3 study drugs occurred in 13.5% vs 8% of pts, respectively. Conclusions: Results from this landmark 3-year OS analysis from COMBI-i- part 3 was consistent with the primary analysis, while the PBO+D+T showed a higher OS rate than previously observed for D+T alone in COMBI D/V studies, with a longer median follow-up. Subgroup analyses showed that ECOG PS 1, age ≥65 years, negative PD-L1 status and high tumor burden were associated with better OS in S+D+T in terms of HR. Clinical trial information: NCT02967692.

Hepatic artery infusion chemotherapy (HAIC) combined with sintilimab and bevacizumab biosimilar (IBI305) for initial unresectable hepatocellular carcinoma (HCC): A prospective, single-arm phase II trial.

4073 Background: Sintilimab plus IBI305, a bevacizumab biosimilar, showed a significant overall survival and progression-free survival benefit versus sorafenib in the first-line setting for patients with unresectable hepatocellular carcinoma. Hepatic arterial infusion chemotherapy is an intraarterial procedure that has been widely used in Asia, with high response rate. This trial was designed to assess the feasibility and efficacy of HAIC combined with sintilimab and IBI305 in advanced unresectable hepatocellular carcinoma. Methods: This is a prospective, single-arm phase II study. Patients with histologically or cytologically diagnosed or clinically confirmed hepatocellular carcinoma, China liver cancer staging (CNLC) stage IIb-IIIb, no previous systemic treatment, Child-Pugh classification A or B, Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 were eligible for inclusion. Patients received FOLOFOX-HAIC, followed by intravenous sintilimab (200 mg every 3 weeks, four cycles) and intravenous IBI305 (7.5 mg/kg every 3 weeks, three cycles). The primary endpoint was objective response rate (ORR) per mRECIST. Secondary endpoint were surgical conversion rate, pCR rate and R0 resection rate. The study is registered with Clinicaltrials.gov: NCT05029973. Results: Between May, 2021 to Sep, 2021, a total of 30 eligible patients were enrolled: median age 54.5 years (range 37-73); M:F 27:3; CNLC stage IIb/IIIa/IIIb: 3/16/11; Child-Pugh class A/B: 28/2; ECOG PS 0/1: 26/4. There were 23(76.7%) patients with hepatitis B and 5(16.7%) with hepatitis C. The median tumor size was 8.75 cm (interquartile range [IQR], 4.9-10.5), 60.0% pts present vascular invasion, and 36.7% had extrahepatic metastasis. Of 30 pts evaluable for response, 20 (66.7%; 95% CI: 47.2%-82.7%) achieved confirmed partial response, and became eligible for surgical resection. Finally, 14 of them received surgical resection and all (100%) achieved R0 resection, 3 pts completed radiofrequency ablation (RAF), 3 pts refused resection or RFA. The pCR rate in the patients completed pathological examination was 52.6% (95% CI: 28.9%-75.6%). The most common TRAEs included hypertension (23.3%), rash (16.7%), and abnormal liver function (10.0%). No grade 3-4 TRAEs were observed. Of note, in patients received surgery, 1 developed grade 1 biliary fistula, 1 developed hepatic failure and finally lead to death Conclusions: HAIC Combined With sintilimab and IBI305 resulted in a promising ORR, R0 surgical conversion rate and pCR rate with a manageable safety for initial unresectable advanced hepatocellular carcinoma. Further follow-up is ongoing. Clinical trial information: NCT05029973.

Time without symptoms or toxicity (TWiST) in patients with newly diagnosed advanced ovarian cancer receiving maintenance olaparib or placebo plus bevacizumab: Analysis of PAOLA-1/ENGOT-ov25 phase III trial.

5562 Background: In the Phase III PAOLA-1/ENGOT-ov25 trial (NCT02477644), maintenance olaparib plus bevacizumab (bev) provided a significant progression-free survival (PFS) benefit, compared with placebo plus bev, in patients (pts) with newly diagnosed advanced ovarian cancer in response after platinum-based chemotherapy (Ray-Coquard et al. NEJM 2019). A subgroup analysis revealed a substantial PFS benefit in HRD-positive (including BRCA1/BRCA2 mutation) pts (median PFS 37.2 vs 17.7 months) leading to US and EU labels for this combination. We analyzed TWiST in PAOLA-1, using several definitions of toxicity (TOX) and by molecular subgroups. Methods: Pts were randomized 2:1 to maintenance olaparib (300 mg bid) plus bev (15 mg/kg, Day 1, q3w) or placebo plus bev, stratified by first-line treatment outcome and tumor BRCAm status. TWiST is defined as PFS minus time with TOX after randomization and before disease progression or censoring for progression, and was a prespecified exploratory endpoint. Definitions of significant symptoms or TOX were explored using the following approaches: 1) all grade ≥2 adverse events (AEs); and 2) all grade ≥2 AEs selected to be correlated to olaparib (fatigue, nausea, vomiting, and anemia). Area under PFS curve was split into TOX:TWIST ratio and compared between the two arms. Results: Between May 7, 2015 and August 31, 2017, 806 eligible pts were randomly assigned to olaparib plus bev (n = 537) or placebo plus bev (n = 269), with a median duration of treatment with olaparib of 17.3 months (range 0.03–33.0) for olaparib plus bev arm and 15.6 months (range 0.07–26.2) for placebo plus bev at data cutoff for primary endpoint analysis. In the Intent-to-treat population, median duration of TWiST for all grade ≥2 AEs for olaparib plus bev vs placebo plus bev arms was 14.1 months (95% confidence interval [CI] 12.5–16.1) vs 7.7 months (95% CI 5.9–9.1), respectively; and 21.9 months (95% CI 20.2–22.5) vs 16.6 months (95% CI 14.6–18.0) considering only grade ≥2 AEs linked to olaparib. The difference was particularly significant within the HRD-positive subgroup where median duration of TWiST was 24.4 months (95% CI 19.3–not evaluable [NE]) vs 7.4 months (5.8–11.2) for TOX linked to all grade ≥2 AEs, and 36.6 months (95% CI 31.9–NE) vs 17.4 months (15.1–19.4) linked to olaparib AEs only for the olaparib plus bev and placebo plus bev arms, respectively. Conclusions: The substantial PFS benefit provided by maintenance olaparib plus bev vs placebo plus bev in pts with newly diagnosed advanced ovarian cancer was supported by significant TWiST benefit. TWiST analyses, including all grade ≥2 symptoms or toxicity related to treatment, confirmed the clinically meaningful benefit from the combination, notably in the HRD-positive subgroup. Clinical trial information: NCT02477644.

Impact of smoking status on the relative efficacy of the EGFR TKI/angiogenesis inhibitor combination therapy in advanced NSCLC—a systematic review and meta-analysis

BackgroundThe ETOP 10-16 BOOSTER trial failed to demonstrate a progression-free survival (PFS) benefit for adding bevacizumab to osimertinib in second line. An exploratory subgroup analysis, however, suggested a PFS benefit of the combination in patients with a smoking history and prompted us to do this study.MethodsA systematic review and meta-analysis to evaluate the differential effect of smoking status on the benefit of adding an angiogenesis inhibitor to epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor therapy was carried out. All relevant randomized controlled trials appearing in main oncology congresses or in PubMed as of 1 November 2021 were used according to the Preferred Reporting Items for Systematic Review and Meta-Analyses statement. Primarily PFS according to smoking status, and secondarily overall survival (OS) were of interest. Pooled and interaction hazard ratios (HRs) were estimated by fixed or random effects models, depending on the detected degree of heterogeneity. Bias was assessed using the revised Cochrane tool for randomized controlled trials (RoB 2).ResultsInformation by smoking was available for 1291 patients for PFS (seven studies) and 678 patients for OS (four studies). The risk of bias was low for all studies. Combination treatment significantly prolonged PFS for smokers [n = 502, HR = 0.55, 95% confidence interval (CI): 0.44-0.69] but not for nonsmokers (n = 789, HR = 0.92, 95% CI: 0.66-1.27; treatment-by-smoking interaction P = 0.02). Similarly, a significant OS benefit was found for smokers (n = 271, HR = 0.66, 95% CI: 0.47-0.93) but not for nonsmokers (n = 407, HR = 1.07, 95% CI: 0.82-1.42; treatment-by-smoking interaction P = 0.03).ConclusionIn advanced EGFR-non-small-cell lung cancer patients, the addition of an angiogenesis inhibitor to EGFR-tyrosine kinase inhibitor therapy provides a statistically significant PFS and OS benefit in smokers, but not in non-smokers. The biological basis for this observation should be pursued and could determine whether this might be due to a specific co-mutational pattern produced by tobacco exposure.

Randomized phase III trial of induction chemotherapy followed by chemoradiotherapy or chemotherapy alone for nonresectable locally advanced pancreatic cancer: First results of the CONKO-007 trial.

4008 Background: Chemotherapy (CT) is the standard of care in nonresectable locally advanced pancreatic cancer. The CONKO-007 trial studied the role of sequential CT and chemoradiotherapy (CRT). Methods: In this randomized multicenter phase III trial resectability was judged by an independent surgical board. Patients (pts) received induction chemotherapy (IC) for 3 months (3 cycles gemcitabine (Gem, 1000 mg/m² d1, 8, 15, q4w) or FOLFIRINOX (6 cycles, q2w)). After IC pts without progression were randomized to either continuing CT for another 3 months or receiving CRT (cumulative dose of 50.4Gy, single dose 1.8Gy + Gem 300 mg/m² weekly, followed by 1 cycle of Gem 1000 mg/m² at d1, 8, 15). The primary endpoint of the study was overall survival (OS) since the begin of IC. Determination of sample size calculated 590 pts to be randomized. Due to the exclusion of pts with progressive disease after IC a total of 830 pts should be enrolled. Due to delayed patient accrual the primary endpoint was changed to R0 resection rate resulting in an estimated sample size of 525 pts. Results: Between 04/2013 and 02/2021 a total of 525 pts were enrolled in 47 sites. 402 pts received IC with FOLFIRINOX and 93 pts with Gem. After IC 190 pts were excluded due to progression or toxicity, 335 were randomized, their median FU was 16 months. Hematological toxicities were significantly increased in the CRT arm, non-hematological toxicities were comparable. R0 CRM- resection rate and pCR rate was significantly higher in the CRT arm. R1-resections occurred significantly more often in the CT arm. Median progression-free survival (PFS) (HR 0.919, 95% CI 0.702-1.203, p=0.540) and OS (HR 0.964, 95% CI 0.760-1.225, p=0.766) did not differ significantly in both arms, whereas the PFS rate tended to be higher in the CRT arm after 2 years. OS rates for CRM- R0 surgery with 87.5. ± 0.05% (1y) and 67.2 ± 0.05% (2y) were significantly higher (p&lt;0.01) than for CRM+ R0 surgery with 66.7 ± 0.15% (1y) and 41.2 ± 0.1% (2y) as well as for patients without or incomplete surgery with 68.5 ± 0.03% (1y) and 26.4 ± 0.03% (2y). Conclusions: The addition of radiotherapy after IC improves the R0 CRM - resection and pCR rate without significant change in R0 resection rate (primary endpoint). Pts with R0 CRM - resections had a better prognosis compared to patients with either R0 CRM+ or incomplete or without surgery. However, this effect on resectability did not translate into a statistically significant PFS or OS benefit in the whole cohort. Clinical trial information: NCT01827553. [Table: see text]