The Current Landscape of Immune Checkpoint Inhibition for Solid Malignancies

doi:10.1016/j.soc.2019.02.008

Surgical Oncology Clinics of North America

Volume 28, Issue 3, July 2019, Pages 369-386

https://doi.org/10.1016/j.soc.2019.02.008 Get rights and content

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Key points

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The introduction of immune checkpoint inhibitors has resulted in unprecedented gains in the treatment and prognosis of advanced/metastatic solid malignancies.
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Initially evaluated in advanced/metastatic melanoma, immune checkpoint inhibitors have also demonstrated efficacy in other malignancies including non–small cell lung cancer, urothelial carcinoma, and MSI-high cancers.
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More recent clinical trials evaluating the use of immune checkpoint inhibitors in the adjuvant and neoadjuvant settings have

Overview of immune checkpoint blockade

The landscape of available treatment options for patients with advanced and metastatic solid malignancies has changed dramatically in recent years. Nowhere is this better highlighted than in the management of advanced and metastatic melanoma with the introduction of molecularly targeted therapies and immune checkpoint inhibitors. Following their success in melanoma, immunotherapies have also been evaluated and their use approved in the management across a variety of other solid malignancies in

Immune Checkpoint Blockade for Unresectable/Metastatic Melanoma

In 2011, ipilimumab (anti-CTLA-4) became the first immune checkpoint inhibitor to gain Food and Drug Administration (FDA) approval based on results of a landmark study by Hodi and colleagues.¹ In this study of 676 patients with unresectable stage III and IV melanoma who had progressed on prior therapy, those treated with ipilimumab demonstrated improved overall survival (OS) and durable responses. This was followed by the approval of the PD-1 inhibitors pembrolizumab² and nivolumab³ in 2014 for

Immune checkpoint blockade for non–small cell lung cancer

Although first approved in melanoma, immune checkpoint blockade was subsequently tested in NSCLC in the metastatic setting after progression on platinum-based chemotherapy or tyrosine kinase inhibitors. CheckMate-017 was a phase 3 randomized trial of patients with advanced squamous NSCLC and disease progression during or after first-line platinum-based chemotherapy in which 272 patients were randomized to either nivolumab or docetaxel.¹⁷ In this study, nivolumab was associated with significant

Immune checkpoint blockade for other solid malignancies

Beyond their efficacy in melanoma and NSCLC, immune checkpoint inhibitors have also demonstrated encouraging activity in other advanced and metastatic malignancies.

Future landscape of immune checkpoint blockade for solid malignancies

The treatment landscape for advanced and metastatic solid malignancies has changed dramatically in recent years with the introduction and success of immune checkpoint inhibitors. Since their earliest successes and FDA approvals in the advanced and metastatic melanoma setting, immune checkpoint inhibitors have now demonstrated efficacy not only in other solid malignancies such as NSCLC, HNSCC, and urothelial carcinomas in the advanced and metastatic setting but also in the adjuvant and

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References (63)

A.M.M. Eggermont et al.
Adjuvant ipilimumab versus placebo after complete resection of high-risk stage III melanoma (EORTC 18071): a randomised, double-blind, phase 3 trial
Lancet Oncol
(2015)
P. Cortazar et al.
Pathological complete response and long-term clinical benefit in breast cancer: the CTNeoBC pooled analysis
Lancet
(2014)
R.S. Herbst et al.
Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomised controlled trial
Lancet
(2016)
L. Fehrenbacher et al.
Atezolizumab versus docetaxel for patients with previously treated non-small-cell lung cancer (POPLAR): a multicentre, open-label, phase 2 randomised controlled trial
Lancet
(2016)
C.J. Langer et al.
Carboplatin and pemetrexed with or without pembrolizumab for advanced, non-squamous non-small-cell lung cancer: a randomised, phase 2 cohort of the open-label KEYNOTE-021 study
Lancet Oncol
(2016)
J.E. Rosenberg et al.
Atezolizumab in patients with locally advanced and metastatic urothelial carcinoma who have progressed following treatment with platinum-based chemotherapy: a single-arm, multicentre, phase 2 trial
Lancet
(2016)
A.V. Balar et al.
Atezolizumab as first-line treatment in cisplatin-ineligible patients with locally advanced and metastatic urothelial carcinoma: a single-arm, multicentre, phase 2 trial
Lancet
(2017)
C.R. Heery et al.
Avelumab for metastatic or locally advanced previously treated solid tumours (JAVELIN Solid Tumor): a phase 1a, multicohort, dose-escalation trial
Lancet Oncol
(2017)
P. Sharma et al.
Nivolumab in metastatic urothelial carcinoma after platinum therapy (CheckMate 275): a multicentre, single-arm, phase 2 trial
Lancet Oncol
(2017)
P. Sharma et al.
Nivolumab monotherapy in recurrent metastatic urothelial carcinoma (CheckMate 032): a multicentre, open-label, two-stage, multi-arm, phase 1/2 trial
Lancet Oncol
(2016)

E.R. Plimack et al.

Safety and activity of pembrolizumab in patients with locally advanced or metastatic urothelial cancer (KEYNOTE-012): a non-randomised, open-label, phase 1b study

Lancet Oncol

(2017)

T. Seiwert et al.

Safety and clinical activity of pembrolizumab for treatment of recurrent or metastatic squamous cell carcinoma of the head and neck (KEYNOTE-012): an open-label, multicentre, phase 1b trial

Lancet Oncol

(2016)

H.L. Kaufman et al.

Avelumab in patients with chemotherapy-refractory metastatic Merkel cell carcinoma: a multicentre, single-group, open-label, phase 2 trial

Lancet Oncol

(2016)

P.A. Ott et al.

Safety and antitumor activity of the anti-PD-1 antibody pembrolizumab in patients with recurrent carcinoma of the anal canal

Ann Oncol

(2017)

M.J. Overman et al.

Nivolumab in patients with metastatic DNA mismatch repair-deficient or microsatellite instability-high colorectal cancer (CheckMate 142): an open-label, multicentre, phase 2 study

Lancet Oncol

(2017)

L. Nebot-Bral et al.

Hypermutated tumours in the era of immunotherapy: the paradigm of personalised medicine

Eur J Cancer

(2017)

F.S. Hodi et al.

Improved survival with ipilimumab in patients with metastatic melanoma

N Engl J Med

(2010)

C. Robert et al.

Pembrolizumab versus Ipilimumab in Advanced Melanoma

N Engl J Med

(2015)

C. Robert et al.

Nivolumab in previously untreated melanoma without BRAF mutation

N Engl J Med

(2015)

A.M.M. Eggermont et al.

Prolonged survival in stage III melanoma with ipilimumab adjuvant therapy

N Engl J Med

(2016)

J. Weber et al.

Adjuvant nivolumab versus ipilimumab in resected stage III or IV melanoma

N Engl J Med

(2017)

G.V. Long et al.

Adjuvant dabrafenib plus trametinib in stage III BRAF-mutated melanoma

N Engl J Med

(2017)

A.M.M. Eggermont et al.

Adjuvant pembrolizumab versus placebo in resected stage III melanoma

N Engl J Med

(2018)

B. Fisher et al.

Effect of preoperative chemotherapy on local-regional disease in women with operable breast cancer: findings from National Surgical Adjuvant Breast and Bowel

J Clin Oncol

(1997)

P. Rastogi et al.

Preoperative chemotherapy: updates of national surgical adjuvant breast and bowel project protocols B-18 and B-27

J Clin Oncol

(2008)

G. Von Minckwitz et al.

Definition and impact of pathologic complete response on prognosis after neoadjuvant chemotherapy in various intrinsic breast cancer subtypes

J Clin Oncol

(2012)

D. Mauri et al.

Neoadjuvant versus adjuvant systemic treatment in breast cancer: a meta-analysis

J Natl Cancer Inst

(2005)

Neoadjuvant pembrolizumab for unresectable stage III and unresectable stage IV melanoma (NeoPembroMel)

Neoadjuvant and adjuvant checkpoint blockade in patients with clinical stage III or oligometastatic stage IV melanoma

Optimal neo-adjuvant combination scheme of ipilimumab and nivolumab (OpACIN-neo)

J. Brahmer et al.

Nivolumab versus docetaxel in advanced squamous-cell non-small-cell lung cancer

N Engl J Med

(2015)

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Personalization of Radiation Therapy in the Primary Treatment of Malignant Epidural Spinal Cord Compression (MESCC)
2023, Seminars in Radiation Oncology
“True” malignant epidural spinal cord compression (MESCC) is used here to describe a lesion compressing of infiltrating the spinal cord associated with neurologic deficits. Radiotherapy alone is the most common treatment, for which several dose-fractionation regimens are available including single-fraction, short-course and longer-course regimens. Since these regimens are similarly effective regarding functional outcomes, patients with poor survival are optimally treated with short-course or even single-fraction radiotherapy. Longer-course radiotherapy results in better local control of malignant epidural spinal cord compression. Since most in-field recurrences occur 6 months or later, local control is particularly important for longer-term survivors who, therefore, should receive longer-course radiotherapy. It is important to estimate survival prior to treatment, which is facilitated by scoring tools. Radiotherapy should be supplemented by corticosteroids, if safely possible. Bisphosphonates and RANK-ligand inhibitors may improve local control. Selected patients can benefit from upfront decompressive surgery. Identification of these patients is facilitated by prognostic instruments considering degree of compression, myelopathy, radio-sensitivity, spinal stability, post-treatment ambulatory status, and patients’ performance status and survival prognoses. Many factors including patients’ preferences must be considered when designing personalized treatment regimens.
A New and Easy-to-Use Survival Score for Patients Irradiated for Metastatic Epidural Spinal Cord Compression
2022, Practical Radiation Oncology
Citation Excerpt :
For selected patients, approaches including SBRT alone or SBRT in combination with separation surgery are used.5,6 Moreover, novel targeted therapies lead to improved survival of many patients with cancer, including patients with metastatic disease.14-18 Thus, the score from 2008 may no longer be as predictive as it was about 10 years ago.
A survival score was created in 2008 to improve treatment personalization of patients irradiated for metastatic epidural spinal cord compression (MESCC). Since then, targeted therapies improved survival of patients with cancer, which may decrease this score's predictive value. A new score appears necessary.
Two hundred sixty-four patients receiving radiation therapy without surgery in prospective trials (2010-2021) were included. A dose-fractionation regimen plus 15 factors were analyzed: age, sex, tumor type, interval tumor diagnosis to MESCC, MESCC sites, affected vertebrae, additional bone lesions, other distant lesions (yes or no), number of organs involved by metastases, time developing motor deficits, ambulatory status, sensory function, sphincter dysfunction, pain, and distress. Six-month survival rates (%) of independent prognostic factors were divided by 10 and summed for each patient. The score was compared with the previous tool for predicting death ≤6 months and survival ≥6 months.
In a multivariate analysis, tumor type (P = .001), other distant lesions (P < .001), and ambulatory status (P < .001) were significant. Based on 6-month survival rates, 4 groups (8-9, 10-13, 14-17, and 18 points) were created with 6-month survival rates of 12.8%, 34.7%, 62.8%, and 90.0%, respectively (version A). For version B, “other distant lesions” was replaced by “number of organs involved by metastases.” Version B included 4 groups (8-10, 11-14, 15-16, and 17 points) with 6-month survival rates of 11.1%, 42.0%, 68.6%, and 91.7%, respectively. Positive predictive values to predict death ≤6 months were 87.2% (version A) and 88.9% (version B) versus 76.6% (3 groups) and 84.6% (5 groups) for the previous score. Positive predictive values to predict survival ≥6 months were 90.0% and 91.7% versus 59.0% and 64.3%.
Both versions of the new score were more precise than the previous tool. Version B appears slightly superior to version A but requires more extensive diagnostic staging that may not be readily available when emergently treating.
The CXCL12-CXCR4/CXCR7 axis as a mechanism of immune resistance in gastrointestinal malignancies
2020, Seminars in Cancer Biology
Citation Excerpt :
While monotherapy with immune checkpoint inhibitors (ICI) targeting the cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) or programmed-death 1 (PD-1) pathways have been effective for melanoma and non-small cell lung carcinoma, similar therapy of gastrointestinal (GI) solid malignancies has not been successful [1,2].
Single agent checkpoint inhibitor therapy has not been effective for most gastrointestinal solid tumors, but combination therapy with drugs targeting additional immunosuppressive pathways is being attempted. One such pathway, the CXCL12-CXCR4/CXCR7 chemokine axis, has attracted attention due to its effects on tumor cell survival and metastasis as well as immune cell migration. CXCL12 is a small protein that functions in normal hematopoietic stem cell homing in addition to repair of damaged tissue. Binding of CXCL12 to CXCR4 leads to activation of G protein signaling kinases such as P13K/mTOR and MEK/ERK while binding to CXCR7 leads to β-arrestin mediated signaling. While some gastric and colorectal carcinoma cells have been shown to make CXCL12, the primary source in pancreatic cancer and peritoneal metastases is cancer-associated fibroblasts. Binding of CXCL12 to CXCR4 and CXCR7 on tumor cells leads to anti-apoptotic signaling through Bcl-2 and survivin upregulation, as well as promotion of the epithelial-to-mesechymal transition through the Rho-ROCK pathway and alterations in cell adhesion molecules. High levels of CXCL12 seen in the bone marrow, liver, and spleen could partially explain why these are popular sites of metastases for many tumors. CXCL12 is a chemoattractant for lymphocytes at lower levels, but becomes chemorepellant at higher levels; it is unclear exactly what gradient exists in the tumor microenvironment and how this influences tumor-infiltrating lymphocytes. AMD3100 (Plerixafor or Mozobil) is a small molecule CXCR4 antagonist and is the most frequently used drug targeting the CXCL12-CXCR4/CXCR7 axis in clinical trials for gastrointestinal solid tumors currently. Other small molecules and monoclonal antibodies against CXCR4 are being trialed. Further understanding of the CXCL12- CXCR4/CXCR7 chemokine axis in the tumor microenvironment will allow more effective targeting of this pathway in combination immunotherapy.
Precision Radiation Therapy for Metastatic Spinal Cord Compression: Final Results of the PRE-MODE Trial
2020, International Journal of Radiation Oncology Biology Physics
Citation Excerpt :
Moreover, the median follow-up times were different: 3 months in the phase 2 cohort and 5 months in the historic control group. Treatment for metastatic disease has improved recently with the introduction of new targeted drugs, such as immune checkpoint inhibitors.27 Taking into account that the median survival in the phase 2 cohort was only 3 months, it becomes obvious that the situation of the patients of the phase 2 cohort was strictly palliative.
To investigate precision radiation therapy for metastatic spinal cord compression and compare it to conventional radiation therapy.
In a multicenter phase 2 study, 40 patients received 5 Gy × 5 fractions of precision radiation therapy (38 volume modulated arc therapy, 2 intensity modulated radiation therapy) for metastatic spinal cord compression and were evaluated for local progression-free survival (LPFS), motor function, ambulatory status, sensory function, sphincter dysfunction, pain, distress, overall survival (OS), and toxicity. Maximum spinal cord dose was 101.5% (myelopathy risk, <0.03%) of the prescription dose. Patients were compared with a historical control group conventionally irradiated with 4 Gy × 5 fractions (propensity score analysis). The equivalent dose in 2 Gy-fractions of 5 Gy × 5 fractions is similar to 3 Gy × 10 fractions, which results in better LPFS than 4 Gy × 5 fractions. It was assumed that 5 Gy × 5 fractions is also superior to 4 Gy × 5 fractions for LPFS. (ClinicalTrials.gov-identifier: NCT03070431)
Six-month rates of LPFS and OS were 95.0% and 42.6%, respectively. Improvement of motor function occurred in 24 patients (60%). Thirty-three patients (82.5%) were ambulatory after radiation therapy. Eight of 16 patients (50.0%) with sensory deficits improved. Pain and distress relief were reported by 61.9% and 54.2% of patients 1 month after radiation therapy. Grade 3 toxicities occurred in 1 patient and grade 2 toxicities in another 3 patients. Of the control group, 664 patients qualified for the propensity score analysis; 5 Gy × 5 fractions was significantly superior to 4 Gy × 5 fractions with regard to LPFS (P = .026) but not motor function (P = .51) or OS (P = .82).
Precision radiation therapy with 5 Gy × 5 fractions was well tolerated and effective and appeared superior to 4 Gy × 5 fractions in terms of LPFS. The retrospective nature of the historic control group, which might have led to a hidden selection bias, needs to be considered when interpreting the results.
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: Disclosure statement: J.A. Wargo is an inventor on a US patent application (PCT/US17/53,717) submitted by The University of Texas MD Anderson Cancer Center that covers methods to enhance checkpoint blockade therapy by the microbiome. J.A. Wargo is a clinical and scientific advisor at Microbiome DX and a consultant at Biothera Pharma, Merck Sharp and Dohme. J.A. Wargo has honoraria from speakers’ bureau of Dava Oncology, Bristol-Myers Squibb, and Illumina, Omniprex, Imedex and is an advisory board member for GlaxoSmithKline, Novartis, and Roche/Genentech, Astra-Zeneca. E.Z. Keung is supported by National Institutes of Health grant T32 CA009599.

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