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It is designed to block the activity of CTLA-4, thereby sustaining an active immune response in its attack on cancer cells. Upregulated IDO-1 activity has been reported in patients receiving immunotherapy of different tumor types such as melanoma, renal cell carcinoma, and NSCLC (31–33). It remains unclear whether IDO-1 activity may comprise a potential resistance mechanism for MSI-H/dMMR patients receiving single-agent anti–PD-1/PD-L1 treatment (34). Patients with a confirmed best overall response of PD on monotherapy had a trend for higher plasma Kyn/Trp ratios at baseline, signaling potentially increased IDO-1 activity (Fig. 4). In most patients with measurable samples, the Kyn/Trp ratio increased at cycle 3 day 1 from baseline levels (10/14, 71.4%). Patients with CRs or PRs tended to have lower percentage changes in plasma Kyn/Trp ratio at cycle 3 day 1 than at baseline.

• In randomized clinical trials in patients with multiple myeloma, the addition of OPDIVO to a thalidomide analogue plus dexamethasone resulted in increased mortality.
• Patients who had active coinfection with HBV and HCV, or HBV and hepatitis D virus, were not eligible.
• Patients (13%) who discontinued treatment because of study drug-related AEs had an ORR (63%) consistent with that of the overall population.
• Kawashima et al. (50), Masuzawa et al. (51), and Vauchier et al. (52) reported that patients with MMR mutations and MSI-H achieved durable benefits from ICIs.

Immunotherapy has dramatically changed the therapeutic landscape of multiple tumors and has boosted enthusiasm regarding cancer treatment. Recent positive results from clinical trials of ICB therapies alone or in combination for “difficult-to-treat” dMMR/MSI-H tumors have led to great hope for immunotherapy application in this specific population. DMMR/MSI-H has been approved by the FDA as an indication of ICB for metastatic Durable Clinical Benefit With Nivolumab Plus Ipilimumab In Dna Mismatch Repair cancers, irrespective of the cancer types, presumably due to the enhanced immune response through the presence of increased somatic mutations and “nonself” neoantigens in these tumors. The novel use of ICB therapies as first-line or neoadjuvant treatments in dMMR/MSI-H tumors may have the potential to expand the indications. DMMR/MSI-H has its unique advantages compared with PD-L1, TMB, TILs, and other new predictors.

1 ICIs in combination with chemotherapy in mUC

Tumor regression was observed in 2 patients with lymphoma; 1 of which obtained a PR of 14-month duration. Tregs as detected by expression of CD4+CD25+CD62L+ declined at early time points but rebounded to levels at or above baseline values at the time of the next infusion. The authors concluded that ipilimumab treatment depressed Treg numbers at early time points in the treatment cycle but was not accompanied by an increase kelleysbookkeeping.com/ in vaccine-specific CD8+ T-cell responses in these patients previously treated with a variety of investigational anti-cancer vaccines. They noted that a phase I/II clinical trial evaluating ipilimumab in patients with follicular lymphoma is currently ongoing. Melanoma is a serious form of skin cancer that arises from melanocytes; however, in rare instances, it can originate in the eye or other non-skin organs.

• Severe to life-threatening (Grade 3-4) endocrinopathies occurred in 9 (1.8%) patients.
• MO  An early report on pembrolizumab, which appeared in the New England Journal of Medicine in 2015, included patients with MMR-D CRC and patients with CRC that was microsatellite stable (MSS).
• The authors concluded that nivolumab plus ipilimumab demonstrated high response rates, encouraging progression-free survival and OS at 12 months, manageable safety, and meaningful improvements in key patient-reported outcomes.
• Another good approach is based on polymerase chain reaction (PCR), which works well in CRC; however, it is less effective in cancers other than CRC and in those with a low level of tumor cellularity.
• The safety, tolerability, pharmacokinetics, and pharmacodynamics of IDE161, a potent, selective, small-molecule inhibitor of PARG, is being evaluated in a phase 1 clinical trial for advanced solid tumors.
• However, not all individuals evidencing high-level PD-L1 expression obtain clinical benefits from immunotherapy (34).
• Patients with MSI-H/dMMR non-CRC were prospectively enrolled in single-arm trials (KEYNOTE-016, 158) or retrospectively identified in multi-cohort trials (KEYNOTE-012, 028) or in patients with one of 10 rare tumor types (KEYNOTE-158).

In the second-line setting, ICIs have demonstrated survival benefit over chemotherapy. We now have EV, sacituzumab govitecan, and erdafitinib to be used in the third- or fourth-line setting depending on FGFR2/3 mutational status and other clinical factors such as patient preference and toxicity profile. MO  We have a lot of data regarding pembrolizumab and nivolumab across multiple different tumor types. These agents seem to be very similar to each other in regard to activity, so little basis exists for choosing one over the other in a monotherapy approach. The bigger question is whether we should use single-agent immunotherapy or combination immunotherapy. Nivolumab/ipilimumab seems to achieve higher rates of response and progression-free survival when compared across trials with nivolumab or pembrolizumab, but it also causes more toxicity.

Other Tumors / Malignancies

Nivolumab plus ipilimumab provides a promising new treatment option for patients with dMMR/MSI-H mCRC. Overman et al. (2018) state nivolumab plus ipilimumab may provide clinical benefit in previously treated patients with DNA mismatch repair-deficient (dMMR)/microsatellite instability-high (MSI-H) metastatic colorectal cancer (mCRC). In the CheckMate-142 trial, 119 patients received nivolumab 3 mg/kg plus ipilimumab 1 mg/kg once every 3 weeks (four doses) followed by nivolumab 3 mg/kg once every 2 weeks. At median follow-up of 13.4 months, investigator-assessed ORR was 55% and disease control rate for ≥ 12 weeks was achieved in 80% of patients. The authors concluded that nivolumab plus ipilimumab demonstrated high response rates, encouraging progression-free survival and OS at 12 months, manageable safety, and meaningful improvements in key patient-reported outcomes. Evaluation of nivolumab plus ipilimumab as a first line therapy (phase II) in patients with dMMR/MSI-H mCRC is ongoing.

ORR was defined as the proportion of enrolled patients in each cohort who achieved a best overall response of confirmed complete response (CR) or partial response (PR). DCR was defined as the proportion who had a best overall response of confirmed CR, confirmed PR, or stable disease (SD). Follow patients closely for evidence of transplant-related complications and intervene promptly.

3 ICIs in combination with antibody-drug conjugates

Lung cancer is one of the most common cancers worldwide and has the highest mortality of all cancers (1). Programmed cell death-protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) inhibitors have increased the 5-year survival rate for non-small cell lung cancer (NSCLC) patients by 20-30%. However, it remains challenging to find patients exhibiting long-term responses to immunotherapy in the present era of precision medicine. The predictive biomarkers of immune checkpoint inhibitor efficacy include the tumor cell surface PD-L1 expression level, tumor mutational burden (TMB), mismatch repair deficiency/high microsatellite instability (dMMR/MSI-H), and tumor-infiltrating lymphocytes (2–4). Studies have confirmed that the efficacy of nivolumab combined with ipilimumab is better than that of nivolumab alone in small cell lung cancer (SCLC) and melanoma [69, 70].

Secondary and exploratory efficacy end points included ORR, disease control rate, and duration of response, assessed by blinded independent central review (BICR) per RECIST version 1.1, ORR per modified RECIST, and overall survival. Additional end points included response stratified by programmed cell death ligand 1 (PD-L1) expression. We assessed patient-reported health status using the 3-level version of the European Quality of Life 5 Dimensions questionnaire (EQ-5D-3L; described in the eAppendix in Supplement 2).

The authors concluded that combined RFA with ipilimumab 3 mg/kg was well-tolerated, however, this approach showed very limited clinical activity in uveal melanoma. In recent years, immunotherapy has become the focus of the revamped cancer therapeutic paradigm. Immunotherapy has brought amazing and long-lasting tumor remission for several common solid malignancies and refractory malignancies [1,2,3,4,5,6].

Meaning 
The manageable safety profile and promising response rates observed in this study support further investigation of nivolumab plus ipilimumab as a treatment option for this patient population. According to interim phase 2 results, GEN-001 in combination with avelumab has a significant objective response rate in patients with gastric and gastroesophageal junction adenocarcinoma. There are indeed a wealth of agents and trials, but the meaningful end points and outcomes of OS, patient-reported quality of life, and pathological response rates, depending on clinical stage, remain critical to determining the best treatment options for our patients. I would like to see us using immunotherapy earlier and in a greater number of patients, who often are able to tolerate single-agent anti–programmed death 1 (PD-1)/PD-L1 treatment better than chemotherapy. MO  An early report on pembrolizumab, which appeared in the New England Journal of Medicine in 2015, included patients with MMR-D CRC and patients with CRC that was microsatellite stable (MSS). The results of this report were dramatic because they showed a tremendous difference in activity between these 2 groups, which clearly indicated that the correct biomarker in CRC was MMR-D.

Immunotherapy in Colorectal Cancer With Mismatch Repair Deficiency

The authors concluded that blockade of CTLA-4 signaling with the use of ipilimumab is well-tolerated at the doses used and has anti-tumor activity in patients with B-cell lymphoma. They stated that further evaluation of ipilimumab alone or in combination with other agents in B-cell lymphoma patients is therefore warranted. Although comparisons are indirect, our results suggest that nivolumab plus ipilimumab may provide improved efficacy in terms of ORR, and, potentially, survival in arm A relative to anti-PD-L1 monotherapy. The emerging data for ICI combinations in bladder cancer are exciting, with the potential to change the therapeutic landscape for all patients with this disease. Up to 50% of patients with mUC are platinum ineligible or decline chemotherapy in the first-line setting, and ICI monotherapy has allowed these patients to receive systemic therapy; some have achieved a durable response with lower toxicity. This is tempered by the finding that patients with tumors with low or no PD-L1 expression might not benefit, and for platinum-eligible patients, chemotherapy remains the SOC.

DR. ANDRÉ PRESENTED the findings for the combination treatment arm, after a median follow-up of 13.4 months. The objective response rate was 55%, with 3.4% being complete responses, and the disease control rate was 80%. The study enrolled 74 patients, who received nivolumab as a single agent (3 mg/kg every 2 weeks) and 119 patients who received nivolumab (3 mg/kg) plus ipilimumab (1 mg/kg) every 3 weeks for four doses, followed by nivolumab (3 mg/kg) every 2 weeks.

Maintenance doses were administered in patients who experienced clinical benefit or at physicians’ discretion. Tumor assessment was assessed per modified World Health Organization criteria at baseline, week 12, week 24, and week 36. Adverse events (AEs) and immune-related AEs (irAEs) were collected according to Common Terminology Criteria for Adverse Events version 3.0. A total of 13 pre-treated patients with metastatic UM were treated at 6 European institutions. Overall, no objective responses were observed; however, 2 patients had stable disease (SD), with a 3rd patient achieving SD after initial progressive disease.