Improvement In Objective Response Rate Research Articles

Vedolizumab for acute gastrointestinal graft-versus-host disease: A systematic review and meta-analysis.

To determine the safety and efficacy of vedolizumab for the prophylaxis and treatment of gastrointestinal involvement of acute graft-versus-host disease (GVHD) (GI-aGVHD). Literature search within PubMed, EMBASE, Web of Science, and Cochrane Library for observational studies and clinical trials that evaluated the effect of vedolizumab on GI-aGVHD was done through 17 May 2022.A bivariate and random-effect meta-analysis derived the pooled observational percentages and pooled risk ratios (RRs) from baseline of primary endpoints including overall response, complete response, mortality, and adverse events. There was a total of 122 participants in eight eligible studies, including one study on the prophylactic use of vedolizumab and seven studies on vedolizumab for the treatment of GI-aGVHD. Of seven studies that reported details on baseline grades of GI-aGVHD, a total of 47 patients (47.95%) were of stage 4, 31 patients (31.63%) were of stage 3, 10 patients (10.2%) were of stage 2, and 10 patients (10.2%) were of stage 1. The use of vedolizumab for the treatment of GI-aGVHD yielded a significantly improved objective response rate (ORR) at 14 days (pooled ORR = 60.53%, pooled RR = 14.14, 95% CI: 2.95-67.71), 28 days (pooled ORR = 50%, RR = 7.36, 95% CI = 2.14-25.37), and 12 months (pooled ORR = 76.92%, RR = 13.66, 95% CI = 3.5-53.35) from baseline. Likewise, the use of vedolizumab was followed by a significantly improved complete response (CR) at 12 months (pooled CR = 27.27%, RR = 5.50, 95% CI = 1.01-29.95), yet the CR at 14 days and 28 days did not reach statistical significance. Fifty-seven out of 87 (pooled overall survival, OS = 34.5%) and 46 out of 65 (pooled OS = 29.2%) patients expired at 6 and 12 months after the use of vedolizumab, respectively. Prophylactic use of vedolizumab was not associated with any specific type of reported adverse events, while patients with GI-aGVHD on vedolizumab presented with significantly increased risks of adverse events including infections (RR = 7.55) and impaired metabolism or nutritional complications (RR = 9.00). All analyses were of a low heterogeneity (all I-squares = 0%). Vedolizumab was safe and effective for the prophylaxis and management of early grade GI-aGVHD. More clinical evidence is warranted to validate these findings. https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=345584, identifier CRD42022345584.

Mass Cytometry Reveals Classical Monocytes, NK Cells, and ICOS+ CD4+ T Cells Associated with Pembrolizumab Efficacy in Patients with Lung Cancer.

Immune checkpoint inhibitors (ICI) have revolutionized the treatment of non-small cell lung cancer (NSCLC), but predictive biomarkers of their efficacy are imperfect. The primary objective is to evaluate circulating immune predictors of pembrolizumab efficacy in patients with advanced NSCLC. We used high-dimensional mass cytometry (CyTOF) in baseline blood samples of patients with advanced NSCLC treated with pembrolizumab. CyTOF data were analyzed by machine-learning algorithms (Citrus, tSNE) and confirmed by manual gating followed by principal component analysis (between-group analysis). We analyzed 27 patients from the seminal KEYNOTE-001 study (median follow-up of 60.6 months). We demonstrate that blood baseline frequencies of classical monocytes, natural killer (NK) cells, and ICOS+ CD4+ T cells are significantly associated with improved objective response rates, progression-free survival, and overall survival (OS). In addition, we report that a baseline immune peripheral score combining these three populations strongly predicts pembrolizumab efficacy (OS: HR = 0.25; 95% confidence interval = 0.12-0.51; P < 0.0001). As this immune monitoring is easy in routine practice, we anticipate our findings may improve prediction of ICI benefit in patients with advanced NSCLC.

Immunotherapy and Hepatocellular Cancer: Where Are We Now?

Simple SummaryHCC is the third-leading cause of cancer death worldwide. Prior to the immunotherapy era, treatment of advanced HCC was dominated by antiangiogenic tyrosine kinase inhibitors, with a quite poor prognosis with a median survival time of around one year. In this review, we aimed to elaborate on all the advances in immunotherapy in HCC from the indisputable first-line therapy atezolizumab–bevacizumab in advanced HCC to promising new strategies. We highlight the new standard of care in advanced HCC, namely, the combination of immune checkpoint inhibitors (ICI) durvalumab–tremelimumab, and also discuss the different combinations of antiangiogenic drugs with ICI. We develop how the combination of ICI with locoregional therapies could become a future treatment in early and intermediate-stage HCC, and, finally, we outline several new cell-therapy-based strategies to follow in the coming years.Immunotherapy has demonstrated its effectiveness in many cancers. In hepatocellular carcinoma (HCC), promising results shown in the first phase II studies evaluating anti-PD-1 or anti-PD-L1 monotherapies resulted in their approval in the United States. Approval was not obtained in Europe; subsequent randomized studies in first- or second-line treatment did not confirm these initial results. However, first data with immunotherapy plus antiangiogenic treatments or dual immunotherapy combinations were positive. In this context, the combination of bevacizumab and atezolizumab took the lead. The IMbrave150 trial revealed an improved objective response rate (ORR), progression-free survival, and overall survival with this combination versus the previous standard, sorafenib. Subsequent results of dual immunotherapy with the anti-CTLA-4 and anti-PD-1 monotherapies tremelimumab and durvalumab (also superior to sorafenib monotherapy) confirmed the value of using a combination in first-line treatment. These significant therapeutic advances, and the increase in ORR, raise two main questions. Whereas response was very limited with previous treatments, the ORR reported with these new combinations are between 20% and 30%. This raises the question of whether immunotherapy (ICI single agent, combination of ICI with antiangiogenic agent or other antitumoral treatment) can be used in patients beyond those in BCLC group C, the traditional candidate group for systemic therapy. We have thus seen an increasing number of patients previously treated with trans-arterial chemoembolization (BCLC group B) receiving these new treatments, and we develop the results of several studies combining loco-regional therapies and immunotherapy-based systemic treatments. The other major question is that of how and when to use these medical treatments as “adjuvants” to interventional radiology or surgery; the results of several works are discussed for this purpose. In this review, we cover all of these points in a fairly comprehensive manner.

Abstract IA007: B cell immunity generation in tertiary lymphoid structures, a major determinant of sarcoma immune response to immunotherapy

Abstract The presence of tertiary lymphoid structures (TLSs) and a high intratumoral density of B lymphocytes have been associated with improved survival in several tumor types. We investigated the impact of TLS on responses to immunotherapy and, analyzing a large-scale retrospective analysis of three independent cohorts of patients with cancer, including sarcomas, who were treated with anti-PD-1 or anti-PD-L1 antibodies, we showed that the presence of mature TLSs was associated with improved objective response rates, progression-free survival and overall survival, independent of PD-L1 expression status and CD8+T cell density. To decipher the role of B cells in such responses, we performed spatial transcriptomics and examined the nature of B cell responses within TLS structure. B cells were enriched in TLS, and therein we could identify all B cell maturation stages toward plasma cell (PC) formation. B cell repertoire analysis revealed clonal diversification, selection, expansion in TLS and the presence of full mature clonotypes at distance. In TLS+ tumors, IgG producing PCs disseminated into the tumor beds along fibroblastic tracks. TLS+ tumors exhibited high frequencies of IgG-producing PCs and IgG-stained and apoptic malignant cells, suggestive of anti-tumor effector activity. We validated these findings in a prospective trial in metastatic Soft Tissue Sarcoma (STS) bearing patients. PEMBROSARC is a multi-cohort phase II study of pembrolizumab combined with low-dose cyclophosphamide in patients with advanced STS. The 6-months non-progressive rate (NPR) and the objective response rates previously reported in cohorts including all comers were 4.9% and 2.4%, respectively. In the cohort enrolling patients selected based on the presence of TLS, the 6-month NPR was 40% and the objective response rate was 30%. Exploratory analyses reveled that infiltration by IgG antibody-producing plasma cells was associated with improved clinical outcome as well as the presence of IgG antibodies on tumor cells. Altogether, these results establish that maturation, selection and amplification of B cells in intratumoral TLSs results in Plasma Cells generation which may produce anti-tumor antibodies. The latter may amplify in situ antitumor immune responses leading to better therapeutic responses to immunotherapy. Citation Format: Wolf H. Fridman. B cell immunity generation in tertiary lymphoid structures, a major determinant of sarcoma immune response to immunotherapy [abstract]. In: Proceedings of the AACR Special Conference: Sarcomas; 2022 May 9-12; Montreal, QC, Canada. Philadelphia (PA): AACR; Clin Cancer Res 2022;28(18_Suppl):Abstract nr IA007.

970TiP SKYSCRAPER-05: Phase II study of neoadjuvant atezolizumab (Atezo) + tiragolumab (Tira) with or without platinum-based chemotherapy (CT) in patients (Pts) with locally advanced resectable stage II‒IIIB NSCLC

For resectable NSCLC, surgery (often with neoadjuvant or adjuvant CT), is the standard of care. However, benefit is modest and there is need to improve outcomes. Atezo (anti-PD-L1) has shown promising efficacy as monotherapy and in combination with CT in NSCLC. Inhibition of the PD-L1 pathway may be amplified by inhibition of TIGIT signaling. In CITYSCAPE (phase II; NCT03563716), tira (anti-TIGIT) + atezo was well tolerated and improved objective response rate vs atezo alone in 1L metastatic PD-L1+ NSCLC. Hypothesis: tira + atezo may provide clinical benefit in the neoadjuvant setting by enhancing anti-tumour immune response and eradicating micrometastases, reducing risk of disease recurrence. SKYSCRAPER-05 (NCT04832854) will evaluate safety, tolerability and preliminary efficacy of neoadjuvant tira + atezo ± CT in pts with resectable NSCLC. In this global, open-label study, ∼82 pts with histologically/cytologically confirmed, resectable Stage II, IIIA, or select IIIB (T3N2 only) NSCLC who are eligible for R0 resection with curative intent; without EGFR/ALK mutations; ECOG PS 0–1; with no prior cancer immunotherapy, CT or radiotherapy for NSCLC will be enrolled into two cohorts. Cohort A: pts with PD-L1 TC ≥50% tumours or Cohort B: pts independent of PD-L1 status. Pts will receive 4 cycles of neoadjuvant tira 600 mg IV + atezo 1200 mg IV Q3W (Cohort A) (CT-free option) or in combination with platinum-doublet CT Q3W (Cohort B). Following resection, pts will receive adjuvant tira + atezo or platinum-based CT Q3W (Cohort A) or adjuvant tira + atezo for 16 cycles (Cohort B) until disease recurrence or unacceptable toxicity. Investigator-selected CT options are cisplatin or carboplatin + pemetrexed, carboplatin + paclitaxel, and cisplatin or carboplatin + gemcitabine. Primary endpoints: central pathology laboratory-assessed major pathological response, treatment-related surgical delays, cancellations/complications and safety. Secondary endpoints: pathological complete response and event-free survival. Exploratory biomarkers will be evaluated. Recruitment is ongoing. NCT04832854. Medical writing assistance, under the direction of the authors, was provided by Ashfield MedComms, an Ashfield Health company. F. Hoffmann-La Roche Ltd.

Injectable pH-responsive hydrogel for combinatorial chemoimmunotherapy tailored to the tumor microenvironment

Although combination chemoimmunotherapy shows promising clinical results for cancer treatment, this approach is largely restricted by variable objective response rate and severe systemic adverse effects of immunotherapeutic antibody and chemotherapeutic drugs. Therefore, an in situ-formed therapeutic silk-chitosan composite scaffold is fabricated in this study to allow local release of the chemotherapeutic drug doxorubicin (DOX) and JQ1 (small molecular inhibitor used for the extraterminal protein BRD4 and bromodomain) with control release kinetics. DOX-JQ1@Gel contains a pH-degradable group that releases therapeutics in a weak acidic tumor microenvironment. The released DOX could directly kill tumor cells or lead to immunogenic cell death, thereby triggering the response of antitumor immunity. Meanwhile, chemotherapy-triggered antigen release and JQ1-mediated PD-L1 checkpoint blockade cumulatively contribute to trigger the response of antitumor immunity. Finally, the DOX-JQ1@Gel is locally injected to evaluate its synergistic cancer therapeutic effect, which is expected to improve objective response rate of immunotherapy and minimize systemic side effects.Graphical

Final overall survival results from SOLO3: Phase III trial assessing olaparib monotherapy versus non-platinum chemotherapy in heavily pretreated patients with germline BRCA1 - and/or BRCA2-mutated platinum-sensitive relapsed ovarian cancer (026)

<b>Objectives:</b> In the open-label Phase III SOLO3 trial (NCT02282020), olaparib monotherapy provided clinically relevant and statistically significant improvements in objective response rate (ORR; primary endpoint) and progression-free survival (PFS; secondary endpoint), compared with single-agent non-platinum chemotherapy, in patients (pts) with germline <i>BRCA1</i> and/or <i>BRCA2</i>-mutated (g<i>BRCA</i>m) platinum-sensitive relapsed ovarian cancer (PSROC) who had received ≥2 prior lines of platinum-based chemotherapy (Penson <i>et al. JCO</i> 2020). We report final overall survival (OS) and second disease progression results from SOLO3. <b>Methods:</b> Pts were randomized (2:1) to olaparib tablets (300 mg bid) or single-agent non-platinum chemotherapy treatment of physician's choice (TPC; paclitaxel [P], topotecan [T], gemcitabine [G], or pegylated liposomal doxorubicin [PLD]). Study treatment continued until objective radiological disease progression, unacceptable toxicity, or other discontinuation criteria were met. The time from randomization to second progression or death (PFS2) and OS were secondary endpoints. As prespecified, this analysis was performed at approximately 60% data maturity for OS. <b>Results:</b> 266 pts were randomized (olaparib, <i>n</i>=178; TPC, <i>n</i>=88 [PLD, <i>n</i>=47; P, <i>n</i>=20; G, <i>n</i>=13; T, <i>n</i>=8]); 12 (14%) TPC pts withdrew before receiving study treatment. At the final data cut-off (DCO; April 16, 2021), 19 (11%) olaparib pts versus no TPC pts were still receiving study treatment. The percentage of pts who left the study prior to death was approximately 2.3 times higher in the TPC arm (22 pts [25%]) than in the olaparib arm (19 pts [11%]). Following disease progression, the majority of pts received subsequent anticancer therapy (119 of 178 [67%] olaparib pts vs 54 of 88 [61%] TPC pts received ≥1 subsequent anticancer regimen); three of 178 (2%) olaparib pts versus 23 of 88 (26%) TPC pts received a PARP inhibitor in their first subsequent line of therapy, with nine of 178 (5%) versus 33 of 88 (38%) pts, respectively, receiving a PARP inhibitor in any subsequent line of therapy. At the final DCO, PFS2 favored olaparib over TPC, although the between-group difference was not statistically significant, and OS was similar in the olaparib and TPC groups (see Table). Adverse events (AEs) were consistent with the known safety profile of olaparib and with previous SOLO3 analyses; no new safety signals were identified. Discontinuation of study treatment due to AEs occurred in 18 of 178 (10%) olaparib pts versus 15 of 76 (20%) TPC pts in the safety analysis set. Circulating tumor DNA analyses are ongoing. <b>Conclusions:</b> In the primary analysis of SOLO3, olaparib monotherapy improved ORR and PFS compared with single-agent non-platinum chemotherapy in heavily pretreated pts with g<i>BRCA</i>m PSROC. In the final analysis, PFS2 favored olaparib monotherapy over TPC, and OS was similar in both treatment groups, supporting the use of olaparib as a chemotherapy-free treatment option in this pt population. No new safety signals were identified.

Study protocol of the FIRE-8 (AIO-KRK/YMO-0519) trial: a prospective, randomized, open-label, multicenter phase II trial investigating the efficacy of trifluridine/tipiracil plus panitumumab versus trifluridine/tipiracil plus bevacizumab as first-line treatment in patients with metastatic colorectal cancer

BackgroundInitial systemic therapy for patients with metastatic colorectal cancer (mCRC) is usually based on two- or three-drug chemotherapy regimens with fluoropyrimidine (5-fluorouracil (5-FU) or capecitabine), oxaliplatin and/or irinotecan, combined with either anti-VEGF (bevacizumab) or, for RAS wild-type (WT) tumors, anti-EGFR antibodies (panitumumab or cetuximab). Recommendations for patients who are not eligible for intensive combination therapies are limited and include fluoropyrimidine plus bevacizumab or single agent anti-EGFR antibody treatment. The use of a monochemotherapy concept of trifluridine/ tipiracil in combination with monoclonal antibodies is not approved for first-line therapy, yet. Results from the phase II TASCO trial evaluating trifluridine/ tipiracil plus bevacicumab in first-line treatment of mCRC patients and from the phase I/II APOLLON trial investigating trifluridine/ tipiracil plus panitumumab in pre-treated mCRC patients suggest favourable activity and tolerability of these new therapeutic approaches.MethodsFIRE-8 (NCT05007132) is a prospective, randomized, open-label, multicenter phase II study which aims to evaluate the efficacy of first-line treatment with trifluridine/tipiracil (35 mg/m2 body surface area (BSA), orally twice daily on days 1–5 and 8–12, q28 days) plus either the anti-EGFR antibody panitumumab (6 mg/kg body weight, intravenously on day 1 and 15, q28 days) [arm A] or (as control arm) the anti-VEGF antibody bevacizumab (5 mg/kg body weight, intravenously on day 1 and 15, q28 days) [arm B] in RAS WT mCRC patients. The primary objective is to demonstrate an improved objective response rate (ORR) according to RECIST 1.1 from 30% (control arm) to 55% with panitumumab. With a power of 80% and a two-sided significance level of 0.05, 138 evaluable patients are needed. Given an estimated drop-out rate of 10%, 153 patients will be enrolled.DiscussionTo the best of our knowledge, this is the first phase II trial to evaluate the efficacy of trifluridine/tipiracil plus panitumumab in first-line treatment of RAS WT mCRC patients. The administration of anti-EGFR antibodies rather than anti-VEGF antibodies in combination with trifluridine/tipiracil may result in an increased initial efficacy.Trial registrationEU Clinical Trials Register (EudraCT) 2019-004223-20. Registered October 22, 2019, ClinicalTrials.govNCT05007132. Registered on August 12, 2021.

Comparison of a histone deacetylase inhibitor plus exemestane with exemestane alone in hormone receptor-positive advanced breast cancer that progressed on prior endocrine therapy: A meta-analysis.

Currently, endocrine therapy is the standard treatment for hormone receptor-positive advanced breast cancer (ABC). Despite the high sensitivity of anti-estrogen therapy, many breast cancer patients still experience disease progression, relapse, and reduced overall survival (OS) because of endocrine resistance. Several underlying mechanisms of this phenomenon include a change in hormone receptor expression, mutations in ESR1 and modification of important signaling pathways, but thus far none of these can be defined as the complete explanation. Additionally, it has been shown that in some breast cancers, expression of the estrogen receptor (ER) can be repressed by epigenetic modifications such as DNA methylation and histone deacetylation, and this could be a mechanism for endocrine resistance. Interestingly, although the efficacy of the combination of histone deacetylase (HADC) inhibitors and exemestane in hormone receptor-positive ABC that progressed on prior endocrine therapy has been investigated in several studies, whether pharmacologic blocking of HDAC activity acts as a therapeutic strategy remains highly controversial. Herein, we conducted a meta-analysis to evaluate the efficacy and safety of an HDAC inhibitor plus exemestane vs. exemestane alone in this setting. Our meta-analysis demonstrated that the combination group exhibited significantly prolonged progression-free survival (PFS) [hazard ratio (HR)=0.776, 95% confidence interval (CI)=0.675-0.892, P=0.000] and an improved objective response rate (ORR) (RR=1.612, 95% CI=1.085-2.396, P=0.018) compared to those treated with exemestane alone. Additionally, in terms of OS, the combination group failed to achieve a significant clinical OS benefit (HR=0.811, 95% CI=0.596-1.104, P=0.183). Although grade 3/4 toxicities were more common in the combination group, those toxicities were mostly asymptomatic and manageable. In conclusion, the addition of an HDAC inhibitor to exemestane significantly improves PFS over exemestane alone in hormone receptor-positive ABC patients who progressed on previous endocrine therapy. Identification of novel biomarkers to select patients who will benefit from this combination strategy is a high priority.

Tiragolumab and atezolizumab in patients with PD-L1 positive non-small-cell lung cancer

Anti-PD-1 and anti-PD-L1 antibodies, alone or in combination with chemotherapy or anti-CTLA-4 antibodies, are standard therapeutic options for patients with advanced non-small-cell lung cancer (NSCLC). In patients with NSCLC with high PD-L1 expression (ie, with more than 50% of cancer cells staining positive for PD-L1 on immunohistochemistry), pembrolizumab or atezolizumab monotherapy can substantially improve objective response rates, progression-free survival, and overall survival compared with chemotherapy, sparing selected patients from chemotherapy. 1 Jassem J de Marinis F Giaccone G et al. Updated overall survival analysis from IMpower110: atezolizumab versus platinum-based chemotherapy in treatment-naive programmed death-ligand 1-selected NSCLC. J Thorac Oncol. 2021; 16: 1872-1882 Summary Full Text Full Text PDF PubMed Scopus (15) Google Scholar , 2 Reck M Rodríguez-Abreu D Robinson AG et al. Five-year outcomes with pembrolizumab versus chemotherapy for metastatic non-small-cell lung cancer with PD-L1 tumor proportion score ≥ 50. J Clin Oncol. 2021; 39: 2339-2349 Crossref PubMed Scopus (114) Google Scholar Combining anti-PD-1 and anti-PD-L1 antibodies with chemotherapy for patients with non-squamous NSCLC with a high PD-L1 expression can push the median overall survival to 27·7–30·0 months (up from 20·2–26·3 months with pembrolizumab or atezolizumab monotherapy), although the combination can have higher adverse events. 3 Gray J Rodríguez-Abreu D Powell SF et al. FP13.02 Pembrolizumab + pemetrexed-platinum vs pemetrexed-platinum for metastatic NSCLC: 4-year follow-up from KEYNOTE-189. J Thorac Oncol. 2021; 16: S224 Summary Full Text Full Text PDF Google Scholar , 4 Socinski MA Nishio M Jotte RM et al. IMpower150 final overall survival analyses for atezolizumab plus bevacizumab and chemotherapy in first-line metastatic nonsquamous NSCLC. J Thorac Oncol. 2021; 16: 1909-1924 Summary Full Text Full Text PDF PubMed Scopus (49) Google Scholar Immunotherapy combinations such as nivolumab plus ipilimumab (with or without chemotherapy) are also standard regimens, but do not appear to add benefit versus single agents, as shown by a median overall survival of 21·2 months reported in a high-PD-L1 population. 5 Paz-Ares LG Ramalingam SS Ciuleanu T-E et al. First-line nivolumab plus ipilimumab in advanced NSCLC: 4-year outcomes from the randomized, open-label, phase 3 CheckMate 227 part 1 trial. J Thorac Oncol. 2022; 17: 289-308 Summary Full Text Full Text PDF PubMed Scopus (25) Google Scholar Therefore, there is an unmet need to improve outcomes for patients with NSCLC with a high expression of PD-L1, by use of immunotherapy combinations that dispense with the need for upfront chemotherapy. Tiragolumab plus atezolizumab versus placebo plus atezolizumab as a first-line treatment for PD-L1-selected non-small-cell lung cancer (CITYSCAPE): primary and follow-up analyses of a randomised, double-blind, phase 2 studyTiragolumab plus atezolizumab showed a clinically meaningful improvement in objective response rate and progression-free survival compared with placebo plus atezolizumab in patients with chemotherapy-naive, PD-L1-positive, recurrent or metastatic NSCLC. Tiragolumab plus atezolizumab was well tolerated, with a safety profile generally similar to that of atezolizumab alone. These findings demonstrate that tiragolumab plus atezolizumab is a promising immunotherapy combination for the treatment of previously untreated, locally advanced unresectable or metastatic NSCLC. Full-Text PDF

Efficacy of next line of therapy after treatment with lenvatinib (LEN) in combination with pembrolizumab (pembro) versus treatment of physician’s choice (TPC) in patients (pts) with advanced endometrial cancer (aEC): Exploratory analysis of Study 309/KEYNOTE-775.

5587 Background: In the multicenter, open-label, randomized, phase 3 Study 309/KEYNOTE-775, LEN + pembro had significant PFS and overall survival benefits, and improved objective response rate vs TPC in pts with aEC following systemic platinum-based treatment (Makker 2022, NEJM). These results were seen in all-comer pts and in pts with DNA mismatch repair proficient (pMMR) disease. Here, we assessed PFS on next line of therapy (PFS2) of each arm. Methods: Pts with aEC and 1 prior platinum-based chemotherapy regimen (or up to 2 if 1 was given in neoadjuvant/adjuvant setting) were randomized (1:1) to receive LEN 20 mg orally QD + pembro 200 mg IV Q3W or TPC (doxorubicin at 60 mg/m2 IV Q3W or paclitaxel at 80 mg/m2 IV QW [3 weeks on; 1 week off]). Randomization was stratified by MMR status (determined centrally); pts with pMMR tumors were further stratified by Eastern Cooperative Oncology Group performance status, geographic region, and history of pelvic radiation. In this prespecified exploratory analysis, PFS2 (defined as the time from randomization to disease progression on next line of treatment or death, whichever came first) was analyzed per investigator assessment in the pMMR and all-comer populations. Results: 827 Pts (pMMR, n=697; MMR deficient [dMMR], n=130) were randomized to LEN + pembro (n=411) or TPC (n=416). At data cutoff (October 26, 2020), 567 pts (LEN + pembro, n=282; TPC, n=285) had discontinued study treatment and 315 (LEN + pembro, n=115; TPC, n=200) had received a subsequent systemic anticancer therapy (Table): most commonly doxorubicin (n=58) in the LEN + pembro arm and paclitaxel (n=57) in the TPC arm. Median PFS2 was longer in the LEN + pembro arm vs the TPC arm in the pMMR population (14.4 vs 9.8 mo; HR 0.62, 95% CI 0.50–0.75) and in the all-comer population (16.0 vs 9.5 mo; HR 0.56, 95% CI 0.46–0.67). Additionally, the PFS2 rate at 6 months favored LEN + pembro vs TPC in the pMMR population (82.0% vs 74.8%) and in the all-comer population (81.7% vs 72.5%). Conclusions: Clinically meaningful improvements in PFS2 were seen in the LEN + pembro group compared with TPC in pMMR and all-comer pts. Clinical trial information: NCT03517449. [Table: see text]

OrienX010, an oncolytic virus, in patients with unresectable stage IIIC–IV melanoma: a phase Ib study

BackgroundMelanoma in people of Asian descent presents primarily in non-sun-exposed areas, such as acral and mucosal melanoma. Compared with the predominant sun-exposed area melanomas in Caucasians, acral and mucosal melanomas...

Correlation between treatment effects on response rate and progression-free survival and overall survival in trials of targeted therapies in molecularly enriched populations

BackgroundThe number of randomized trials of agents targeting oncogene-addicted tumors has surged in the past 10 years. Using a meta-analysis, we explored whether improvements in objective response rate (ORR) in comparative trials using targeted agents could serve as a potential surrogate endpoint for improvements in progression-free survival (PFS) or overall survival (OS) in populations with oncogene-addicted cancer.Patients and methodsUsing commercial text mining software I2E, we searched ClinicalTrials.gov and MEDLINE databases for randomized, phase III trials based on prospectively defined criteria, including (i) use of agents targeting EGFR activating mutations, ALK rearrangements, BRAF V600E or V600K mutations, and BCR-ABL fusion protein; (ii) molecularly enriched trial population or subpopulation; (iii) control arm only randomized to chemo/cytotoxic therapy. Correlative analyses were performed using ORR, OS, and PFS data from trials that met these criteria.ResultsA total of 62 trials were identified; 15 met all of the prespecified criteria. The ORR effect size (both the difference in ORR between arms and the log odds ratio) and log PFS hazard ratio were strongly correlated: –0.78 (P = 0.0007) for the ORR difference model; –0.74 (P = 0.0017) for the log odds ratio model. ORR effect size was positively correlated with the log OS hazard ratio, but more weakly: –0.67 (P = 0.013) for the ORR difference model and –0.58 (P = 0.036) for the log odds ratio model. Analysis of the treatment effects between OS and PFS found no correlation.ConclusionsThese analyses identified a strong correlation between treatment effects on ORR and PFS in randomized clinical trials investigating agents targeting oncogene-driven cancers. A weaker correlation was observed between ORR and OS. These meta-analysis results support the use of a high ORR forming the basis of an initial regulatory approval in biomarker-driven studies.

Exploratory analysis of the impact of prior immune checkpoint inhibitor (ICI) on trastuzumab deruxtecan (T-DXd; DS-8201) clinical outcomes and biomarkers (BM) in DESTINY-Gastric01 (DG-01), a randomized, phase 2, multicenter, open-label study in patients (pts) with HER2+ advanced gastric or gastroesophageal junction adenocarcinoma.

322 Background: T-DXd is a HER2-targeting antibody-drug conjugate. In primary analyses of DG-01 (NCT03329690), T-DXd showed clinically meaningful improvement in objective response rate (ORR) and overall survival (OS) vs chemotherapy in the primary cohort of pts with HER2+ advanced gastric cancer (AGC; IHC3+ or IHC2+/ISH+; Shitara K et al. NEJM 2020;382:2419). In the context of emerging first-line ICI-based regimens in AGC, we conducted a post hoc analysis of T-DXd clinical outcomes and baseline BMs in pts with or without prior ICI. Methods: DG-01 primary cohort enrolled pts who progressed on ≥2 prior lines with centrally confirmed HER2+ AGC. Efficacy and safety were assessed in pts with or without prior ICI (defined as any ICI-related treatment received prior to T-DXd). Exploratory BM analysis in the T-DXd arm assessed RNA sequencing (RNAseq) of tumor biopsies and ctDNA of liquid biopsies taken immediately before T-DXd treatment. A linear regression model and Wilcoxon rank-sum test were used to identify differentially expressed genes and signature scores between pts with or without prior ICI. Results: Prior ICI was received in 35.2% (44/125) of pts treated with T-DXd and 27.4% (17/62) treated with chemotherapy. The table shows efficacy in pts with or without prior ICI. Safety data in the T-DXd arm were similar between pts with or without prior ICI, including adjudicated drug-related interstitial lung disease/pneumonitis; 9.1% (4/44) of pts with prior ICI and 9.9% (8/81) of pts without prior ICI. Among 34 T-DXd-treated pts with RNAseq data, 12 received prior ICI. Searching for differentially expressing genes (fold change ≥2, P≤0.01) identified multiple genes with a higher trend for expression in tumors with prior ICI, including immune-oncology (IO)-related molecules, CXCL9 and PD-1 (log2 fold change 2.3 and 1.4, P=7.3e-05 and 2.8e-03, respectively). Furthermore, gene signature analysis showed a concurrent higher trend of multiple chemokine gene expressions in the prior ICI group. Conclusions: This exploratory analysis suggests that treatment with T-DXd results in better outcomes than chemotherapy regardless of prior ICI. Given a relatively small sample size, the relationship between changes in IO-related signatures and efficacy of T-DXd warrants further evaluation in larger cohorts. Clinical trial information: NCT03329690. [Table: see text]

REVIVE study: A prospective observational study in chemotherapy (CTx) after nivolumab (NIVO) therapy for advanced gastric cancer (AGC).

257 Background: NIVO therapy is a standard care treatment for heavily pretreated patients with AGC. Improvement in objective response rate (ORR) to CTx after NIVO therapy for various cancer types has been reported. However, the efficacy and safety of CTx for AGC after progression on NIVO remains unclear. Methods: The REVIVE trial was a prospective, multicenter, observational study that evaluated the efficacy and safety of CTx in NIVO-refractory or NIVO-intolerant patients (pts) with AGC (UMIN000032182). The primary endpoint was overall survival (OS) of CTx following NIVO therapy. The median threshold and expected survival times were set as 4.0 and 7.0 months (M). The secondary endpoints are ORR, disease control rate (DCR), progression-free survival (PFS), and incidence of adverse events (AEs), including immune-related adverse events (irAEs). CTx consisted of irinotecan alone (IRI), trifluridine/tipiracil alone (FT), and oxaliplatin-containing regimens (OX). Results: Of 395 pts treated with NIVO who met the eligibility at formal registration from Jun 2018 to Sep 2020, 199 pts who received CTx after NIVO were evaluated. Pt characteristics were as follows: median age, 69 years; male, 70%; ECOG PS 0/1/2, 38/51/12%; histology (diffuse/intestinal), 39/59%; metastatic lesions (peritoneum/liver/lung), 38/34/15%; number of metastatic organ sites (0–1/≥2), 40/60%; measurable lesions, 83%; and CTx regimens (IRI/FT/OX), 64/31/5%. Median OS and PFS were 7.5 M (95%CI, 6.7–9.7) at 145 events for OS and 2.9 M (95%CI, 2.2–3.5) at 184 events for PFS. The ORR and DCR were 17.0% (95%CI, 11.6–23.6) and 46.7% (95%CI, 38.9–54.6). Median OS, median PFS, ORR, and DCR according to CTx regimens (IRI/FT/OX) were 8.1/7.1/6.2 M, 3.3/2.8/2.4 M, 18.9/10.9/25.0%, and 47.8/43.5/50.0%, respectively. At the start of CTx, 42 pts had irAEs due to prior NIVO therapy. The most common any-grade and grade ≥3 AEs during CTx included decreased appetite (46% and 7.5%), fatigue (26% and 2.5%), nausea (24% and 1.5%), constipation (16% and 0%), and diarrhea (28% and 4.0%). No treatment-related deaths were observed. Conclusions: Prior NIVO therapy may lead to improved prognosis after CTx without unexpected AEs in pts with AGC, warranting further investigations after NIVO is approved as first-line treatment.[Table: see text]

Tumor mutational burden predicts the efficacy of pembrolizumab monotherapy: a pan-tumor retrospective analysis of participants with advanced solid tumors

BackgroundSeveral studies have evaluated the relationship between tumor mutational burden (TMB) and outcomes of immune checkpoint inhibitors. In the phase II KEYNOTE-158 study of pembrolizumab monotherapy for previously treated recurrent...

Phase 3, randomized, open-label study of pembrolizumab plus lenvatinib versus chemotherapy for first-line treatment of advanced or recurrent endometrial cancer: ENGOT-en9/LEAP-001

BackgroundPembrolizumab plus lenvatinib is a novel combination with promising efficacy in patients with advanced and recurrent endometrial cancer. This combination demonstrated high objective response rates in a single-arm phase 1b/2...

Effectiveness and safety of immune checkpoint inhibitors in combination with palliative radiotherapy in advanced melanoma: A systematic review.

Radiotherapy is frequently added to immune checkpoint inhibitors (ICI) when treating melanoma. We sought to describe the efficacy of combination ICI and palliative radiotherapy (pRT) and assess safety, focusing on immune related adverse events (irAE). A systematic search for studies investigating the combination of pRT and ICI was conducted. Five hundred-two articles were identified; nine met inclusion criteria. Improvements in objective response rate (p = 0.02), complete response (p = 0.04), and one-year local control (p < 0.005) were demonstrated when pRT was added to ICI. While some studies revealed improved overall and progression free survival, findings were mixed. No significant increases in adverse events or irAE were seen with the combined treatment compared with ICI alone. The included studies revealed that the addition of pRT to ICI is effective and safe in patients with advanced melanoma. Measures of survival varied. More studies are warranted to identify optimal conditions for combination treatment.

Effect of molecular targeted agents in chemotherapy for treating platinum-resistant recurrent ovarian cancer: A systematic review and meta-analysis.

This study aimed to investigate the effect of molecular targeted agents (MTAs) in chemo on platinum-resistant recurrent ovarian cancer (ROC). We performed this meta-analysis according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statements. Randomized controlled trials reporting data about platinum-resistant ovarian cancer treated by MTAs were included. The endpoints for the present study included overall survival and progression-free survival. We analyzed 9 randomized controlled trials including 3631 patients with ROC. The pooled analysis indicated that a combination of MTAs with chemo could markedly increase objective response rate in those patients (P = .012). Nevertheless, the survival rate of those patients was not markedly changed (P = .19). Besides, the combination of MTAs with chemo dramatically aggravated the occurrence of adverse events (P < .05). Moreover, it resulted in the termination of treatment (P = .044) in those patients, but it had no effect on fatal adverse events (P = .16). Our results indicated that the combination of MTAs with chemo notably improved objective response rate in patients with platinum-resistant ROC, but its benefit did not translate into survival benefits.

Mature tertiary lymphoid structures predict immune checkpoint inhibitor efficacy in solid tumors independently of PD-L1 expression.

Only a minority of patients derive long-term clinical benefit from anti-PD1/PD-L1 monoclonal antibodies. The presence of tertiary lymphoid structures (TLS) has been associated with improved survival in several tumor types. Here, using a large-scale retrospective analysis of three independent cohorts of cancer patients treated with anti-PD1/PD-L1 antibodies, we showed that the presence of mature TLS was associated with improved objective response rate, progression-free survival, and overall survival independently of PD-L1 expression status and CD8+ T-cell density. These results pave the way for using TLS detection to select patients who are more likely to benefit from immune checkpoint blockade.