The transformative success of antibodies targeting the PD-1 (programmed death 1) B7-H1 (B7 homolog 1) pathway (anti-PD therapy) has revolutionized cancer treatment. However, only a fraction of ...patients with solid tumors and some hematopoietic malignancies respond to anti-PD therapy, and the reason for failure in other patients is less known. By dissecting the mechanisms underlying this resistance, current studies reveal that the tumor microenvironment is a major location for resistance to occur. Furthermore, the resistance mechanisms appear to be highly heterogeneous. Here, we discuss recent human cancer data identifying mechanisms of resistance to anti-PD therapy. We review evidence for immune-based resistance mechanisms such as loss of neoantigens, defects in antigen presentation and interferon signaling, immune inhibitory molecules, and exclusion of T cells. We also review the clinical evidence for emerging mechanisms of resistance to anti-PD therapy, such as alterations in metabolism, microbiota, and epigenetics. Finally, we discuss strategies to overcome anti-PD therapy resistance and emphasize the need to develop additional immunotherapies based on the concept of normalization cancer immunotherapy.
Treatment options for advanced thyroid cancer refractory to standard therapies are limited. The safety and efficacy of pembrolizumab were evaluated in patients with advanced differentiated thyroid ...cancer expressing programmed death ligand 1 (PD-L1).
Patients with advanced thyroid cancer were enrolled in the nonrandomized, phase Ib KEYNOTE-028 trial conducted to evaluate safety and antitumor activity of the anti-programmed death 1 (PD-1) antibody pembrolizumab in advanced solid tumors. Key eligibility criteria were advanced papillary or follicular thyroid cancer, failure of standard therapy, and PD-L1 expression in tumor or stroma cells (assessed by immunohistochemistry). Pembrolizumab 10 mg/kg was administered every 2 weeks up to 24 months or until confirmed progression or intolerable toxicity. The primary endpoint was objective response rate (ORR) per Response Evaluation Criteria in Solid Tumors, version 1.1.
Twenty-two patients were enrolled: median age was 61 years; 59% were women; and 68% had papillary carcinoma. Median follow-up was 31 months (range, 7-34 months). Treatment-related adverse events were observed in 18 (82%) patients; those occurring in ≥15% of patients were diarrhea (n = 7) and fatigue (n = 4). One grade ≥ 3 treatment-related adverse event occurred (colitis, grade 3); no treatment-related discontinuations or deaths occurred. Two patients had confirmed partial response, for an ORR of 9% (95% confidence interval CI, 1-29%); response duration was 8 and 20 months. Median progression-free survival was 7 months (95% CI, 2-14 months); median overall survival was not reached (95% CI, 22 months to not reached).
Results of this phase Ib proof-of-concept study suggest that pembrolizumab has a manageable safety profile and demonstrate evidence of antitumor activity in advanced differentiated thyroid cancer in a minority of patients treated. Further analyses are necessary to confirm these findings.
Clinicaltrials.gov identifier: NCT02054806 . Registered 4 February 2014.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Anti-programmed cell death protein 1 (PD-1) agents have become the standard of care for platinum-refractory recurrent/metastatic head and neck squamous cell carcinoma (HNSCC) and are currently being ...evaluated in various disease settings. However, despite the gain in overall survival seen in some of the clinical trials, the majority of patients display primary resistance and do not benefit from these agents. Taking into consideration the potentially severe immune-related toxicities and their high cost, the search for predictive biomarkers of response is crucial. Besides Programmed death ligand-1 (PD-L1) expression, other biomarkers such as immune infiltration, tumor mutational burden or immune-gene expression profiling have been explored, but none of them has been validated in this disease. Among these, the microbiota has recently garnered tremendous interest since it has proven to influence the efficacy of PD-1 blockade in some tumor types. With the accumulating evidence on the effect of the microbiota in HNSCC tumorigenesis and progression, the study of its potential role as a predictive immune biomarker is warranted. This review examines the available evidence on emerging immune predictive biomarkers of response to anti-PD-1/PD-L1 therapy in HNSCC, introducing the microbiota and its potential use as a predictive immune biomarker in this disease.
Part 1 of the RUBY trial (NCT03981796) evaluated dostarlimab plus carboplatin–paclitaxel compared with placebo plus carboplatin–paclitaxel in patients with primary advanced or recurrent endometrial ...cancer (EC). At the first interim analysis, the trial met one of its dual primary endpoints with statistically significant progression-free survival benefits in the mismatch repair-deficient/microsatellite instability-high (dMMR/MSI-H) and overall populations. Overall survival (OS) results are reported from the second interim analysis.
RUBY is a phase III, global, double-blind, randomized, placebo-controlled trial. Part 1 of RUBY enrolled eligible patients with primary advanced stage III or IV or first recurrent EC who were randomly assigned (1 : 1) to receive either dostarlimab (500 mg) or placebo, plus carboplatin–paclitaxel every 3 weeks for 6 cycles followed by dostarlimab (1000 mg) or placebo every 6 weeks for up to 3 years. OS was a dual primary endpoint.
A total of 494 patients were randomized (245 in the dostarlimab arm; 249 in the placebo arm). In the overall population, with 51% maturity, RUBY met the dual primary endpoint for OS at this second interim analysis, with a statistically significant reduction in the risk of death hazard ratio (HR) = 0.69, 95% confidence interval (CI) 0.54-0.89, P = 0.0020 in patients treated with dostarlimab plus carboplatin–paclitaxel versus carboplatin–paclitaxel alone. The risk of death was lower in the dMMR/MSI-H population (HR = 0.32, 95% CI 0.17-0.63, nominal P = 0.0002) and a trend in favor of dostarlimab was seen in the mismatch repair-proficient/microsatellite stable population (HR = 0.79, 95% CI 0.60-1.04, nominal P = 0.0493). The safety profile for dostarlimab plus carboplatin–paclitaxel was consistent with the first interim analysis.
Dostarlimab in combination with carboplatin–paclitaxel demonstrated a statistically significant and clinically meaningful OS benefit in the overall population of patients with primary advanced or recurrent EC while demonstrating an acceptable safety profile.
•RUBY compared dostarlimab + chemotherapy to chemotherapy alone in patients with primary advanced/recurrent EC.•RUBY showed statistically significant and clinically relevant improvements in OS with dostarlimab + chemotherapy.•These are clinically important results for patients with primary advanced/recurrent EC.•This represents a new standard of care for primary advanced/recurrent EC.
Une patiente de 50 ans a présenté une polyradiculonévrite (PRN) dysautonomique pure sans atteinte motrice ou sensitive dans le cadre de mélanome métastatique traité par anti-PD-1.
La patiente ...présenta en septembre 2018 un mélanome nodulaire du vertex muté BRAF V600K, avec des métastases pulmonaires découvertes en juillet 2019 et traitées par 4 cures de pembrolizumab (anti-PD-1), arrêté en octobre 2019 devant la découverte de métastases cérébrales. Elle présenta en décembre 2019 un syndrome occlusif en rapport avec un iléus paralytique, répondant à des hautes doses de corticoïdes, ainsi que d’autres signes dysautonomiques : une hypotension orthostatique sévère, une bradycardie ainsi qu’une rétention aiguë d’urine. À l’ENMG, il n’y avait pas de signe de neuropathie des membres, mais une atteinte dysautonomique d’origine neurologique avec une altération des réflexes cutanés sympathiques. L’absence d’anomalie à la ponction lombaire et de nouvelle métastase à l’IRM cérébrale, la négativité des anticorps antigangliosides et antineuronaux, et la glycémie normale ont permis d’exclure les diagnostics différentiels et d’évoquer une complication liée aux anti-PD1. Un traitement par Ig IV 2g/kg a été initié. Mais, devant l’absence d’amélioration, une intensification thérapeutique par échanges plasmatiques a été décidée, avec un rythme initial hebdomadaire, suivi d’un espacement progressif, permettant une résolution de la symptomatologie.
Les complications neurologiques des immunothérapies sont rares (< 5 %) avec une fréquence augmentée si association anti-CTLA4 et PD-1 (12 %). La physiopathologie est mal connue. Les atteintes sont variées : atteintes centrales (myélites, encéphalites) ou périphériques (PRN, syndromes myasthéniques). Le traitement repose sur un arrêt de l’immunothérapie et une corticothérapie, voire des immunosuppresseurs. Le pronostic post-traitement est généralement favorable.
Les complications neurologiques des immunothérapies sont rares mais peuvent être sévères. Elles représentent un véritable challenge diagnostique et thérapeutique compte tenu de l’essor des immunothérapies.
The commensal microbiota has been implicated in the regulation of a diverse array of physiological processes, both within the gastrointestinal tract and at distant tissue sites. Cancer is no ...exception, and distinct aspects of the microbiota have been reported to have either pro- or anti-tumor effects. The functional role of the microbiota in regulating not only mucosal but also systemic immune responses has led to investigations into the impact on cancer immunotherapies, particularly with agents targeting the immunologic checkpoints PD-1 and CTLA-4. Microbial sequencing and reconstitution of germ-free mice have indicated both positive and negative regulatory bacteria likely exist, which either promote or interfere with immunotherapy efficacy. These collective findings have led to the development of clinical trials pursuing microbiome-based therapeutic interventions, with the hope of expanding immunotherapy efficacy. This review summarizes recent knowledge about the relationship between the host microbiota and cancer and anti-tumor immune response, with implications for cancer therapy.
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Immune-related adverse events (irAEs) typically occur within 4 months of starting anti-programmed cell death protein 1 (PD-1)-based therapy anti-PD-1 ± anti-cytotoxic T-lymphocyte-associated protein ...4 (CTLA4), but delayed irAEs (onset >12 months after commencement) can also occur. This study describes the incidence, nature and management of delayed irAEs in patients receiving anti-PD-1-based immunotherapy.
Patients with delayed irAEs from 20 centres were studied. The incidence of delayed irAEs was estimated as a proportion of melanoma patients treated with anti-PD-1-based therapy and surviving >1 year. Onset, clinical features, management and outcomes of irAEs were examined.
One hundred and eighteen patients developed a total of 140 delayed irAEs (20 after initial combination with anti-CTLA4), with an estimated incidence of 5.3% (95% confidence interval 4.0-6.9, 53/999 patients at sites with available data). The median onset of delayed irAE was 16 months (range 12-53 months). Eighty-seven patients (74%) were on anti-PD-1 at irAE onset, 15 patients (12%) were <3 months from the last dose and 16 patients (14%) were >3 months from the last dose of anti-PD-1. The most common delayed irAEs were colitis, rash and pneumonitis; 55 of all irAEs (39%) were ≥grade 3. Steroids were required in 80 patients (68%), as well as an additional immunosuppressive agent in 27 patients (23%). There were two irAE-related deaths: encephalitis with onset during anti-PD-1 and a multiple-organ irAE with onset 11 months after ceasing anti-PD-1. Early irAEs (<12 months) had also occurred in 69 patients (58%), affecting a different organ from the delayed irAE in 59 patients (86%).
Delayed irAEs occur in a small but relevant subset of patients. Delayed irAEs are often different from previous irAEs, may be high grade and can lead to death. They mostly occur in patients still receiving anti-PD-1. The risk of delayed irAE should be considered when deciding the duration of treatment in responding patients. However, patients who stop treatment may also rarely develop delayed irAE.
•The incidence of delayed irAEs >12 months after commencing anti-PD-1 was 5.3%.•Delayed irAEs occurred in 118 patients; these were often high grade (39% G3+) including two delayed irAE-related deaths.•Delayed irAEs were often difficult to manage; 68% required steroids and 23% required an additional immunosuppressive agent.•Most occurred during anti-PD-1 therapy (74%), but delayed irAEs were also reported up to 26 months after stopping anti-PD-1.
In order to update recommendations on treatment, supportive care, education and follow-up of patients with invasive cutaneous squamous cell carcinoma (cSCC), a multidisciplinary panel of experts from ...the European Dermatology Forum, the European Association of Dermato-Oncology and the European Organization of Research and Treatment of Cancer was formed. Recommendations were based on evidence-based literature review, guidelines and expert consensus. Treatment recommendations are presented for common primary cSCC (low risk, high risk), locally advanced cSCC, regional metastatic cSCC (operable or inoperable) and distant metastatic cSCC. For common primary cSCC (the most frequent cSCC type), first-line treatment is surgical excision with postoperative margin assessment or microscopically controlled sugery. Safety margins containing clinical normal-appearing tissue around the tumour during surgical excision and negative margins as reported in the pathology report are necessary to minimise the risk of local recurrence and metastasis. In case of positive margins, a re-excision shall be done, for operable cases. Lymph node dissection is recommended for cSCC with cytologically or histologically confirmed regional nodal involvement. Radiotherapy should be considered as curative treatment for inoperable cSCC, or for non-surgical candidates. Anti-PD-1 antibodies are the first-line systemic treatment for patients with metastatic or locally advanced cSCC who are not candidates for curative surgery or radiation, with cemiplimab being the first approved systemic agent for advanced cSCC by the Food and Drug Administration/European Medicines Agency. Second-line systemic treatments for advanced cSCC include epidermal growth factor receptor inhibitors (cetuximab) combined with chemotherapy or radiation therapy. Multidisciplinary board decisions are mandatory for all patients with advanced disease who require more than surgery. Patients should be engaged with informed decisions on management and be provided with best supportive care to optimise symptom management and improve quality of life. Frequency of follow-up visits and investigations for subsequent new cSCC depend on underlying risk characteristics.
•Surgical excision with negative margins is an important goal whenever feasible.•Radiotherapy is indicated for inoperable cSCC or patients not suitable for surgical intervention.•Multidisciplinary board decisions are necessary in the management of patients with advanced disease.•Anti-PD-1 antibody therapy is first-line systemic treatment for locally advanced or mcSCC.•Follow-up evaluations depend on underlying risk characteristics.
BACKGROUNDMucosal melanoma (MM) is a rare melanoma subtype with distinct biology and poor prognosis. Data on the efficacy of immune checkpoint inhibitors (ICIs) are limited. We determined the ...efficacy of ICIs in MM, analyzed by primary site and ethnicity/race. PATIENTS AND METHODSA retrospective cohort study from 25 cancer centers in Australia, Europe, USA and Asia was carried out. Patients with histologically confirmed MM were treated with anti-programmed cell death protein 1 (PD-1) ± ipilimumab. Primary endpoints were response rate (RR), progression-free survival (PFS), overall survival (OS) by primary site (naso-oral, urogenital, anorectal, other), ethnicity/race (Caucasian, Asian, Other) and treatment. Univariate and multivariate Cox proportional hazards model analyses were conducted. RESULTSIn total, 545 patients were included: 331 (63%) Caucasian, 176 (33%) Asian and 20 (4%) Other. Primary sites included 113 (21%) anorectal, 178 (32%) urogenital, 206 (38%) naso-oral and 45 (8%) other. Three hundred and forty-eight (64%) patients received anti-PD-1 and 197 (36%) anti-PD-1/ipilimumab. RR, PFS and OS did not differ by primary site, ethnicity/race or treatment. RR for naso-oral was numerically higher for anti-PD-1/ipilimumab 40%, 95% confidence interval (CI) 29% to 54% compared with anti-PD-1 (29%, 95% CI 21% to 37%). Thirty-five percent of patients who initially responded progressed. The median duration of response (mDoR) was 26 months (95% CI 18 months-not reached). Factors associated with short PFS were Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≥3 (P < 0.01), lactate dehydrogenase (LDH) more than the upper limit of normal (ULN) (P = 0.01), lung metastases (P < 0.01) and ≥1 previous treatments (P < 0.01). Factors associated with short OS were ECOG PS ≥1 (P < 0.01), LDH >ULN (P = 0.03), lung metastases (P < 0.01) and ≥1 previous treatments (P < 0.01). CONCLUSIONSMM has poor prognosis. Treatment efficacy of anti-PD-1 ± ipilimumab was similar and did not differ by ethnicity/race. Naso-oral primaries had numerically higher response to anti-PD-1/ipilimumab, without difference in survival. The addition of ipilimumab did not show greater benefit over anti-PD-1 for other primary sites. In responders, mDoR was short and acquired resistance was common. Other factors, including site and number of metastases, were associated with survival.
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