Association of immune-related adverse events (irAEs) with clinical benefit in patients with metastatic urothelial carcinoma (mUC) treated with immune-checkpoint inhibitors (ICIs).

e16038 Background: In other cancers such as metastatic lung and melanoma, pts who experience irAEs may have a greater degree of clinical benefit. We sought to evaluate whether the development of irAEs correlates with clinical benefits in mUC pts. Methods: We identified mUC pts who received PD-1/L1 inhibitors at the Dana-Farber Cancer Institute (DFCI). The severity of irAEs was graded using CTCAE v.5.0. Clinical benefit was defined as any objective reduction (complete- or partial- response) in tumor burden. Fisher’s exact test was used to evaluate for differences in the proportion of pts experiencing clinical benefit between pts experiencing an irAEs within 90 days after starting therapy and those who did not experience an irAEs. The log-rank test assessed differences in progression-free survival (PFS) and overall survival (OS) between cohorts. Results: A total of 199 mUC pts were enrolled between July 2013 and October 2018 [median (range) age, 69.6 (26.6-89.0) years; 141 men (70.9%), 58 women (29.1%)]. 114 (57.3%) pts were treated with anti-PD-1 and 85 (42.7%) with anti-PD-L1. irAEs were observed in 67 pts (33.7%), of which 34 (17.1%) < 90 days from start of therapy. Common irAEs included 20 (29.9%) hypothyroidism, 17 (25.4%) colitis, 12 (17.9%) rash/pruritus, and 10 (14.9%) transaminitis. Grade ≥3 irAEs were observed in 14 pts (20.9%).13 (40.6%) pts with irAE < 90 days experienced clinical benefit compared with 21 (17.8%) of pts with no irAE (p-value = 0.008). No difference (p = 0.26 and 0.18) was observed for either PFS (6-month PFS = 19.2% vs 35.3% for no irAE and irAE < 90 days) or OS (1-year OS = 41.8% vs 57.7% for no irAE vs irAE < 90 days). Conclusions: The development of irAEs within 90 days from starting therapy in mUC pts may herald clinical benefit in pts with mUC. Further evaluation of this potential relationship in a large prospective study is warranted.

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Evaluation of different MET genotypes as biomarkers for immunotherapy outcomes in NSCLC patients.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.e21032 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. e21032-e21032

Author(s):

Xuanzong Li ◽

Linlin Wang

Keyword(s):

Checkpoint Inhibitors ◽

Progression Free Survival ◽

Rank Test ◽

Wild Type ◽

Exact Test ◽

Entire Cohort ◽

Kaplan Meier ◽

Tumor Mutational Burden ◽

The Difference ◽

Nsclc Patients

e21032 Background: Previous studies suggested that MET exon 14 ( METex14) mutation regarding as a distinct subset was sensitive to MET-inhibitors, but poorly response to immunotherapy. Conversly, MET non-exon-14 (non-ex14) mutations including those undetermined functions and affecting the kinase or extracellular domains were found to be associated with the resistance to MET-inhibitors. However, therapeutic strategies for MET-non-ex14 mutant cancer are still largely unknown, and the relationship between MET-non-ex14 mutations and the efficacy of immune checkpoint inhibitors (ICIs) has never been reported. Using two public ICIs-treated cohorts, we aimed to assess the role of MET mutations including both METex14 and MET-non-ex14 mutations in NSCLC patients undergoing ICIs therapy. Methods: A total of 385 ICIs-treated NSCLC patients were enrolled to our study. MET mutations were defined as any nonsynonymous mutations, and we divided them into METex14 and MET-non-ex14 mutation subsets according to the mutated-position on MET. Kruskal-Wallis test was used to analyze the difference of tumor mutational burden (TMB) score, and the Fisher’s exact test was applied to compare the rates of durable clinical benefit (DCB). Log-rank test was used to analyze the differences between Kaplan-Meier survival curves. Results: In the entire cohort, we found that 17 patients (17/385, 4.4%) had MET mutations, most of which were pure METex14 mutations (10/17, 58.8%). The median TMB of patients in the entire NSCLC cohort was 6.89 mut/Mb. MET-non-ex14 mutant patients (7/385, 1.8%) possessed a significantly higher TMB than METex14-mutant (10/385, 2.6%) and MET wild-type (368/385, 95.6%) sub-cohorts, respectively (median TMB, 17.92 mut/Mb versus 4.17 mut/Mb, p = 0.008; 17.92 mut/Mb versus 6.96 mut/Mb, p = 0.01, respectively). DCB was more common in patients harbored MET-non-ex14 mutations than patients with METex14 mutations and MET wild-type (66.7% versus 14.3%, p = 0.103; 66.7% versus 29.9%, p = 0.075, respectively). We found that patients with MET-non-ex14 mutations had a numerically longer progression free survival (PFS) than those with METex14 mutations and MET wild-type (p = 0.169). Moreover, the PFS was significantly longer in MET-non-ex14-mutant subgroup than patients with METex14 mutations (median PFS, 9.1 versus 2.1 months, p = 0.025). Correspondingly, the overall survival (OS) was significantly longer in MET-non-ex14-mutant subgroup than their wild-type counterparts (median OS, not reached versus 11 months, p = 0.039). Additionally, patients with MET-non-ex14 mutations exhibited relatively better OS versus METex14-mutant patients (median OS, not reached versus 18 months, p = 0.175). Conclusions: MET-non-ex14 mutations were associated with higher TMB, improved DCB rate, and could act as a favorable prognostic biomarker in ICIs-treated NSCLC patients.

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Outcome of KRAS mutated (m) non-small cell lung cancer (NSCLC) patients (pts) treated with immune checkpoint inhibitors (immuneCI).

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.15_suppl.e20526 ◽

2017 ◽

Vol 35 (15_suppl) ◽

pp. e20526-e20526

Author(s):

Nuria Pardo Aranda ◽

Cristina Viaplana ◽

Jordi Remon ◽

Alex Martinez Marti ◽

Susana Cedres Perez ◽

...

Keyword(s):

Clinical Benefit ◽

Checkpoint Inhibitors ◽

Current Smoker ◽

Rank Test ◽

Fisher Exact Test ◽

Exact Test ◽

Smoking Pattern ◽

Third Line ◽

Metastatic Sites ◽

Nsclc Patients

e20526 Background: The most frequent genetic alteration in advanced NSCLC is KRASm in ~25% of tumors. This event associates with smoking pattern and high mutational burden, which correlate with the efficacy of CI in NSCLC. There is in silico evidence that coexisting KRASm and TP53m positively impact immuneCI benefit , but this association needs clinical validation. Methods: We retrospectively assess the efficacy of PD-1/PDL-1 CI (atezolizumab, pembrolizumab, nivolumab or durvalumab) in a cohort of NSCLC patients whose tumors were KRASm (with or without coexisting TP53m) as assessed by a next-generation sequencing test. Endpoints were clinical benefit rate (CBR), defined as partial response or stable disease > 4 months (m), and time to progression (TTP) on immuneCI. Fisher-exact test and log-rank test P values are described. Results: 25 pacients were identified, 68% female, median age 54 y (33-75), 95% former/current smoker; 95% adenocarcinoma; 59% with 2 or more metastatic sites; 36% immuneCI as third-line or beyond (median time from first-line to immuneCI of 7.5 m). 20 tumors had KRASm in codon 12, 3 codon 13 and 2 in codon 61. Overall, CBR was 36% (CI95% 19%-57%) and median TTP was 3.7 m (CI95% 2.2-NA). Coexisting KRASm/ TP53m (n = 11) did not associate with higher CB (27% vs 50%, p = 0.56). A trend for lower TTP in the KRASm/ TP53m vs TP53 wild-type was observed (2.1 vs 5.6 m, HR 0.3; p = 0.11). Conclusions: NSCLC patients whose tumors are KRASm can have substantial benefit with immuneCI. In our series, the population with KRASm/ TP53m tumors did not derive higher clinical benefit from this therapeutic intervention

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Baseline neutrophil-to-eosinophil ratio (NER) and its association with clinical outcomes in patients with metastatic renal cell carcinoma (mRCC) treated with immune checkpoint inhibitors (CPI).

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.e16569 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. e16569-e16569

Author(s):

Deepak Ravindranathan ◽

Yuan Liu ◽

Dylan J. Martini ◽

Jacqueline T Brown ◽

Bassel Nazha ◽

...

Keyword(s):

Clinical Outcomes ◽

Clinical Benefit ◽

Checkpoint Inhibitors ◽

Progression Free Survival ◽

P Value ◽

Proportional Hazard ◽

Free Survival ◽

Cox Proportional Hazard ◽

Significant Difference

e16569 Background: Inflammatory markers have been studied as prognostic markers in patients with mRCC treated with CPIs. Recently, eosinophilia has been found to be associated with improved survival of patients with melanoma treated with CPIs. We reported baseline NER in patients with mRCC treated with CPIs and its association with clinical outcomes. Methods: We conducted a retrospective analysis of patients with mRCC treated with CPIs at Winship Cancer Institute from 2015-2018. Clinical outcomes were measured as overall survival (OS), progression-free survival (PFS), and clinical benefit (CB). OS and PFS were calculated from CPI-initiation to date of death and radiographic or clinical progression, respectively. Patients with baseline NER were categorized into high or low; high defined as NER > 49.2 and low defined as NER < 49.2. Univariate (UVA) and multivariate (MVA) analyses were carried out for OS and PFS using Cox proportional hazard model. Results: A total of 184 patients were studied with a median follow up of 25.4 months. Median age was 63 years old with 72% male and 20% black. About 25% were in high NER group. The high NER patients had significantly shorter OS in both UVA (HR: 0.58, p-value=0.017) and MVA (HR: 0.62, p-value=0.046) (Table). There was no significant difference between groups for PFS. Clinical benefit was seen in 47.3% of patients with low baseline NER and 40% with high NER. Conclusions: High baseline NER was associated with worse OS in patients with mRCC treated with CPIs. Larger, prospective studies are warranted to validate this hypothesis generating data.[Table: see text]

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Role of Maintenance Gemcitabine in Advanced Carcinoma Gallbladder

South Asian Journal of Cancer ◽

10.1055/s-0040-1721216 ◽

2020 ◽

Vol 09 (04) ◽

pp. 204-208

Author(s):

Manish Sharma ◽

Vineet Talwar ◽

Udip Maheshwari ◽

Venkata Pradeep Babu Koyyala ◽

Varun Goel ◽

...

Keyword(s):

Side Effects ◽

Progression Free Survival ◽

Final Analysis ◽

Response To Treatment ◽

Rank Test ◽

P Value ◽

Weekly Cycle ◽

Kaplan Meier ◽

Carcinoma Gallbladder ◽

Grade 3

Abstract Objective The aim of this study is to investigate the effects of gemcitabine maintenance on progression-free survival (PFS) in patients with metastatic gallbladder cancer (GBC). Materials and Methods Sixty patients with unresectable or metastatic GBC having ongoing response to treatment with initial six cycles of gemcitabine and a platinum-based doublet chemotherapy were prospectively randomized on day 21 of the 6th cycle in 1:1 fashion to receive either maintenance gemcitabine 1 g/m2 intravenously on day 1 and day 8 of three weekly cycle or observation. Survival analysis was performed using the Kaplan–Meier method and comparisons by the log-rank test. A p-value < 0.05 was considered as statistically significant. Results Of 60 patients, a total of 56 were available for final analysis. The median PFS was 4.7 months (3.1–6.3) in gemcitabine arm and 2.6 months (2.4–2.8) in observation arm, hazard ratio (HR) 0.196 (95% confidence interval [CI]: 0.1–0.39), p < 0.001. Median overall survival in gemcitabine arm was 12.4 months (9.15–15.6) as opposed to 9.9 months (8.29–11.5) in observation arm, HR 0.76 (95% CI: 0.43–1.35), p = 0.354. The grade 3 or 4 side effects in maintenance arm were transaminitis (17.9%), thrombocytopenia (17.8%), neutropenia (14.2%), and febrile neutropenia (7.1%). Conclusions Maintenance gemcitabine therapy in unresectable/metastatic GBC patients responding to first-line gemcitabine and platinum treatment contributes to increase PFS with minimal and manageable side effects.

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Efficacy and Safety of [225Ac]Ac-PSMA-617 Augmented [177Lu]Lu-PSMA-617 Radioligand Therapy in Patients with Highly Advanced mCRPC with Poor Prognosis

Pharmaceutics ◽

10.3390/pharmaceutics13050722 ◽

2021 ◽

Vol 13 (5) ◽

pp. 722

Author(s):

Florian Rosar ◽

Jonas Krause ◽

Mark Bartholomä ◽

Stephan Maus ◽

Tobias Stemler ◽

...

Keyword(s):

Molecular Imaging ◽

Poor Prognosis ◽

Progression Free Survival ◽

Tumor Burden ◽

Efficacy And Safety ◽

Radioligand Therapy ◽

Castration Resistant ◽

Pet Ct ◽

Visceral Metastases ◽

Grade 3

The use of 225Ac in prostate-specific membrane antigen (PSMA)-targeted radioligand therapy (RLT), either as monotherapy or in combination with 177Lu, is a promising therapy approach in patients with metastatic castration-resistant prostate carcinoma (mCRPC). In this study, we report the efficacy and safety of [225Ac]Ac-PSMA-617 augmented [177Lu]Lu-PSMA-617 RLT in 177Lu-naive mCRPC patients (n = 15) with poor prognosis (presence of visceral metastases, high total tumor burden with diffuse bone metastases or a short PSA doubling time of <2 months). Biochemical (by PSA serum value) and molecular imaging response (by [68Ga]Ga-PSMA-11 PET/CT) was assessed after two cycles of [177Lu]Lu-PSMA-617 RLT, with at least one [225Ac]Ac-PSMA-617 augmentation. In addition, PSA-based progression-free survival (PSA-PFS), overall survival (OS) and toxicity (according to CTCAE) were analyzed. We observed a biochemical- and molecular imaging-based partial remission in 53.3% (8/15) and 66.7% (10/15) of patients, respectively. The median PSA-PFS and OS was 9.1 and 14.8 months, respectively. No serious acute adverse events were recorded. Two out of fifteen patients experienced grade 3 anemia. No other grade 3/4 toxicities were observed. RLT-related xerostomia (grade 1/2) was recorded in 2/15 patients. Our data showed a high clinical efficacy with a favorable side effects profile of [225Ac]Ac-PSMA-617 augmented [177Lu]Lu-PSMA-617 RLT in this highly challenging patient cohort.

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First-line nivolumab (NIVO) plus ipilimumab (IPI) plus two cycles of chemotherapy (chemo) versus chemo alone (4 cycles) in patients with advanced non-small cell lung cancer (NSCLC): Two-year update from CheckMate 9LA.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.9000 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. 9000-9000

Author(s):

Martin Reck ◽

Tudor-Eliade Ciuleanu ◽

Manuel Cobo ◽

Michael Schenker ◽

Bogdan Zurawski ◽

...

Keyword(s):

Clinical Benefit ◽

Performance Status ◽

Objective Response ◽

Stage Iv ◽

Progression Free Survival ◽

Expression Level ◽

First Line ◽

Ecog Performance Status ◽

Grade 3

9000 Background: In the randomized phase 3 CheckMate 9LA trial (NCT03215706), first-line NIVO + IPI combined with 2 cycles of chemo significantly improved overall survival (OS), progression-free survival (PFS), and objective response rate (ORR) vs chemo alone (4 cycles). Clinical benefit was observed regardless of programmed death ligand 1 (PD-L1) expression level and histology. Here we report data with 2 years’ minimum follow-up from this study. Methods: Adult patients (pts) with stage IV / recurrent NSCLC, ECOG performance status ≤ 1, and no known sensitizing EGFR/ALK alterations were stratified by PD-L1 (< 1% vs ≥ 1%), sex, and histology (squamous vs non-squamous) and were randomized 1:1 to NIVO 360 mg Q3W + IPI 1 mg/kg Q6W + chemo (2 cycles; n = 361) or chemo alone (4 cycles; n = 358). Pts with non-squamous NSCLC in the chemo-alone arm could receive pemetrexed maintenance. The primary endpoint was OS. Secondary endpoints included PFS and ORR by blinded independent central review, and efficacy by different PD-L1 levels. Safety was exploratory. Results: At a minimum follow-up of 24.4 months for OS (database lock: Feb 18, 2021), pts treated with NIVO + IPI + chemo continued to derive OS benefit vs chemo, with a median OS of 15.8 months vs 11.0 months, respectively (HR, 0.72 [95% CI, 0.61–0.86]); 2-year OS rates were 38% vs 26%. Median PFS with NIVO + IPI + chemo vs chemo was 6.7 months vs 5.3 months (HR, 0.67 [95% CI, 0.56–0.79]); 8% and 37% of pts who had disease progression received subsequent immunotherapy, respectively. ORR was 38% with NIVO + IPI + chemo vs 25% with chemo. Similar clinical benefit with NIVO + IPI + chemo vs chemo was observed in all randomized pts and across the majority of subgroups, including by PD-L1 expression level (Table) or histology. Any grade and grade 3–4 treatment-related adverse events were reported in 92% and 48% of pts in the NIVO + IPI + chemo arm vs 88% and 38% in the chemo arm, respectively. Conclusion: With 2 years’ minimum follow-up, first-line NIVO + IPI + chemo demonstrated durable survival and benefit versus chemo in pts with advanced NSCLC; no new safety signals were identified. Clinical trial information: NCT03215706. [Table: see text]

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TRYHARD, a randomized phase II trial (RTOG Foundation 3501) of concurrent accelerated radiation plus cisplatin (cis) with or without lapatinib (Lap) for stage III- IV Non-HPV head and neck carcinoma (HNC).

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.6014 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. 6014-6014

Author(s):

Stuart J. Wong ◽

Pedro A. Torres-Saavedra ◽

Nabil F. Saba ◽

George Shenouda ◽

Jeffrey Bumpous ◽

...

Keyword(s):

Overall Survival ◽

Phase Ii ◽

Phase Ii Trial ◽

Progression Free Survival ◽

Final Analysis ◽

Stage Iii ◽

Adverse Event Rate ◽

Rank Test ◽

Days Of Therapy ◽

Grade 3

6014 Background: Chemoradiation (CRT) with cis or anti-EGFR Ab has been shown to improve survival of patients with stage III-IV HNC. Since Lap, a dual EGFR and HER2 inhibitor, has shown effectiveness with CRT in a pilot non-HPV HNC cohort, the RTOG Foundation launched a phase II trial to test the hypothesis that adding Lap to the RT-cis for frontline therapy of stage III-IV Non-HPV HNC improves progression-free survival (PFS). Methods: Patients with stage III-IV carcinoma of the oropharynx (p16-negative), larynx, and hypopharynx, having Zubrod performance of 0-1, and meeting predefined blood chemistry criteria were enrolled after providing consent. Patients were randomized (1:1) to 70 Gy (6 weeks) + 2 cycles of CDDP (q3 weeks) plus either Lap (1500 mg daily, Arm A) or placebo (Arm B) starting 1 week prior to RT and concurrent with RT and for 3 months post RT. PFS was the primary endpoint. The protocol specified 69 PFS events (142 patients) for the final analysis based on HR = 0.65, 80% power, 1-sided alpha 0.20, and one interim efficacy and futility analysis at 50% information. PFS rates between arms for all randomized patients were compared by 1-sided log-rank test (1-sided alpha 0.1803). Overall survival (OS) was a secondary endpoint. Results: From 10/’12 to 04/’17, 142 patients were enrolled, of whom 127 were randomized, 63 to Arm A and 64 to Arm B. Arms A vs B, respectively, were similar in baseline patient characteristics, radiation delivery, completing ≥ 70 Gy (85.7% vs. 82.8%) and cisplatin delivery, completing 200 (±5%) mg/m2 (65.1% vs 70.3%), but dissimilar in Lap/placebo delivery (median dose, 87000 mg vs. 125250 mg). Median follow-up was 4.1 years for surviving patients. The final analysis suggests no improvement in PFS of adding Lap to CRT (HR [A/B]: 0.91, 95% confidence interval CI 0.56-1.46; P= 0.34; 2-year rates: 50.6%, CI 37.5-63.7% vs. 56.2% CI 43.0-69.4%), or in OS (HR: 1.06, CI 0.61-1.86; P = 0.58; 2-year rates: 71.8% CI 60.1-83.5% vs. 76% CI 64.5-87.4%), death within 30 days of therapy (3.3% vs. 3.4%), and overall treatment-related grade 3-5 adverse event rate (86.7% vs. 84.7%). Grade 3-4 mucositis rates on Arm A and Arm B were 21.7% vs. 23.7%, all grade dysphagia and rash rates were 43.3% vs. 59.3%, and 13.3% vs. 6.8%, respectively. Conclusions: The addition of Lap to the radiation-cisplatin platform did not improve progression-free or overall survival in unselected non-HPV HN. Thus, dual EGFR, HER-2 inhibition does not appear to enhance the effects of chemoradiation. Although we showed that accrual to a non-HPV HN specific trial is feasible, new strategies must be investigated to improve the outcome for this poor prognosis HN population.

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Phase 1, 2 trial of concurrent anti-PD1 and stereotactic radiosurgery for melanoma and non-small cell lung cancer brain metastases (NCT02858869).

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.2022 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. 2022-2022

Author(s):

Mohammad Khurram Khan ◽

Tahseen Nasti ◽

Troy Kleber ◽

David H. Lawson ◽

Melinda Lynne Yushak ◽

...

Keyword(s):

T Cells ◽

Brain Metastases ◽

Stereotactic Radiosurgery ◽

Clinical Benefit ◽

Progression Free Survival ◽

Free Survival ◽

Early Activation ◽

Previously Treated ◽

The Mean ◽

Grade 3

2022 Background: The safety and efficacy of concurrent pembrolizumab (anti-PD1) and stereotactic radiosurgery (SRS) for brain metastases (BM) is unknown. Methods: Patients with melanoma or NSCLC, 1-10 brain metastases, ≥ 1 extra-cranial lesion, age ≥ 18, and ECOG 0-1 were treated with anti-PD1 every 3 weeks. SRS was administered 1-2 days after starting anti-PD1. SRS used three different radiation arms: Arm A used 6 Gray (Gy) in 5 fractions (fx), Arm B used 9 Gy in 3 fx, and Arm C used 18-21 Gy in single fx. Primary endpoint was grade 3 CNS toxicity at 3 months (CTCAE v 4.0). Secondary endpoints were overall survival (OS), local control (LC) within the SRS field, intra-cranial progression free survival (IC-PFS), extra-cranial progression free survival (EC-PFS), rate of extra-cranial clinical benefit, and immunological changes. OS, LC, IC-PFS, and EC-PFS were estimated using the Kaplan-Meier method, and covariates were compared using log-rank tests. 95% confidence intervals for 6-month and 12-month were estimated using Greenwood’s formula. Results: 25 patients were treated from 2016 until 2020. The mean age was 61. The mean number of CNS lesions was 2.7. The mean number of extra-cranial lesions was 2.5. Six were enrolled on Arm A, 12 on Arm B, and 7 on Arm C. 21 had melanoma. 4 had NSCLC. Of the melanoma, 8 were BRAF-, 10 were BRAF+, and 3 had unknown mutation status. 12 patients (48%) had progressed on prior immunotherapy and/or other oncological therapies. The trial met its primary endpoint, with no grade 3 CNS toxicity at 3 months. Two patients (8%) experienced ≥ Grade 3 anti-PD1 related toxicity, and no grade 5 toxicity was noted. The median OS was 32.8 months. The 6 and 12 month OS were 79.1% (56.5-90.8%) and 67.8% (43.3-83.5%), respectively. The 1 year OS was similar between previously treated and treatment naïve patients (71.8% vs. 65.6%), suggesting some role for SRS in overcoming therapy resistance. However, with longer follow-up, the OS trended worse (p=0.07) for previously treated patients. LC was 95.7% (72.9-99.4%) at 6 and 12 months. IC-PFS at 6 months was 69.1% (45.8-83.9%), and at 12 months was 57.5% (33.7-75.5%). The EC-PFS at 6 and 12 month was 54.5% (32.1-72.4%) and 43.6% (22.3-63.2%), respectively. Clinical benefit, which was defined as a best overall response of stable disease or better according to RECIST 1.1, occurred in 12 patients (48%). No outcome differences were noted amongst the three different SRS arms. 70% of the patients demonstrating early activation (within 3 weeks of starting SRS/anti-PD1) of CD8+PD1+Ki67+ T cells demonstrated a clinical benefit. 100% of patients that failed to show early activation of CD8+PD1+Ki67+ T cells progressed. Conclusions: Concurrent pembrolizumab (Anti-PD-1) and SRS is safe and effective. Early activation of CD8+PD1+Ki67+ T cells correlates with improved outcome. Further trials testing pembrolizumab and SRS are justified. Clinical trial information: NCT02858869.

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Association of the neutrophil to eosinophil ratio with response to immunotherapy-based combinations in metastatic renal cell carcinoma.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.6_suppl.341 ◽

2021 ◽

Vol 39 (6_suppl) ◽

pp. 341-341

Author(s):

Matthew D Tucker ◽

Katy Beckermann ◽

Kristin Kathleen Ancell ◽

Kerry Schaffer ◽

Renee McAlister ◽

...

Keyword(s):

Renal Cell Carcinoma ◽

Cell Carcinoma ◽

Clinical Outcomes ◽

Metastatic Renal Cell Carcinoma ◽

Renal Cell ◽

Objective Response ◽

Progression Free Survival ◽

Rank Test ◽

Cancer Center ◽

Exact Test

341 Background: Neutrophilia is known to be associated with worse prognosis in metastatic renal cell carcinoma (mRCC); however, less is known about the role of eosinophils in the response to immunotherapy (IO). We investigated the association of the baseline neutrophil to eosinophil ratio (NER) with outcomes to IO-based combination treatment in mRCC. Methods: Patients with mRCC treated with ipilimumab plus nivolumab, pembrolizumab plus axitinib, or avelumab plus axitinib at the Vanderbilt-Ingram Cancer Center were retrospectively identified. Patients on >10mg prednisone and patients with prior IO were excluded. Baseline NER (at time of first IO) and association with progression free survival (PFS), overall survival (OS), and objective response rate (ORR) were investigated. Data cutoff was 9/1/2020. Analysis for PFS and OS was performed using the log-rank test and Mantel-Haenszel method, and analysis of the odds ratio for ORR was performed using Fischer’s exact test. Results: Sixty-one patients were identified: 89% clear cell histology, 74% prior nephrectomy, 69% IMDC intermediate risk, and 72% treatment-naïve. Patients with baseline NER < median (N=31) had improved clinical outcomes compared to patients with baseline NER > median (N=30) (Table). Improvement in PFS by NER was maintained when stratified by anti-PD-1/CTLA-4 and anti-PD(L)-1/VEGF (p= 0.0062 and p= 0.049); however, differences in OS and ORR were no longer significant. The median baseline NER among patients with partial response (PR) was significantly lower at 22.7 (95% CI 18.9-31.1) vs. 51.6 (95% CI 39.5-93.1) among those with progressive disease (PD) (p= 0.0054). For comparison, the median neutrophil to lymphocyte ratio was not significantly different between PR (2.60) and PD (3.84, p= 0.056). Conclusions: Patients with a low baseline NER treated with IO-based combinations had improved clinical outcomes compared to patients with a high baseline NER. Additional investigation of this parameter in larger cohorts is warranted. [Table: see text]

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Ramucirumab in Combination with Pembrolizumab in Treatment-Naïve Advanced Gastric or GEJ Adenocarcinoma: Safety and Antitumor Activity from the Phase 1a/b JVDF Trial

Cancers ◽

10.3390/cancers12102985 ◽

2020 ◽

Vol 12 (10) ◽

pp. 2985

Author(s):

Ian Chau ◽

Nicolas Penel ◽

Andres O. Soriano ◽

Hendrik-Tobias Arkenau ◽

Jennifer Cultrera ◽

...

Keyword(s):

Antitumor Activity ◽

Checkpoint Inhibitors ◽

Objective Response ◽

Progression Free Survival ◽

Clinical Activity ◽

Metastatic Setting ◽

Duration Of Response ◽

Treatment Naïve ◽

Combined Positive Score ◽

Grade 3

Ramucirumab (anti-VEGFR2) plus pembrolizumab (anti-PD1) demonstrated promising antitumor activity and tolerability among patients with previously treated advanced cancers, supporting growing evidence that combination therapies modulating the tumor microenvironment may expand the spectrum of patients who respond to checkpoint inhibitors. Here we present the results of this combination in first-line patients with metastatic G/GEJ cancer. Twenty-eight patients (≥18 years) with no prior systemic chemotherapy in the advanced/metastatic setting received ramucirumab (8 mg/kg days 1 and 8) plus pembrolizumab (200 mg day 1) every 3 weeks as part of JVDF phase 1a/b study. The primary endpoint was safety. Secondary endpoints included progression-free survival (PFS), objective response rate (ORR), and overall survival (OS). Tumors were PD-L1-positive (combined positive score ≥ 1) in 19 and -negative in 6 patients. Eighteen patients experienced grade 3 treatment-related adverse events, most commonly hypertension (14%) and elevated alanine/aspartate aminotransferase (11% each), with no grade 4 or 5 reported. The ORR was 25% (PD-L1-positive, 32%; PD-L1-negative, 17%) with duration of response not reached. PFS was 5.6 months (PD-L1-positive, 8.6 months; PD-L1-negative, 4.3 months), and OS 14.6 months (PD-L1-positive, 17.3 months; PD-L1-negative, 11.3 months). Acknowledging study design limitations, ramucirumab plus pembrolizumab had encouraging durable clinical activity with no unexpected toxicities in treatment-naïve biomarker-unselected metastatic G/GEJ cancer, and improved outcomes in patients with PD-L1-positive tumors.

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