The impact of sequencing PD-1/PD-L1 inhibitors and stereotactic radiosurgery for patients with brain metastasis

Abstract Background The response of brain metastases (BM) treated with stereotactic radiosurgery (SRS) and immune checkpoint inhibitors (ICIs; programmed cell death 1 and its ligand) is of significant interest. Methods Patients were divided into cohorts based on ICI sequencing around SRS. The primary outcome was best objective response (BOR) that was lesion specific. Secondary outcomes included overall objective response (OOR), response durability, radiation necrosis (RN), and overall survival (OS). Results One hundred fifty patients underwent SRS to 1003 BM and received ICI. Five hundred sixty-four lesions (56%) treated with concurrent ICI (±5 half-lives) demonstrated superior BOR, OOR, and response durability compared with lesions treated with SRS and delayed ICI. Responses were best in those treated with immediate (±1 half-life) ICI (BOR: −100 vs −57%, P < 0.001; complete response: 50 vs 32%; 12-month durable response: 94 vs 71%, P < 0.001). Lesions pre-exposed to ICI and treated with SRS had poorer BOR (−45%) compared with ICI naive lesions (−63%, P < 0.001); best response was observed in ICI naive lesions receiving SRS and immediate ICI (−100%, P < 0.001). The 12-month cumulative incidence of RN with immediate ICI was 3.2% (95% CI: 1.3–5.0%). First radiographic follow-up and best intracranial response were significantly associated with longer OS; steroids were associated with inferior response rates and poorer OS (median 10 vs 25 mo, P = 0.002). Conclusions Sequencing of ICI around SRS is associated with overall response, best response, and response durability, with the most substantial effect in ICI naive BM undergoing immediate combined modality therapy. First intracranial response for patients treated with immediate ICI and SRS may be prognostic for OS, whereas steroids are detrimental.

Download Full-text

Discontinuation of BRAF/MEK-Directed Targeted Therapy after Complete Remission of Metastatic Melanoma—A Retrospective Multicenter ADOReg Study

Cancers ◽

10.3390/cancers13102312 ◽

2021 ◽

Vol 13 (10) ◽

pp. 2312

Author(s):

Henner Stege ◽

Maximilian Haist ◽

Michael Schultheis ◽

Maria Isabel Fleischer ◽

Peter Mohr ◽

...

Keyword(s):

Targeted Therapy ◽

Checkpoint Inhibitors ◽

Patient Characteristics ◽

Complete Response ◽

Second Line ◽

Treatment Cessation ◽

Durable Response ◽

Ongoing Treatment ◽

Number Of Patients ◽

The Impact

The advent of BRAF/MEK inhibitors (BRAFi/MEKi) has significantly improved progression-free (PFS) and overall survival (OS) for patients with advanced BRAF-V600-mutant melanoma. Long-term survivors have been identified particularly among patients with a complete response (CR) to BRAF/MEK-directed targeted therapy (TT). However, it remains unclear which patients who achieved a CR maintain a durable response and whether treatment cessation might be a safe option in these patients. Therefore, this study investigated the impact of treatment cessation on the clinical course of patients with a CR upon BRAF/MEK-directed-TT. We retrospectively selected patients with BRAF-V600-mutant advanced non-resectable melanoma who had been treated with BRAFi ± MEKi therapy and achieved a CR upon treatment out of the multicentric skin cancer registry ADOReg. Data on baseline patient characteristics, duration of TT, treatment cessation, tumor progression (TP) and response to second-line treatments were collected and analyzed. Of 461 patients who received BRAF/MEK-directed TT 37 achieved a CR. TP after initial CR was observed in 22 patients (60%) mainly affecting patients who discontinued TT (n = 22/26), whereas all patients with ongoing TT (n = 11) maintained their CR. Accordingly, patients who discontinued TT had a higher risk of TP compared to patients with ongoing treatment (p < 0.001). However, our data also show that patients who received TT for more than 16 months and who discontinued TT for other reasons than TP or toxicity did not have a shorter PFS compared to patients with ongoing treatment. Response rates to second-line treatment being initiated in 21 patients, varied between 27% for immune-checkpoint inhibitors (ICI) and 60% for BRAFi/MEKi rechallenge. In summary, we identified a considerable number of patients who achieved a CR upon BRAF/MEK-directed TT in this contemporary real-world cohort of patients with BRAF-V600-mutant melanoma. Sustained PFS was not restricted to ongoing TT but was also found in patients who discontinued TT.

Download Full-text

Are immune checkpoint inhibitors (ICI) a valid option for papillary renal cell carcinoma (pRCC)? A multicenter retrospective study.

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.7_suppl.582 ◽

2019 ◽

Vol 37 (7_suppl) ◽

pp. 582-582 ◽

Cited By ~ 4

Author(s):

Manon De Vries-Brilland ◽

Marine Gross-Goupil ◽

Elouen Boughalem ◽

Benoit Beuselinck ◽

Constance Thibault ◽

...

Keyword(s):

Retrospective Study ◽

Checkpoint Inhibitors ◽

Objective Response ◽

Papillary Renal Cell Carcinoma ◽

Complete Response ◽

Best Response ◽

Third Line ◽

Line Setting

582 Background: pRCC is the most common non-clear cell RCC (nccRCC) and represents up to 15% of RCC. Pivotal studies evaluating ICI mostly excluded nccRCC. Therefore the efficacy of ICI in pRCC remains to be demonstrated. Methods: We retrospectively investigated the activity and safety of PD-1/PD-L1 inhibitors (PD-1i) specifically in patients (pts) with metastatic pRCC from 15 centers in France and Belgium. Pts baseline characteristics, treatment outcome and safety were collected. Primary endpoint was time-to-treatment failure (TTF). Secondary endpoints included objective response rate (ORR), overall survival (OS) and treatment-related adverse events (TRAEs). Results: From 02/2016 to 09/2018, 50 pRCC pts treated with PD-1i were included. Median age was 63 years (range: 27-84), 36 (72%) were male. Histology included 14 (28%) type 1 pRCC, 30 (60%) type 2 pRCC, 6 (12%) unclassified pRCC. PD-1i was used in first line setting in 5 pts (10%), in second line in 29 pts (58%) and in third line or beyond in 16 pts (32%). IMDC risk group at PD-1i start was 22% good, 44% intermediate and 33% poor. ICI used were PD-1 inhibitors in 47 pts (94%) and PD-L1 inhibitors in 3 pts (6%). PD-1 in was used as monotherapy in 94% of pts. With a median follow up of 10.7 months (95% Confidence Interval (CI): 6.8-14.8), the median TTF was 3.7 months (95% CI: 3.1, 10.1). In type 1, the median TTF was 7.1 months (95% CI: 3.2-NA) and 3.2 months (95% CI: 2.9-NA) in type 2. Median treatment duration was 3.2 months (range: 0.4-24.5, IQR: 2.4-6.4). Among the 45 pts evaluable for ORR, best response was complete response/partial response in 8 pts (16%), stable disease in 13 pts (26%) and progressive disease in 24 pts (48%). ORR was 25% in type 1 pRCC and 15% in type 2 pRCC. Median OS was 17.6 months (95% CI 11.4- not reached). TRAEs of grade 3-4 were noted in 6 patients (12%) which led to treatment discontinuation, no grade 5 were observed. Conclusions: This retrospective study is the largest cohort of metastatic pRCC treated with PD-1i to date. PD-1i exhibit limited activity in this pRCC population, with better TTF and ORR in type 1 pRCC. Our findings underline the need for further prospective clinical trials evaluating ICI combinations in pts with pRCC.

Download Full-text

Prognostic Significance of Tumor Response at the End of Therapy in Group III Rhabdomyosarcoma: A Report From the Children's Oncology Group

Journal of Clinical Oncology ◽

10.1200/jco.2008.19.5933 ◽

2009 ◽

Vol 27 (22) ◽

pp. 3705-3711 ◽

Cited By ~ 43

Author(s):

David A. Rodeberg ◽

Julie A. Stoner ◽

Andrea Hayes-Jordan ◽

Simon C. Kao ◽

Suzanne L. Wolden ◽

...

Keyword(s):

Alternative Therapy ◽

Prognostic Significance ◽

Complete Response ◽

Disease Recurrence ◽

Radiographic Measurement ◽

Clinical Group ◽

Group Iii ◽

Best Response ◽

Pathology Reports ◽

The Impact

Purpose Some patients with rhabdomyosarcoma (RMS) achieve less than a complete response (CR) despite receiving all planned therapy. We assessed the impact of best response at the completion of all therapy on patient outcome. Patients and Methods We studied 419 clinical group III participants who completed all protocol therapy without developing progressive disease for Intergroup Rhabdomyosarcoma Study (IRS) IV. Response (complete resolution [CR], partial response [PR; ≥ 50% decrease], or no response [NR; < 50% decrease and < 25% increase]) was determined by radiographic measurement and categorized by the best response. Results At the end of therapy, 341 participants (81%) achieved a best response of CR and 78 (19%) had a best response of PR/NR. Five-year failure-free survival was similar for participants achieving CR (80%) and PR/NR (78%). After adjustment for age, nodal status, primary site, and histology, there was no significant indication of lower risk of failure (hazard ratio [HR], 0.77; 95% CI, 0.46 to 1.27; P = .3) nor death (HR, 0.63; 95% CI, 0.36 to 1.09; P = .1) for CR versus PR/NR participants. Seventeen participants with a best response of PR/NR had surgical procedures; eight (50%) of 16 with available pathology reports had residual viable tumor and only three achieved a complete resection. Resection of residual masses was not associated with improved outcome. Conclusion CR status at the end of protocol therapy in clinical group III participants was not associated with a reduction of disease recurrence and death. Aggressive alternative therapy may not be warranted for RMS patients with a residual mass at the end of planned therapy.

Download Full-text

Efficacy of Chemotherapy or Chemo-Anti-PD-1 Combination after Unsatisfactory Response of Anti-PD-1 Therapy for Relapsed and Refractory Hodgkin Lymphoma: A Retrospective Series from Lysa Centers

Blood ◽

10.1182/blood.v130.suppl_1.652.652 ◽

2017 ◽

Vol 130 (Suppl_1) ◽

pp. 652-652

Author(s):

Cédric Rossi ◽

Julia Gilhodes ◽

Marie Maerevoet ◽

Charles Herbaux ◽

Pauline Brice ◽

...

Keyword(s):

Clinical Trials ◽

Hodgkin Lymphoma ◽

Research Funding ◽

Checkpoint Inhibitors ◽

Objective Response ◽

Complete Response ◽

High Rate ◽

High Dose ◽

Group 2 ◽

Group 1

Abstract Introduction: Hodgkin lymphoma (HL) pts who relapse after high-dose therapy (HDT) and autologous stem cell transplantation (ASCT) and brentuximab vedotin (BV) therapy have a poor outcome. For these relapsed and refractory (R/R) HL pts, anti-PD-1 therapy gives a high rate of objective responses. However, the rate of complete response (CR) remains modest and in the updated results of anti-PD-1 therapy clinical trials, about 50% of pts are still without progressive disease after one year of treatment. As anti-PD-1 therapy modifies the anticancer immune response, we hypothesize that anti-PD-1 therapy may increase sensitivity to chemotherapy (CT) given after anti-PD-1 therapy (sequential strategy) or in combination with anti-PD-1 therapy after an unsatisfactory response to immunotherapy (concomitant strategy). We retrospectively analyzed these two clinical situations in 30 R/R HL pts from LYSA centers treated with anti-PD-1 therapy. Methods: We included R/R HL pts from 14 LYSA centers who received anti-PD-1 therapy in the context of clinical trials (N=4) or an authorization for temporary use (ATU) from the French medical drug agency (N=26). Before the anti-PD-1 therapy, pts had received a median of six (range, 2-14) lines of therapy, 69% had HDT+ASCT, 14% had allograft and 93% had been treated with BV. We considered two groups of pts: i. 19 pts (63%) in whom the anti-PD-1 therapy was stopped at the introduction of CT (Group 1); ii. 11 pts (37%) with an unsatisfactory response to anti-PD-1 therapy in whom a combination of CT with immunotherapy was initiated to optimize the response (Group 2). The quality of the response after the introduction of CT was evaluated retrospectively by each treating physicians according to Cheson 2007 or 2014 criteria. We also determined whether new CT treatments after and in combination with anti-PD-1 therapy led to unexpected toxicities and whether new treatment schedules made pts eligible for allograft. Results: At the start of anti-PD-1, the median age of pts was 37 years old (range, 20-75), 24% had Ann Arbor III/IV stages, 34% had B symptoms and 21% had a performance status (PS) of 2-3. Patients received a median of 10 infusions (range, 2-52) of anti-PD-1 therapy with nivolumab (N=26, 87%) or pembrolizumab (N=4, 13%). The best responses achieved during anti-PD-1 therapy were a complete response (CR) for 5 patients, a partial response (PR) for 17 pts, stable disease (SD) for 2 pts and progression for 6 pts. In group 1, 17 pts were in progression, one pt in PR, and another pt in SD at the end of anti-PD-1 therapy alone. In group 1, after anti-PD-1 therapy, the pts were treated with vinblastine (N=3), gemcitabine (N=2) or bendamustine alone (N=3) or in combination with BV (N=4), GVD (N=1), ICE (N=1), DHAP (N=1), escalated BEACOPP (N=1), vinorelbine (N=1), vepeside (N=1) and caelyx (N=1). In group 2, before the combination, the response status was progression for 7 pts and PR for 4 pts. In group 2, to optimize the response to anti-PD-1, pts received vinblastine (N=7), gemcitabine (N=2) and BV (N=2). In the 28 evaluable pts, 11/18 (61%) in group 1 and 9/10 (90%) in group 2 showed an improved response after chemotherapy alone or combination with anti-PD-1 therapy respectively. In group 1, there were 6 CR (32%), 5 PR (26%), 1 SD (5%) and 6 PD (32%) (Figure 1B). In group 2, there were 5 CR (45%), 5 PR (45%) and 1 SD (10%) (Figure 1A). Of note, among the ten pts treated with vinblastine, 4 were in CR, 3 in RP, 1 in SD and 2 in progression. No unexpected toxicity was observed during the CT. Four pts had an allograft after the sequential CT (N=3) and concomitant CT strategy (N=1). Three pts were in CR 274, 279 and 480 days after the allograft and the fourth has not yet been evaluated. Allografts are now scheduled for 6 pts. With a median follow-up of 9.1 months (95%CI, 6.1-14) following the initiation of chemotherapy (alone or combined) the median PFS and OS were 8.4 and 14.6 months, respectively. Conclusions: Our retrospective study showed that pts with an unsatisfactory response or PD with anti-PD-1 therapy had a new objective response with CT alone (61%) or CT in combination with anti-PD-1 therapy (90%). This response could make some pts eligible for allograft. Prospective clinical trials are needed to confirm the synergistic effect of CT with anti-PD-1 therapy and to determine which CT provides the best results in combination with these checkpoint inhibitors. Figure 1 Figure 1. Disclosures Ysebaert: Janssen: Consultancy, Research Funding, Speakers Bureau. Ghesquières: Celgene and Mundipharma: Consultancy, Honoraria; Roche: Research Funding.

Download Full-text

Investigate the efficacy of immunotherapy for treatment of pancreatic adenocarcinoma (PDAC) with mismatch repair deficiency (dMMR).

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.3_suppl.415 ◽

2021 ◽

Vol 39 (3_suppl) ◽

pp. 415-415

Author(s):

Arish Noor ◽

Luis E. Aguirre ◽

Kirsten Blue ◽

Trenton Avriett ◽

Estrella M. Carballido ◽

...

Keyword(s):

Pancreatic Adenocarcinoma ◽

Metastatic Disease ◽

Checkpoint Inhibitors ◽

Objective Response ◽

Locally Advanced ◽

Progression Free Survival ◽

Complete Response ◽

Median Number ◽

Cancer Center ◽

Duration Of Response

415 Background: Immune checkpoint inhibitors (ICI) have been approved in solid tumors with dMMR. However, only limited data are available for PDAC with dMMR given the rarity of dMMR in PDAC. We evaluated efficacy of ICIs in PDAC with dMMR. Methods: Retrospective clinical and pathologic data were collected for patients (pts) with pancreatic adenocarcinoma from May 2017 to June 2020 at Moffitt cancer center. Results: We identified 10 pts with dMMR PDAC. The median age was 64.5 years (range: 42-86) and 4 pts were male. 4 pts had resectable disease, 3 had locally advanced and 3 had metastatic disease at initial diagnosis. MSH6 deficiency (def) was found in 2 cases, PMS2 def in 2, MLH/PMS2 def in 5, and MSH2/MSH6 in 1. 7 pts were treated with ICIs. 3 pts had locally advanced and 4 had metastatic disease when they started ICIs. 5 received Pembrolizumab (pem), 1 received ipilimumab/ nivolumab (ipi/nivo), and 1 received pem then ipi/nivo after progressive disease (PD) on pem. The median number of prior lines of chemotherapy was 1 (range 0-2). 6 pts were evaluable, and 1 had rapid disease progression after 1 dose of pem. Among 6 evaluable pts, 3 had an objective response (1: complete response and 2: partial response), and 2 had stable disease (SD). Median progression-free survival was 8.2 mo, and median overall survival was not reached with median follow-up (FU) of 6.8 mo. The median duration of response was not reached with a median FU of 22.6 mo. The pt with CR remained disease-free for up to 22 months. The pt whose treatment was switched to ipi/nivo after PD on pem achieved SD > 4mo on ipi/nivo. While on immunotherapy, one patient with ipi/nivo developed immunotherapy associated rash requiring systemic steroids, and another on pem developed hypothyroidism requiring levothyroxine. Conclusions: This series suggest ICIs can provide durable clinical efficacy in pts with dMMR PDAC.

Download Full-text

A phase I trial evaluating NBTXR3 activated by radiotherapy in combination with nivolumab or pembrolizumab in patients with advanced cancers.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.2590 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. 2590-2590

Author(s):

Colette Shen ◽

Jessica M. Frakes ◽

Jiaxin Niu ◽

Ari Rosenberg ◽

Jared Weiss ◽

...

Keyword(s):

Phase I ◽

Phase I Trial ◽

Tumor Regression ◽

Checkpoint Inhibitors ◽

Objective Response ◽

Kidney Injury ◽

Complete Response ◽

Intratumoral Injection ◽

Primary Objective ◽

Open Label

2590 Background: Immune checkpoint inhibitors (ICIs) targeting PD-1 are an effective treatment for a variety of cancers. However, the majority of patients (pts) exhibit resistance to ICIs. Overcoming this resistance represents a major challenge in immuno-oncology. Emerging evidence suggests radiation therapy (RT) produces an immunomodulatory effect that may act synergistically with ICIs. However, RT dose and ultimate efficacy are limited by toxicity to surrounding healthy tissues. NBTXR3, a novel radioenhancer administered by direct intratumoral injection (ITI), is designed at the nanoscale to increase RT dose deposit within tumor cells and subsequent tumor cell killing, without increasing toxicity to surrounding healthy tissue. Preclinical data suggest NBTXR3/RT can trigger a local and systemic anti-tumor immune response and overcome anti-PD-1 resistance. NBTXR3/RT combined with anti-PD-1 may prime the immune system to increase the proportion of ICI responders, or convert ICI non-responders to responders. Methods: This is a multicenter, open-label, phase I trial [NCT03589339] to evaluate NBTXR3/RT/anti-PD-1 in 3 cohorts: (1) Locoregional recurrent or recurrent and metastatic head and neck squamous cell carcinoma (HNSCC) amenable to HN re-irradiation, and metastases from any primary cancer eligible for anti-PD-1 (nivolumab or pembrolizumab) treatment specifically localized in the lung (2) or liver (3), respectively. Stereotactic body RT (SBRT) is delivered at tumor-site selective doses per standard practice. The primary objective is NBTXR3/RT/anti-PD-1 recommended phase 2 dose in each cohort. Secondary objectives are anti-tumor response (objective response rate), safety and feasibility of NBTXR3 injection. Results: Nine pts have been treated: 3 HNSCC, 4 lung, 2 liver. 7/9 pts were anti-PD-1 non-responders. Overall tumor regression was observed in 8/9 pts. NBTXR3/RT/anti-PD-1 resulted in tumor regression in 6/7 pts who had progressed on prior anti-PD-1. A complete response in the injected lymph node lasting over 1 year was observed in 1 anti-PD-1 naïve pt. 2 SAEs related to anti-PD-1 and possibly related to NBTXR3 (G5 pneumonitis, G4 hyperglycemia) were observed in 1 anti-PD-1 naïve HNSCC pt and considered DLTs. This pt also experienced 2 other SAEs related to anti-PD-1 (G4 diabetic ketoacidosis, G4 acute kidney injury). SBRT-related safety profile was as expected. Updated results will be presented. Conclusions: Data from this first-in-human phase I trial evaluating NBTXR3/RT/anti-PD-1 in pts with advanced cancers, show NBTXR3 ITI is feasible and well-tolerated. NBTXR3/RT/anti-PD-1 demonstrated promising signs of efficacy. Of particular interest, NBTXR3/RT can overcome ICI resistance in pts having progressed on prior anti-PD-1, supporting further development of NBTXR3 in combination with anti-PD-1 as well as other ICIs. Clinical trial information: NCT03589339.

Download Full-text

Prognostic Factors and Biomarkers of Responses to Immune Checkpoint Inhibitors in Lung Cancer

International Journal of Molecular Sciences ◽

10.3390/ijms20194931 ◽

2019 ◽

Vol 20 (19) ◽

pp. 4931 ◽

Cited By ~ 13

Author(s):

Andrea Bianco ◽

Fabio Perrotta ◽

Giusi Barra ◽

Umberto Malapelle ◽

Danilo Rocco ◽

...

Keyword(s):

Lung Cancer ◽

T Cell ◽

Cancer Treatment ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Checkpoint Inhibitors ◽

T Cell Subsets ◽

Durable Response ◽

Lung Cancer Treatment ◽

The Impact

Manipulation of the immune response is a game changer in lung cancer treatment, revolutionizing management. PD1 and CTLA4 are dynamically expressed on different T cell subsets that can either disrupt or sustain tumor growth. Monoclonal antibodies (MoAbs) against PD1/PDL1 and CTLA4 have shown that inhibitory signals can be impaired, blocking T cell activation and function. MoAbs, used as both single-agents or in combination with standard therapy for the treatment of advanced non-small cell lung cancer (NSCLC), have exhibited advantages in terms of overall survival and response rate; nivolumab, pembrolizumab, atezolizumab and more recently, durvalumab, have already been approved for lung cancer treatment and more compounds are in the pipeline. A better understanding of signaling elicited by these antibodies on T cell subsets, as well as identification of biological determinants of sensitivity, resistance and correlates of efficacy, will help to define the mechanisms of antitumor responses. In addition, the relevance of T regulatory cells (Treg) involved in immune responses in cancer is attracting increasing interest. A major challenge for future research is to understand why a durable response to immune checkpoint inhibitors (ICIs) occurs only in subsets of patients and the mechanisms of resistance after an initial response. This review will explore current understanding and future direction of research on ICI treatment in lung cancer and the impact of tumor immune microenvironment n influencing clinical responses.

Download Full-text

Radiotherapy Scheme Effect on PD-L1 Expression for Locally Advanced Rectal Cancer

Cells ◽

10.3390/cells9092071 ◽

2020 ◽

Vol 9 (9) ◽

pp. 2071

Author(s):

Jihane Boustani ◽

Valentin Derangère ◽

Aurélie Bertaut ◽

Olivier Adotevi ◽

Véronique Morgand ◽

...

Keyword(s):

Rectal Cancer ◽

Tumor Regression ◽

Checkpoint Inhibitors ◽

Objective Response ◽

Locally Advanced ◽

Progression Free Survival ◽

Advanced Rectal Cancer ◽

Locally Advanced Rectal Cancer ◽

Tumor Regression Grade ◽

The Impact

In locally advanced rectal cancer, radiotherapy (RT) followed by surgery have improved locoregional control, but distant recurrences remain frequent. Although checkpoint inhibitors have demonstrated objective response in several cancers, the clinical benefit of PD-1/PD-L1 blockade remains uncertain in rectal cancer. We collected data from biopsies and surgical specimens in 74 patients. The main objective was to evaluate the impact of neoadjuvant RT and fractionation on PD-L1 expression. Secondary objectives were to study the relation between PD-L1 expression and tumor regression grade (TRG), progression-free survival (PFS), overall survival (OS), and CD8 TILs infiltration. Median rates of cells expressing PD-L1 pre- and post-RT were 0.15 (range, 0–17) and 0.5 (range, 0–27.5), respectively (p = 0.0005). There was no effect of RT fractionation on PD-L1+ cell rates. We found no relation between CD8+ TILs infiltration and PD-L1 expression and no difference between high-PD-L1 or low-PD-L1 expression and TRG. High-to-high PD-L1 expression profile had none significant higher OS and PFS compared to all other groups (p = 0.06). Median OS and PFS were higher in biopsies with >0.08 PD-L1+ cells. High-to-high PD-L1 profile and ypT0-2 were significantly associated with higher OS and PFS. This study did not show the differential induction of PD-L1 expression according to fractionation.

Download Full-text

Immune Checkpoint Inhibitors for the Treatment of Bladder Cancer

Cancers ◽

10.3390/cancers13010131 ◽

2021 ◽

Vol 13 (1) ◽

pp. 131

Author(s):

Antonio Lopez-Beltran ◽

Alessia Cimadamore ◽

Ana Blanca ◽

Francesco Massari ◽

Nuno Vau ◽

...

Keyword(s):

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Checkpoint Inhibitors ◽

Objective Response ◽

Line Treatment ◽

Second Line ◽

First Line ◽

Durable Response ◽

First Line Therapy ◽

Line Therapy

A number of immune checkpoint inhibitors (ICIs) have been approved as first-line therapy in case of cisplatin-ineligible patients or as second-line therapy for patients with metastatic urothelial carcinoma (mUC) of the bladder. About 30% of patients with mUC will respond to ICIs immunotherapy. Programmed death-ligand 1 (PD-L1) expression detected by immunohistochemistry seems to predict response to immune checkpoint inhibitors in patients with mUC as supported by the objective response rate (ORR) and overall survival (OS) associated with the response observed in most clinical trials. Pembrolizumab, an anti-PD-1 antibody, demonstrated better OS respective to chemotherapy in a randomized phase 3 study for second-line treatment of mUC. Nivolumab, a PD-1 antibody, also demonstrated an OS benefit when compared to controls. Atezolizumab, Durvalumab, and Avelumab antibodies targeting PD-L1 have also received approval as second-line treatments for mUC with durable response for more than 1 year in selected patients. Atezolizumab and Pembrolizumab also received approval for first-line treatment of patients that are ineligible for cisplatin. A focus on the utility of ICIs in the adjuvant or neoadjuvant setting, or as combination with chemotherapy, is the basis of some ongoing trials. The identification of a clinically useful biomarker, single or in association, to determine the optimal ICIs treatment for patients with mUC is very much needed as emphasized by the current literature. In this review, we examined relevant clinical trial results with ICIs in patients with mUC alone or as part of drug combinations; emphasis is also placed on the adjuvant and neoadjuvant setting. The current landscape of selected biomarkers of response to ICIs including anti-PD-L1 immunohistochemistry is also briefly reviewed.

Download Full-text

Achievement of Complete Response Is a Strong Prognostic Factor In Elderly Newly Diagnosed Myeloma: Retrospective Analysis of 1175 Patients

Blood ◽

10.1182/blood.v116.21.1949.1949 ◽

2010 ◽

Vol 116 (21) ◽

pp. 1949-1949

Author(s):

Francesca Gay ◽

Alessandra Larocca ◽

P.W. Wijermans ◽

Sara Bringhen ◽

Tommasina Guglielmelli ◽

...

Keyword(s):

Board Of Directors ◽

Complete Response ◽

New Drugs ◽

Response To Treatment ◽

Maximal Response ◽

High Dose ◽

Newly Diagnosed ◽

Advisory Committees ◽

Best Response ◽

The Impact

Abstract Abstract 1949 Introduction: There is extensive evidence from numerous studies in the transplant setting that achievement of complete response (CR) or at least very good partial response (VGPR) is significantly associated with prolonged progression-free survival (PFS) and overall survival (OS). In elderly myeloma patients CR was a rare event since new drugs has been added to standard melphalan-prednisone (MP). After the introduction of novel agents, CR represents an achievable goal, also outside of the transplant setting. Aims: to assess the impact of response to treatment on time-to-event parameters (PFS and OS) in elderly myeloma patients. Methods: We retrospectively analysed newly diagnosed myeloma patients, older than 65 years old, or younger but not eligible for high-dose chemotherapy and transplant. Patients were enrolled in 3 multicentre randomized European trials of the GIMEMA and Hovon groups, and were treated with MP (n=332), MP plus thalidomide (MPT, n=332), MP plus bortezomib (VMP, n=257) or MP plus bortezomib-thalidomide followed by bortezomib-thalidomide maintenance (VMPT-VT, n=254). PFS, OS and duration of CR were analysed by the Cox proportional hazards model, comparing the two arms by the Wald test and calculating 95% confidence interval (CI). Univariate and multivariate analyses were performed for the following variables: age at diagnosis (>75 vs. ≤75 yrs), International Staging System (ISS) stages, type of chemotherapy and best response achieved. Best response was treated as a time-dependent variable. Results: A total of 1,175 patients, enrolled from November, 2001 to January, 2009, were retrospectively analysed. The best response to treatment was available in 1,136 patients: CR was reported in 195, VGPR in 212, PR in 397. Baseline characteristics according to best response achieved in patients who obtained CR, VGPR or PR were similar. Since response rates vary according to treatment regimens the proportion of patients who received MP, MPT, VMP, and VMPT-VT was different in the different response categories. After a median follow-up of 29 months, PFS was significantly higher in patients who achieved CR compared to those who obtained VGPR (HR 0.16; 95% CI 0.10–0.24; p<0.001) or PR (HR 0.07; 95% CI 0.04–0.13; p<0.001). The advantage in PFS translated into an advantage in OS: patients obtaining CR have a significantly prolonged OS than patients who achieved VGPR (HR 0.15; 95% CI 0.08–0.28; p<0.001) or PR (HR 0.08; 95% CI 0.04–0.16, p<0.001), (table). In multivariate analysis CR achievement was as an independent predictor of longer PFS and OS, regardless of age, ISS stage, and treatment administered. In patients > 75 years, both PFS and OS were shorter as compared to younger patients. Despite these differences, the impact of CR on outcome was identical. In the subgroup of patients > 75 years, PFS was significantly prolonged in patients who achieved CR, compared with those who obtained VGPR (HR 0.26; 95% CI 0.12–0.58, p = 0.001) or PR (HR 0.20; 95% CI 0.10–0.41, p < 0.001). Accordingly, OS was significantly higher in patients who achieved CR, compared with those who obtained VGPR (HR 0.13; 95% IC 0.03–0.58; p = 0.007), or PR (HR 0.12; 95% IC 0.03–0.51, p = 0.004), (table). No significant PFS differences between patients obtaining CR during the first 6 months of treatment or later were seen (HR 1.06; 95% IC 0.49–2.27; p=0.878). Similarly, no OS differences between these two groups were detected (p = 0.676). Duration of CR was comparable in patients who obtained CR during or after the first 6 months of treatment (HR 0.66; 95% CI 0.30–1.45; p = 0.305). Patients whose CR lasted more than 18 months have a significant OS benefit compared to patients who did not (p=0.006). Conclusions: These finding highlight the importance of CR, also outside of the transplant setting, regardless of age, ISS and treatment administered, and support the use of new drugs, also in patients older than 75 years, to achieve and maintain maximal response. Disclosures: Gay: Celgene: Honoraria. Bringhen:Calgene: Honoraria; Janssen-Cilag: Honoraria. Guglielmelli:Celgene: Honoraria; Janssen Cilag: Honoraria. Boccadoro:Celgene: Membership on an entity's Board of Directors or advisory committees; Janssen-Cilag: Membership on an entity's Board of Directors or advisory committees. Sonneveld:Celgene: Membership on an entity's Board of Directors or advisory committees; Johnson & Johnson : Membership on an entity's Board of Directors or advisory committees. Palumbo:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen-Cilag: Honoraria, Membership on an entity's Board of Directors or advisory committees.

Download Full-text