Switch Maintenance Research Articles

Phase III FIRE-4 study (AIO KRK-0114): Influence of baseline liquid biopsy results in first-line treatment efficacy of FOLFIRI/cetuximab in patients with tissue RAS-WT mCRC.

3507 Background: FIRE-4 (AIO KRK-0114) is performed in RAS wild-type (wt) mCRC patients. This randomized study tests the efficacy of early switch maintenance during 1st-line therapy (part 1) and re-challenge with cetuximab (part 2) in later-line treatment. In part 1, arm A patients continued FOLFIRI/Cet until progression or intolerable toxicity. In arm B, patients received FOLFIRI/Cet for 8-12 cycles, after which maintenance therapy with 5-FU/FA plus bevacizumab (5-FU/Bev) was applied. The first randomization evaluates the question if an early switch from cetuximab to bevacizumab may prolong PFS. Within the translational protocol, serial baseline liquid biopsy were taken to analyze RAS and BRAF mutations. Methods: Within this randomized, controlled, open-label phase-III study, patients received FOLFIRI (irinotecan plus 5-FU/FA) plus cetuximab at the standard dosing schedule. In arm A, FOLFIRI plus cetuximab was continued until progression or intolerable toxicity. In arm B, patients received 8 cycles of FOLFIRI plus cetuximab (in case of tumor response) or 12 cycles (in case of stable disease) followed by maintenance with 5-FU/FA plus bevacizumab (5mg/kg) until disease progression or intolerable toxicity. Overall survival after second randomization (part 2) is evaluated as a primary endpoint. Liquid Biopsies were analyzed by RAS BEAMing and BRAF ddPCR technology. Results: From August 2015 to January 2021, 673 patients were randomized, and liquid biopsies of 540 patients were evaluable at baseline. Of those, 70 (13%) were RAS mutant and 38 (7%) BRAFV600E mutant at baseline. Patients with a detectable RASmut had a significant shorter PFS and OS when compared to RASwt patients (PFS: 9.0mo vs. 11.5mo; p < 0.001; OS: 22.1mo vs 33.6mo; p < 0.001). Whereas, for RASwt patients no difference for both arms with respect to PFS and OS could be observed, RASmut patients (n = 70) had a clear trend towards shorter survival in the standard FOLFIRI cetuximab arm (PFS: 6.4mo vs. 10.1mo, p = 0.54; OS: 24.9mo vs. 16.3mo, p = 0.10). Patients with a BRAF mutation in liquid biopsy had median survival times as expected for BRAF mutant patients (PFS = 5.5mo; OS = 12.0mo). In the standard arm, with a continuous administration of cetuximab, the conversion rate from RASwt to RASmut was significantly higher at progression than in the switch maintenance arm. Conclusions: Liquid biopsy detected RAS mutation in 13% of patients deemed RASwt based on tissue analyses. These patients show outcome characteristics expected for RAS mutant patients (median PFS of 9.0 months and median OS of 22 months). The study thus shows the clinical relevance of liquid biopsy in the verification of RAS mutational status. Clinical trial information: NCT02934529 .

Phase 2 trial of epidermal growth factor (EGF) vaccine CIMAvax in combination with pembrolizumab in first line and maintenance setting in advanced non–small cell lung cancer patients.

TPS2677 Background: CIMAvax-EGF is a novel growth-factor depleting immunotherapy consisting of human recombinant EGF conjugated to recombinant P64k derived from Neisseria meningitidis, that elicits an anti-EGF antibody response, resulting in reduction of circulating EGF levels. A randomized phase 3 study of CIMAvax-EGF administered as switch maintenance therapy after first-line platinum-based chemotherapy in patients with advanced NSCLC demonstrated overall survival (OS) advantage in comparison to best supportive care alone, particularly in patients with high baseline serum EGF levels. A phase 1 trial combining CIMAvax-EGF with nivolumab, an anti-PD1 immune checkpoint inhibitor, showed that the combination is safe and appears to induce higher rate of good anti-EGF antibody response within the first 8 weeks of therapy compared to historical comparison group receiving CIMAvax-EGF alone. CIMAvax-EGF is currently being investigated in combination with pembrolizumab in a multi-arm phase II trial as 1L therapy in combination with pembrolizumab for patients with EGFR/ALK wildtype NSCLC and PD-L1 > 50% (Cohort C) and as maintenance therapy after completing 1L chemoimmunotherapy for patients with PD-L1 < 50% (Cohorts D and E). Accrual to this trial is ongoing (NCT02955290). Methods: This is an open-label, non-randomized, multi-site, phase 2 basket trial. CIMAvax-EGF (2.4 mg IM every 2 weeks x 4 doses, then every 4 weeks thereafter) is being tested as first-line therapy in combination with pembrolizumab (200 mg IV every 4 weeks) in patients with advanced NSCLC with PD-L1 ≥ 50% (Cohort C), using a Simon two stage design (n up to 41). A safety lead-in consisting of the first 6 NSCLC patients was completed. There were no G3 or higher adverse events attributed to the combination within the first 4 weeks of protocol treatment. Patients with advanced squamous NSCLC (Cohort D, n=50) and non-squamous NSCLC (without EGFR/ALK/ROS-1/KRAS mutations; Cohort E, n=45) with PD-L1 expression <50% and no evidence of progression of disease by RECIST 1.1 criteria after at least 4 cycles of induction platinum-based doublet with pembrolizumab, prior to initiation of standard of care maintenance therapy will be enrolled to receive protocol treatment with pembrolizumab in combination with CIMAvax-EGF as maintenance therapy. The primary endpoint is to evaluate objective response rate (Cohort C), and 12-month PFS in Cohorts D and E. Secondary endpoints include 12-month overall survival in all cohorts. Exploratory objectives include characterizing tissue-based immune and EGFR signaling profile as well as serum EGF levels, anti-EGF antibody levels and other blood-based biomarkers in relation to clinical outcomes. Clinical trial information: NCT02955290 .

Outcomes with immune checkpoint inhibitors (ICI) in patients (pts) with MTAP alterations (alt) in advanced urothelial carcinoma (aUC).

4574 Background: MTAP loss of function alt in aUC has been associated with poor prognosis. MTAP is an enzyme involved in the adenine salvage pathway and deficiency of the protein leads to susceptibility to antifolate agents, e.g., pemetrexed. MTAP loss has also been correlated with immunosuppressive tumor microenvironment, inducing a “cold tumor” that may be less responsive to ICI. Response and outcomes to ICI in pts with MTAP altered aUC need further assessment. We hypothesized that pts with MTAP altered aUC would have lower response and shorter survival on ICI. Methods: We used our database from 26 centers (US/Europe) of pts with aUC treated with ICI. We included pts with available NGS data who received ICI for aUC. We excluded pts with pure non-UC, treated with adjuvant ICI, ICI combinations, or on clinical trials. Outcomes (observed response rate [ORR], progression free survival [PFS] and overall survival [OS]) were compared in pts who received either 1st line [1L] or 2nd line and beyond [2+L] ICI with and without MTAP alt. We compared ORR using logistic regression; PFS and OS were compared using Kaplan-Meier and Cox proportional hazards. We separately describe outcomes in pts with MTAP alt who received avelumab switch maintenance. Results: 211 pts from 8 centers met inclusion criteria with available MTAP alt status; 174 received ICI as distinct aUC treatment line (16% had MTAP alt; n=28) either in 1L or 2+L setting; 37 pts received avelumab switch maintenance (19% had MTAP alt; n=7). Pts with known MTAP status were 72% men, 91% White, 72% pure UC, 25% upper tract UC, 64% ECOG PS 0-1, 56% visceral mets, 18% bone mets, 15% liver mets. Median follow up from starting ICI was 44 months [mo] (IQR 29-51). ORR to ICI (1L + 2+L) in pts with MTAP alt was 25% (95%CI 10-47) vs 47% (95%CI 39-55%) in pts without MTAP alt [OR 3.11 (95%CI 1.15-7.82)]. PFS for pts with MTAP alt was not significantly different vs pts without MTAP alt (median 3 vs 6 mo, respectively: HR 1.46 [95%CI 0.91-2.35]). OS was similar between groups (median 14 vs 15 mo, respectively: HR 0.93 [95%CI 0.53-1.63]). Table describes outcomes by ICI treatment line (1L, 2+L, maintenance) in pts with and without MTAP alt. Conclusions: In pts with aUC receiving ICI, the presence of MTAP alt was significantly associated with lower ORR and a trend towards shorter PFS compared to absence of MTAP alt. Limitations include retrospective nature, small sample size, selection/confounding biases, lack of randomization and central scan review. Findings need external validation and might inform discussion on the optimal therapy sequence in aUC. [Table: see text]

Advancements in Systemic Therapy for Pancreatic Cancer.

Outcomes for patients with advanced pancreatic cancer have improved in the past 12 years, mainly because of progress made in systemic therapies. New treatment strategies for advanced pancreatic cancer include switch maintenance with cytotoxic therapies, induction maintenance, and the utilization of targeted agents for patients with actionable variants, as well as ongoing development of cytotoxic regimens, such as NALIRIFOX. The activity of immunotherapy has been disappointing to date, but novel combinations and identifying appropriate patient populations may further unlock its potential.

Response and outcomes of maintenance avelumab after platinum-based chemotherapy (PBC) in patients (pts) with advanced urothelial carcinoma (aUC): "Real world" experience.

472 Background: PBC followed by avelumab switch maintenance in non-progressors is the standard first line (1L) aUC treatment. We describe clinical features and outcomes in a ‘real-world’ cohort treated with avelumab maintenance for aUC. We hypothesized that outcomes would be similar with JavelinBladder100 trial data. Methods: This was a retrospective cohort study of pts from 12 sites who received 1L switch maintenance avelumab after no progression to PBC for aUC. We calculated overall response rate (ORR), median overall and progression-free survival (mOS, mPFS) using Kaplan Meier method from avelumab start. We also described OS and PFS for specific subsets using Cox regression. Results: We found 77 pts with aUC (78% pure, 22% mixed UC) with median age 68, 81% men, 91% White, 17% upper tract primary, 66% prior cisplatin, 17% liver metastasis (mets), 80% ECOG PS 0-1 at time of PBC start. There was a median of 6 weeks (range 1-30) from end of PBC to avelumab start; median follow-up time from avelumab start was 22 months (95%CI 16-24). ORR with avelumab maintenance: 28% (complete response [CR] 17%, partial response [PR] 11%), stable disease (SD) 32%; progression as best response 30% (10% unknown); mPFS 7 months (95%CI 5-9), mOS 22 months (95%CI 16-NR). Table shows HR for OS and PFS for specific subsets. Absence (vs presence) of liver mets (p=0.04), ECOG PS 0-1 (vs >1; p=0.01) and CR/PR (vs SD) to 1L PBC (p=0.03) were associated with longer OS. Conclusions:‘Real world’ outcomes with avelumab maintenance in pts with aUC align with JavelinBladder100 trial data (but higher ORR). Good PS, response to PBC and absence of liver mets are favorable prognostic factors. Limitations include moderate sample size, retrospective design, lack of randomization and central scan review, possible selection and confounding biases. Other studies (e.g. PATRIOT-II) can generate more data in pts on maintenance avelumab outside clinical trials. [Table: see text]

TROPHU-U-01 cohort 5: Evaluation of maintenance sacituzumab govitecan (SG) plus zimberelimab (ZIM), ZIM, or avelumab in cisplatin-eligible patients (pts) with unresectable or metastatic urothelial cancer (mUC).

TPS598 Background: SG is an antibody-drug conjugate composed of an anti-trophoblast cell-surface antigen-2 (Trop-2) antibody coupled to a topoisomerase-I inhibitor, SN-38, via a hydrolyzable linker. In Cohort 1 of the phase 2 TROPHY-U-01 trial, SG monotherapy resulted in a 27% objective response rate (ORR) and median overall survival (OS) of 10.9 months with an overall manageable toxicity profile in pts with locally advanced or mUC who previously received platinum-based therapy and a checkpoint inhibitor (CPI; Tagawa S, et al. J Clin Oncol. 2021). These results led to accelerated FDA approval of SG in this population. The CPI ZIM is a fully human IgG4 monoclonal antibody targeting PD-1. CPIs are active in mUC, including avelumab that is FDA-approved as switch maintenance therapy for locally advanced or mUC that has not progressed with first-line platinum-based chemotherapy. Cohort 5 of the TROPHY-U-01 trial will evaluate the safety, tolerability, and efficacy of SG + ZIM vs ZIM alone vs avelumab as switch maintenance in pts with mUC who have received gemcitabine (GEM)/cisplatin without progressive disease (PD). Methods: TROPHY-U-01 (NCT03547973) is a multicohort, open-label, global, phase 2 trial. Cohort 5 includes pts who have not progressed after completion of 4-6 cycles of GEM/cisplatin. Key eligibility requirements include ≥18 y; ECOG PS 0-1; available tissue for biomarker testing; adequate blood counts without transfusion or growth factor within 2 weeks of study drug initiation; creatinine clearance ≥30 mL/min. A safety lead-in of 6-8 pts will be conducted, where pts will be treated with SG 10 mg/kg IV on D1 and D8 of a 21-D cycle plus ZIM 360 mg IV q3wk on a 21-D cycle. On safety lead-in, if SG + ZIM is deemed safe, pts will be randomized 1:1:1. Those in Arm 1 will receive SG 10 mg/kg IV on D1 and D8 of a 21-D cycle followed by ZIM 360 mg IV, q3wk (D1 of a 21-D cycle). Pts in Arm 2 will receive avelumab 800 mg IV q2wk (D1 of a 14-D cycle). Pts in Arm 3 will receive ZIM 360 mg IV q3wk. All pts will continue treatment until PD, unacceptable toxicity, or loss of clinical benefit. The primary endpoint is progression-free survival based on central review by RECIST 1.1 criteria. Secondary endpoints include OS (all arms), safety/tolerability of SG in combination with ZIM (Arm 1). Cohort 5 aims to enroll an estimated 158 pts. A sample size of 50 pts per randomized arm is determined based on clinical consideration for exploring the activity of anticancer agents. Clinical trial information: NCT03547973 .

TROPHY-U-01 cohort 6: Sacituzumab govitecan (SG), SG plus zimberelimab (ZIM), SG plus ZIM plus domvanalimab (DOM), or carboplatin (CARBO) + gemcitabine (GEM) in cisplatin-ineligible patients (pts) with treatment-naive metastatic urothelial cancer (mUC).

TPS592 Background: SG is an antibody-drug conjugate composed of an anti-trophoblast cell-surface antigen-2 (Trop-2) antibody coupled to SN-38 via a proprietary hydrolyzable linker. In Cohort 1 of the phase 2 TROPHY-U-01 trial, SG monotherapy resulted in a 27% objective response rate (ORR) and median overall survival (OS) of 10.9 months with an overall manageable toxicity profile in pts with locally advanced or mUC who previously received platinum-based therapy and a checkpoint inhibitor (CPI; Tagawa S, et al. J Clin Oncol. 2021). The results led to accelerated FDA approval of SG for this population. ZIM (anti-PD-1) and DOM (anti-TIGIT) are CPIs under clinical investigation for anti-tumor activity. Cohort 6 of TROPHY-U-01 trial (C6) will assess SG monotherapy vs SG plus CPI combinations (SG + ZIM; SG + ZIM + DOM) vs CARBO/GEM followed by avelumab maintenance in treatment naive cis-ineligible pts with locally advanced or mUC. Methods: TROPHY-U-01 (NCT03547973) is a multicohort, open-label, global, phase 2 trial. C6 includes pts with cis-ineligible unresectable locally advanced or mUC who are ≥18 y; have an ECOG performance status 0-1; have available tissue for biomarker testing; have no prior mUC therapy, except (neo)adjuvant chemotherapy with recurrence >12 mo from completion; are CPI-naive or >12 mo from completion; have adequate hematologic and hepatic function; and have creatinine clearance ≥30 mL/min. A safety lead-in will occur where 6-8 pts will be treated with SG 10 mg/kg on D1 and D8 of a 21-D cycle + ZIM 360 mg q3wk. A second safety lead-in will occur where 6-8 pts will be treated with SG 10 mg/kg on D1 and D8 of a 21-D cycle + ZIM 360 mg q3wk + DOM 1200 mg q3wk. After the safety lead-in, pts will be randomized 1:2:2:2 to: Arm 1: SG 10 mg/kg on D1 and D8 of a 21-D cycle; Arm 2: SG 10 mg/kg on D1 and D8 of a 21-D cycle and ZIM 360 mg q3wk; Arm 3: SG 10 mg/kg on D1 and D8 of a 21-D cycle and ZIM 360 mg q3wk and DOM 1200 mg q3wk; and Arm 4: CARBO (AUC 4.5-5) on D1 of each 21-D cycle + GEM 1000 mg/m2 on D1 and D8 of each 21-D cycle for the first 4-6 cycles followed by switch maintenance avelumab 800 mg q2wk in the absence of progression. All pts will continue treatment until progression, unacceptable toxicity, or loss of clinical benefit. Primary endpoint is ORR per central review based on RECIST 1.1. Secondary endpoints include progression-free survival, duration of response, and clinical benefit rate by central review and investigator review, as well as ORR by investigator review, and OS, and safety and tolerability (Arms 1-3). C6 aims to enroll an estimated 226 pts. With 60 subjects each in Arms 2-4, a comparison of Arm 2 or 3 vs Arm 4 will have ~88% power at one-sided α of 0.05 to demonstrate an improvement in ORR, with a null hypothesis of ORR 40% for Arms 2-3 and an alternative hypothesis of ORR at 65% for Arms 2-4. Clinical trial information: NCT03547973 .

Alliance A032002 (ART): Phase II randomized trial of atezolizumab versus atezolizumab and radiation therapy for platinum-ineligible/refractory metastatic urothelial cancer.

TPS589 Background: In patients (pts) with metastatic unresectable urothelial cancer, platinum-based chemotherapy remains the standard of care for first-line treatment followed by switch maintenance avelumab if disease control is achieved with chemotherapy. Outside of this setting, single agent immunotherapy is often used in pts that have recurrence after platinum-based chemotherapy or are platinum ineligible. Atezolizumab is a PD-L1 inhibitor currently approved for pts that have urothelial cancers expressing positive PD-L1 or pts ineligible for receiving platinum-based chemotherapy. Tumor-targeted radiotherapy can generate immune-stimulating effects without immune suppression as was previously thought. Moreover, it has become clear that radiotherapy can induce profound effects on tumor cells and the tumor microenvironment that can enhance or trigger an anticancer immune response. While numerous trials have investigated the abscopal effect, this trial will have specific parameters regarding drug type, radiation dose and administration. Methods: A032002 is a phase 2 trial addressing pts that are platinum ineligible or refractory to platinum-based chemotherapy. 144 pts will be randomized to receive either atezolizumab or atezolizumab and single site radiation therapy. The atezolizumab regimen is 1200 mg every 3 weeks. Administration of radiotherapy will occur to one non-target site (8 Gy x 3) for pts randomized to the atezolizumab + radiotherapy arm. All pts will undergo centralized PD-L1 testing (SP142 monoclonal primary antibody), which can be performed on archival tissue; a new biopsy is only required if no archival tissue is available. Key eligibility criteria include age ≥ 18 years, ECOG performance status 0-2, histologically confirmed metastatic urothelial cancer, having at least one measurable site per RECIST 1.1 to monitor for abscopal response, one site targetable for radiation, and tissue available for PD-L1 testing. The primary endpoint is tumor response within 6 months of randomization. Tumor response is defined as a complete response (CR) or partial response (PR) as assessed by the treating physician using RECIST 1.1 criteria. For a one-sided log rank test with a type 1 error rateof 0.10, the study has 90% power to detect a 20% increase in response rate. Key secondary endpoints include tumor response using iRECIST, progression-free survival and overall survival. Quality of life assessments include EORTC QLQ-C30, QLQ-BLM30 and PROMIS-Fatigue. Tissue, urine and blood samples will be collected and biobanked for future correlative science. Enrollment to ART began in December 2021. The study is available for participation at all US NCTN sites with a projected enrollment of 3 years. Support: U10CA180821, U10CA180882. Clinical trial information: NCT04936230 .

Management of Locally Advanced Unresectable or Metastatic Urothelial Carcinoma: Expert Opinion from an Indian Panel via Delphi Consensus Method

Introduction Currently, there are no guidelines for the management of locally advanced unresectable or metastatic urothelial carcinoma (mUC) from an Indian perspective. There is a lack of consensus on the utility of treatment options in first-line (1L) and second-line (2L) settings, especially in cisplatin- and platinum-unfit mUC patient subgroups. Objective This articles aims to develop evidence-based practical consensus recommendations for the management of mUC in Indian settings. Methods Modified Delphi consensus methodology was considered to arrive at a consensus. An expert scientific committee of 15 medical oncologists from India constituted the panel. Twelve clinically relevant questions were grouped into five categories for presentation and discussion: (1) cisplatin and platinum ineligibility criteria; (2) programmed death ligand 1 and fibroblast growth factor receptor (FGFR) testing in mUC patients; (3) treatment options in 1L settings; (4) role of switch maintenance; and (5) treatment options in 2L. Statements that reached high (≥ 80%) and moderate (60–79%) levels of consensus in the first round (electronic survey) did not undergo the second Delphi round. The questions that received a low level of consensus (< 60%) were discussed during the virtual meeting. Results Renal impairment (creatinine clearance [CrCl] < 60 mL/min) and New York Heart Association class 3 heart failure are important assessment criteria for determining cisplatin ineligibility. Patients are unfit for any platinum-based chemotherapy in case of Eastern Cooperative Oncology Group performance status> 3 or severe renal impairment (CrCl < 30 mL/min). Gemcitabine and platinum with cisplatin over carboplatin were preferred in 1L settings. In patients unfit for cisplatin-based regimens, carboplatin–gemcitabine chemotherapy was preferred over immunotherapy (atezolizumab or pembrolizumab). Selected patients who are platinum ineligible may be considered for immunotherapy. Post-induction chemotherapy, those who do not progress may be strongly considered for avelumab maintenance. Experts recommended erdafitinib in FGFR-positive mUC patients in 2L settings. In FGFR-negative patients, immunotherapy (pembrolizumab, nivolumab, or avelumab) may be preferred over chemotherapy (paclitaxel, docetaxel, or vinflunine). Enfortumab vedotin and sacituzumab govitecan may be considered for further lines of therapy. Conclusion Expert panel consensus will offer expert guidance to oncologists/clinicians on the management of mUC in Indian settings. Key Points

Camrelizumab combined with apatinib and albumin-bound paclitaxel followed by camrelizumab plus apatinib as first-line therapy for unresectable or metastatic pancreatic cancer.

703 Background: Pancreatic carcinoma has complex immunosuppressive tumor microenvironment that acts to insulate the tumor against an effective cytotoxic immune response. Apatinib (small molecular agent targeting the VEGFR-2), has shown the potential additive or synergistic antitumor effects with camrelizumab (anti-PD-1 agent) in vitro study. The inhibition of VEGF signaling pathway could trigger immune suppression provoked. Considering the anti-PD-1 agent plus antiangiogenic drug might avoid the substantial cumulative toxicities and obtain well tolerance, the specific and optimized therapeutic agents and treatment strategy to carry out chemotherapy-free strategy as maintenance or sequential (switch maintenance) therapy is hopeful and noteworthy. Methods: In this single-arm, single-center, exploratory study, patients (pts) who were pathologically or cytologically diagnosed as unresectable or metastatic pancreatic cancer and had not received systemic treatment before, with an ECOG performance status of 0-2. Pts received camrelizumab (200 mg intravenously once every 3 weeks) plus albumin-bound paclitaxel (125 mg/m2 intravenously on day 1,8 every 3 weeks) and apatinib (250 mg once daily orally on days 1–21 of each 3-week cycle) for 4–6 cycles, and pts without progressive disease (PD) after completing 4–6 cycles of initial camrelizumab plus albumin-bound paclitaxel and apatinib were administrated subsequent camrelizumab (200 mg intravenously once in 3 weeks) plus apatinib (250 mg once daily orally on days 1–21 of each 3-week cycle). Primary endpoint was progressionfree survival (PFS) by RECIST 1.1. Secondary endpoints included overall response rate (ORR), disease control rate (DCR), overall survival (OS) and safety. Results: From 09/2021 to 08/2022 13 pts were enrolled (median age 60, 77% male). At data cutoff, 5 pts continued to receive subsequent camrelizumab plus apatinib, 12 pts were included in the efficacy analysis. The ORR was 16.7%, with confirmed 2 (16.7%) PR. SD were 9 (75.0%) with a DCR of 91.7%. All pts experienced treatment-related AEs (TRAEs), the ≥grade 3 TRAEs were GGT increased (31%), blood bilirubin increased (8%), alanine aminotransferase increased (8%), aspartate aminotransferase increased (8%), alkaline phosphatase increased (8%), creatinine increased (8%), hypoesthesia (8%) and malaise (8%). Of 13 patients, 5 (38%) had TRAEs leading to any treatment interruption, and 5 (38%) patients had TRAEs leading to any dose reduction, respectively. None patient died because of TRAEs. Conclusions: Camrelizumab combined with apatinib and albumin-bound paclitaxel followed by camrelizumab plus apatinib demonstrated encouraging antitumor activity and manageable toxicity as firstline therapy for patients with unresectable or metastatic pancreatic cancer. Clinical trial information: ChiCTR2100045844 .

Phase III FIRE-4 study (AIO KRK-0114): Evaluation of first-line treatment efficacy of FOLFIRI/cetuximab in patients with RAS-WT mCRC receiving the first cycle of treatment with chemotherapy only.

100 Background: FIRE-4 (AIO KRK-0114) is performed in RAS wild-type (wt) mCRC patients. This randomized study tests the efficacy of early switch maintenance during 1st-line therapy (part 1) and re-challenge with cetuximab (part 2) in later-line treatment. In part 1, all patients received first-line induction treatment with FOLFIRI plus cetuximab (FOLFIRI/Cet). In arm A, patients were randomized to continue FOLFIRI/Cet until progression or intolerable toxicity. In arm B, patients received FOLFIRI/Cet for 8-12 cycles, after which maintenance therapy with 5-FU/FA plus bevacizumab (5-FU/Bev) was applied. The first randomization evaluates the question if an early switch from cetuximab to bevacizumab during maintenance therapy may prolong PFS. The study protocol explicitly allowed a first cycle of chemotherapy to be applied before randomization. Methods: Within this randomized, controlled, open-label phase-III study, patients received FOLFIRI (irinotecan plus 5-FU/FA) plus cetuximab every two weeks at the standard dosing schedule. In arm A, FOLFIRI plus cetuximab was continued until progression or intolerable toxicity. De- and re-escalation was allowed according to the local standard of care. In arm B, patients received 8 cycles of FOLFIRI plus cetuximab (in case of tumor response) or 12 cycles (in case of stable disease) followed by maintenance with 5-FU/FA plus bevacizumab (5mg/kg) until disease progression or intolerable toxicity. Overall survival after second randomization (part 2) is evaluated as a primary endpoint. Here, we report PFS in first-line (part 1) as a secondary study endpoint of the study. Other secondary endpoints included ORR, OS, safety, and tolerability. Results: From August 2015 to January 2021, 672 patients were randomized, and 656 patients were assigned to treatment in 120 German and 10 Austrian centers (327 arm A and 329 in arm B). Of those, 205 patients received one cycle of FOLFIRI alone before randomization. In both arms, ORR was comparable for patients receiving cetuximab from the first cycle when compared to those receiving one cycle of chemotherapy only (arm A: 58.7% vs 62.9% (p = 0.54), arm B 60.2% vs 55.6% (p = 0.48). PFS was also not influenced in both arms (arm A: 10.8mo vs. 10.6mo (p = 0.91); arm B 11.2mo vs. 11.4mo (p = 0.62)). Preliminary results suggest that also OS (event rate 38.3%) was not influenced by one cycle applied without cetuximab (arm A: 33.7 mo vs. 29.1 mo (p = 0.20); arm B: 35.6 mo vs. 28.9 mo (p = 0.13)). Conclusions: Application of one initial cycle with chemotherapy alone did not influence the efficacy of a first-line strategy of FOLFIRI plus cetuximab. If RAS mutational analysis is not timely available, a start with FOLFIRI alone adding cetuximab in cycle 2 seems to be safe with respect of overall efficacy. Clinical trial information: NCT02934529 .

Wild Horse Optimization with Deep Learning-Driven Short-Term Load Forecasting Scheme for Smart Grids

Energy is a major driver of human activity. Demand response is of the utmost importance to maintain the efficient and reliable operation of smart grid systems. The short-term load forecasting (STLF) method is particularly significant for electric fields in the trade of energy. This model has several applications to everyday operations of electric utilities, namely load switching, energy-generation planning, contract evaluation, energy purchasing, and infrastructure maintenance. A considerable number of STLF algorithms have introduced a tradeoff between convergence rate and forecast accuracy. This study presents a new wild horse optimization method with a deep learning-based STLF scheme (WHODL-STLFS) for SGs. The presented WHODL-STLFS technique was initially used for the design of a WHO algorithm for the optimal selection of features from the electricity data. In addition, attention-based long short-term memory (ALSTM) was exploited for learning the energy consumption behaviors to forecast the load. Finally, an artificial algae optimization (AAO) algorithm was applied as the hyperparameter optimizer of the ALSTM model. The experimental validation process was carried out on an FE grid and a Dayton grid and the obtained results indicated that the WHODL-STLFS technique achieved accurate load-prediction performance in SGs.

Survival of NSCLC Patients Treated with Cimavax-EGF as Switch Maintenance in the Real-World Scenario.

Introduction: In Cuba, lung cancer represents the first cause of mortality for both sexes. Non-small cell lung cancer (NSCLC) is the most prevalent histology. Overall, 75-85% of NSCLC overexpress EGFR and its ligands. EGFR overexpression has been implicated in the malignant transformation by promoting cell proliferation and survival. CIMAvax-EGF is a therapeutic vaccine composed of recombinant-human EGF conjugated to a carrier protein and Montanide as an adjuvant. CIMAvax-EGF is intended to induce antibodies against self-EGF that block the EGF-EGFR interaction. Objectives: To characterize the efficacy and safety of CIMAvax-EGF as maintenance in NSCLC patients treated in the real-world setting. Results: 106 patients diagnosed with advanced NSCLC at the National Institute of Oncology and Radiobiology, who had at least stable disease after first-line therapy, were enrolled in the study. The initial four CIMAvax-EGF doses were administered every 2 weeks and then, patients received monthly re-immunizations. Globally, 52.8% of the patients were 65 years or older, 77.4% had an ECOG 1 and 62.3% had an adenocarcinoma. The median survival time (MST) was 14.6 months. Patients younger than 65 years had a MST of 16.7 months and subjects with ECOG 0 survived for 29 months. The median progression-free survival was 8.16 months. Overall, 36.8% and 19.8% of patients maintained disease control at 6 and 12 months, respectively. The most frequent adverse events were pain (27.3%) or induration (7.3%) at the injection site and local erythema (10.9%). Conclusion: CIMAvax-EGF, as an EGF depleting immunotherapy used as switch-maintenance was safe and effective in patients with NSCLC.

The role of switch maintenance therapy in urothelial cancers.

Maintenance therapy with immune checkpoint inhibitors (ICIs) has changed the treatment paradigm of metastatic urothelial carcinoma (mUC). The JAVELIN Bladder 100 trial established avelumab, one of several ICIs in use today, as a life-prolonging maintenance therapy for patients with advanced urothelial carcinoma. Platinum-based chemotherapy is most often used in the first-line treatment of mUC, and while response rates approach about 50%, disease control is usually short-lived upon completion of the standard three to six cycles of chemotherapy. Much progress has been made in recent years in the second-line space and beyond with the use of ICIs, antibody-drug conjugates (ADCs), and tyrosine kinase inhibitors (TKIs) in eligible patients at the time of disease progression post-platinum-based chemotherapy. However, many patients with progressive mUC after first-line chemotherapy suffer from rapid progression of disease, treatment toxicity with subsequent lines of therapy, and a limited life expectancy. Until the results of the JAVELIN Bladder 100 trial were presented in 2020, there were no maintenance strategies proven to be beneficial over best supportive care after disease control is achieved with first-line platinum-based chemotherapy. To date, standard of care frontline treatment of metastatic urothelial cancer remains to be four to six cycles of platinum-based chemotherapy followed by maintenance avelumab. This review summarizes the current evidence available on maintenance therapies in mUC, as well as several highly anticipated clinical trials that we hope will result in further progress in the management of this aggressive cancer and improve patient outcomes.

Switch Maintenance Therapy for Metastatic Urothelial Carcinoma.

While switch maintenance therapy is being increasingly investigated in solid tumors, it is a standard in only a few. We conducted a systematic review on switch maintenance therapy for metastatic urothelial carcinoma. In this systematic review, we conducted a literature search in PubMed and Cochrane databases up to 2021, based on PRISMA statement guidelines. One hundred and fifty eight articles were identified and after a three-step selection process and six articles, using different agents were included in evidence synthesis. The primary end points were effect on overall survival, progression free survival, safety and tolerability. In the pre-immunotherapy era, targeted therapies like sunitinib, lapatinib and vinflunine were studied as switch maintenance therapy in metastatic urothelial carcinoma but did not show any overall survival benefit. Use of anti-PD-1/PD-L1 agents have shown promise as switch maintenance therapy; pembrolizumab showed improvement in progression free survival in a phase 2 trial and avelumab showed improvement in overall survival and progression free survival in the phase 3 JAVELIN Bladder 100 trial. Immunotherapy with anti-PD-1/PD-L1 agents has emerged as an effective switch maintenance strategy in patients with metastatic urothelial carcinoma. Intensification of the immunotherapy backbone in this setting can potentially further enhance outcomes. Emerging evidence shows a potential role of Poly (ADP-ribose) polymerase (PARP) inhibitors in this setting as well. Results from ongoing and planned studies will help us understand which switch maintenance approaches would be most effective for improving outcomes in metastatic urothelial carcinoma.

Limited predictive impact of tumor size dynamics on further tumor shrinkage after 4 cycles of first-line chemotherapy in patients with advanced urothelial carcinoma.

To investigate the correlation between tumor size changes during the initial 4 cycles of first-line chemotherapy and tumor shrinkage following 2 additional cycles of chemotherapy in patients with advanced urothelial carcinoma (aUC) who experienced disease control after initial chemotherapy. We retrospectively reviewed 128 patients with aUC who received first-line chemotherapy. We analyzed 51 patients with disease control (stable disease or better) at the end of the fourth cycle. Of these, 47 patients received 1 to 2 additional cycles of chemotherapy, whereas the remaining patients underwent observation. For patients who received additional chemotherapy, the change in tumor size after additional chemotherapy (cycles 5-6) was defined as "no shrinkage" (tumor growth), "minor shrinkage" (no tumor growth or ≤10% reduction in tumor size), or "shrinkage" (>10% reduction in tumor size). Then, we investigated the relationship between the rate of tumor size change during the initial 4 cycles and that after additional chemotherapy. Of the patients who received additional chemotherapy, the change in tumor size was categorized as no shrinkage in 21 patients (44.7%), minor shrinkage in 18 patients (38.3%), and shrinkage in 8 patients (17%). Regarding predictors of tumor shrinkage after additional chemotherapy, the rate of tumor size change between the cycles 3 and 4 (area under the receiver operating characteristics curve = 0.642) was correlated with the trend of the tumor shrinkage (P = 0.009) and the likelihood of beneficial tumor shrinkage after additional chemotherapy (minor shrinkage + shrinkage; P = 0.02). However, the change in tumor size between cycles 1 and 2, cycles 1 and 4, or cycles 3 and 4 was not satisfactorily predictive of further tumor shrinkage because of substantial overlaps of the tumor size changes. Only a small subset of patients would have substantial tumor shrinkage by additional cycles after successful induction of 4 cycle chemotherapy. Tumor size dynamics during the initial 4 cycles of chemotherapy displayed limited ability to predict the subset of patients with further tumor shrinkage after additional chemotherapy. Therefore, it might be better to consider switch maintenance immunotherapy for patients who experience disease control after the fourth cycle of first-line chemotherapy.

MSR33 Application and Feasibility of Indirect Treatment Comparison of Switch Maintenance and Non-Maintenance Oncology Regimens to Inform HTA Decision-Making

MSR33 Application and Feasibility of Indirect Treatment Comparison of Switch Maintenance and Non-Maintenance Oncology Regimens to Inform HTA Decision-Making

Association of the Time to Immune Checkpoint Inhibitor (ICI) Initiation and Outcomes With Second Line ICI in Patients With Advanced Urothelial Carcinoma.

Early progression on first-line (1L) platinum-based therapy or between therapy lines may be a surrogate of more aggressive disease and poor outcomes in advanced urothelial carcinoma (aUC), but its prognostic role regarding immune checkpoint inhibitor (ICI) response and survival is unclear. We hypothesized that shorter time until start of second-line (2L) ICI would be associated with worse outcomes in aUC. We performed a retrospective multi-institution cohort study in patients with aUC treated with 1L platinum-based chemotherapy, who received 2L ICI. Patients receiving switch maintenance ICI were excluded. We defined time to 2L ICI therapy as the time between the start of 1L platinum-based chemotherapy to the start of 2L ICI and categorized patients a priori into 1 of 3 groups: less than 3 months versus 3-6 months versus more than 6 months. We calculated overall response rate (ORR) with 2L ICI, progression-free survival (PFS) and overall survival (OS) from the start of 2L ICI. ORR was compared among the 3 groups using multivariable logistic regression, and PFS, OS using cox regression. Multivariable models were adjusted for known prognostic factors. We included 215, 215, and 219 patients in the ORR, PFS, and OS analyses, respectively, after exclusions. ORR difference did not reach statistical significance between patients with less than 3 months versus 3-6 months versus more than 6 months to 2L ICI. However, PFS (HR 1.64; 95% CI 1.02-2.63) and OS (HR 1.77; 95% CI 1.10-2.84) was shorter among those with time to 2L ICI less than 3 months compared to those who initiated 2L ICI more than 6 months. Among patients with aUC treated with 2L ICI, time to 2L ICI less than 3 months was associated with lower, but not significantly different ORR, but shorter PFS and OS compared to 2L ICI more than 6 months. This highlights potential cross resistance mechanisms between ICI and platinum-based chemotherapy.

The role of maintenance therapy in the treatment of advanced urothelial cancer: a comprehensive systematic review and network meta-analysis

Concerns increase with maintenance therapy for advanced urothelial cancer (aUC). We perform a comprehensive network meta-analysis (NMA) to investigate the efficacy and toxicities of maintenance therapy in aUC patients. Trials assessing maintenance treatment with either a continuous or a switch strategy for aUC were identified. The primary outcome was overall survival (OS), and secondary outcome was progression-free survival (PFS) and toxicities. Nine articles reporting eight trials were included. The pooled hazard ratio demonstrated that maintenance therapy significantly improved OS giving HR 0.83 (95%CI: 0.74–0.93, P = 0.0013) and PFS with HR of 0.78 (95%CI: 0.62–0.99, P = 0.05), but increased the risk of developing severe adverse events and treated-related discontinues (P < 0.05). Sub-group analysis indicated that ‘switch’ ICI (immune checkpoint inhibitor) maintenance therapy significantly improved OS and PFS when compared to best support care (BSC) (P < 0.05). NMA showed that chemotherapy followed by ‘switch’ maintenance with ICI significantly improved OS (HR 0.70, 95%CI: 0.57–0.87) when compared to BSC. ‘Continuous’ maintenance with ICI alone had a tendency to improve OS (HR 0.85, 95%CI: 0.71–1.01), and TA (HR0.93, 95%CI: 0.58–1.50) and vinflunine (HR 0.74, 95%CI: 0.44–1.24) was no significantly associated with a lower likelihood of disease death. Based on the analysis of the treatment ranking, ‘switch’ maintenance with ICI appeared as the best treatment approach. Our pooled results confirm that maintenance therapy yields a significant survival advantage for aUC patients. NMA indicates that switch maintenance with ICI is the optimum maintenance treatment for aUC and reduces mortality by about a third.

EGFR Mutation-positive Lung Cancer in Real-world Treatment Outcomes: A Multicenter Study from Thailand

Background: Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKI) have been the standard of care as first-line (1L) therapy for patients with advanced EGFR mutated lung cancer since 2009. In Thailand, however, it was not fully introduced to all health care funds until 2020. The purpose of this study was to determine the overall survival (OS) and treatment pattern in the period before EGFR-TKI became universally available to all patients.&#x0D; Methods: This was a retrospective study conducted at 10 medical centers in Thailand. Patients harboring the common mutation (exon 19 deletion or exon 21 L858R) diagnosed during January 2013 and December 2019 were enrolled.&#x0D; Results: This study included 284 patients with a median follow-up time of 19.8 months and a death rate of 80.3% (228/284). Clinical characteristics included median age 62.5 years, female 65.5%, never-smoking 74.3%, stage 3B/4/recurrence 2.1/93.3/4.6%, exon 19/exon 21- 60.9/38.7%. Treatment patterns to EGFR-TKI included not receiving (NR) (9.5%), first-line (1L) (56.0%), switch maintenance (MN) (3.5%), second-line (2L) (21.8%) and third-line (3L) or more (9.2%). Median OS of patient receiving EGFR-TKI as NR, 1L+MN, 2L and 3L or more was 11.10 (95%CI: 8.21 to14.00), 19.08 (95%CI: 15.76 to 22.41), 23.06 (95%CI: 15.91 to 30.21) and 32.46 (95%CI: 21.61 to 43.30) months (p=0.006), respectively. Factors contributing to poor prognosis in the multivariate model included poor ECOG-PS (HR 3.17, 95%CI: 1.96-5.13), not receiving EGFR-TKI (HR 3.83, 95%CI, 1.94-7.56) and receiving EGFR-TKI 1L (HR 2.30, 95%CI: 1.40-3.79)&#x0D; Conclusion: OS of patients with EGFR mutation positive lung cancer treated with EGFR-TKIs in Thailand was comparable to clinical studies. EGFR-TKI treatment should be provided to patients as early as possible, but TKI remained beneficial at later points in the treatment timeline.