Prolonged Clinical Response Research Articles

Editorial: Advances in SIBO Treatment: The Synergistic Role of Rifaximin and Probiotics

A study conducted by Abu-Hammour et al. Published in the December 2024 issue of the Jordan Medical Journal (1) explored the effectiveness of combining rifaximin with probiotics in treating Small Intestinal Bacterial Overgrowth (SIBO). Participants were divided into two groups based on the timing of probiotic administration: concurrent (Group A) and sequential (Group B). Both treatment approaches have shown significant effectiveness, with 69.8% of patients in Group A and 74.8% in Group B achieving a negative lactulose hydrogen breath test (LHBT) after treatment. Additionally, the overall clinical response rates were also remarkable, exceeding 86% in both groups. Interestingly, no side effects were reported, highlighting the safety of rifaximin and probiotics as a therapeutic combination. Furthermore, the study found no statistically significant difference between the two regimens, indicating that whether probiotics are administered concurrently or sequentially, the outcomes remain favorable. However, the sequential regimen did show a more prolonged clinical response, which could offer additional therapeutic benefits, especially for patients who may require longer-term management. These results contribute to a growing body of evidence supporting the synergistic effects of rifaximin and probiotics in treating SIBO (2). The addition of probiotics, whether started simultaneously with rifaximin or in a staggered manner, enhances treatment outcomes by not only eradicating harmful bacteria but also promoting the restoration of the gut's beneficial microbiota. This dual approach is particularly relevant given the complex pathophysiology of SIBO, which involves both bacterial overgrowth and disturbances in the gut's microbiome. It is essential to highlight the diagnostic challenges in SIBO which have been linked to several gastrointestinal and extraintestinal diseases. While small bowel aspiration and culture is the accepted gold standard for diagnosis, breath testing (GBT) is widely used in the routine clinical setting including lactulose and glucose hydrogen breath tests, which often result in varying levels of sensitivity and specificity (3). Despite these challenges, the use of non-invasive methods like the lactulose hydrogen breath test remains a cornerstone of SIBO diagnosis, with some studies suggesting that it may offer better sensitivity compared to glucose-based tests, particularly in cases of distal SIBO. The study by Abu-Hammour and colleagues is an important step toward refining SIBO treatment protocols. It underscores the need for personalized treatment strategies that consider both the microbiological and clinical aspects of the disease. Furthermore, it opens the door for future research to explore the optimal duration and timing of probiotic administration, as well as the potential benefits of combining rifaximin with other novel therapeutic agents. In conclusion, the addition of probiotics to rifaximin therapy offers a promising, well-tolerated approach to treating SIBO, with no significant differences in efficacy between concurrent and sequential use. This study reinforces the importance of addressing both bacterial overgrowth and microbiome imbalance in the management of SIBO, providing a potential model for future therapeutic strategies in this prevalent and often debilitating condition.

FC23 High induction dosing of risankizumab in patients with moderate-to-severe plaque leads to marked suppression of resident memory T cell number and function in resolved psoriatic skin

Abstract Risankizumab, a humanized monoclonal antibody that specifically inhibits IL-23, is approved to treat moderate-to-severe plaque psoriasis. In Phase 2, double-blinded, single-centre KNOCKOUT (NCT05283135) study, we evaluated higher-than-approved risankizumab induction doses (300 and 600 mg) for efficacy measures and modulation of lesional resident memory T cells (TRM), cells responsible for psoriasis recurrences. A total of 20 patients were enrolled, and 16 patients completed Week 52. Patients were randomized 1:1 to receive subcutaneous risankizumab 300 or 600 mg at Weeks 0, 4, and 16, with no further dosing. Static Physician’s Global Assessment (sPGA) was monitored throughout the study and reported here with modified non-responder imputation. At Week 16, 94.4% [n = 17, 95% confidence interval, CI (72.7, 99.9)] of all patients achieved sPGA 0/1 and 66.7% [n = 12, 95% CI (41.0, 86.7)] achieved sPGA 0. At Week 52, 36 weeks after the last dose, sPGA 0/1 and sPGA 0 responses were achieved by 61.1% [n = 11, 95% CI (35.7, 82.7)] and 44.4% [n = 8, 95% CI (21.5, 69.2)] of all patients, respectively. We also performed single-cell RNA-sequencing of biopsy samples at baseline and at Week 52 from both dose groups. In lesions of patients receiving the higher dose (600 mg) of risankizumab, the number of CD8+ tissue-resident memory T (TRM) cells was markedly reduced, with more marked suppression of the intercellular communication network between TRM and keratinocytes compared with the lower dose (300 mg) group. A shift towards increased crosstalk between Tregs and TRM, was noted, particularly in the 600 mg dose group. Mechanistically, the IL-23 blockade also impaired the expression of IL15 and IL7 in keratinocytes, which are known survival factors for CD8+ TRM. Furthermore, keratinocyte-derived TNFSF15 (TL1A), a known inflammatory signal for TH17 maintenance, was strongly attenuated in the 600 mg dose group compared with the 300 mg dose group. These findings suggest that the high and prolonged therapeutic clinical responses seen with high induction doses of risankizumab may be explained by the marked suppression of TRM number and function.

Efficacy of Rifaximin and Probiotics in the Treatment of Small Intestinal Bacterial Overgrowth When Used Concomitantly or Sequentially

Background: With the prevalence of small intestinal bacterial overgrowth (SIBO) on the rise, treatment has become of paramount importance for patients suffering from this disease. Antibiotics used to treat SIBO include rifaximin, ciprofloxacin, metronidazole, and neomycin. Probiotics reinforce the small intestine's internal microbiota and help cure many diseases. Aim: In this study, we aimed to evaluate the efficacy of rifaximin together with a multi-strain probiotic in patients with SIBO. In a multi-center open-labeled prospective study, recruited patients were randomized into two groups treated with rifaximin as a base and probiotics that varied in the timing of initiation (concomitantly; group A or sequentially; group B) for treating the clinical manifestations of the disease. The primary endpoint evaluated the clinical response to treatment, and the secondary endpoint evaluated the eradication rates. Results: Eradication rates revealed that 69.8% of the patients in group A and 74.8% of the patients in group B were successfully treated and returned with negative lactulose hydrogen breath test results. Clinical response rates were divided into partial and complete responders; partial responders were reported in 23.3% and 26.6% of patients in groups A and B, respectively, and complete responders were reported in 62.7% and 59.5% of patients in groups A and B, respectively. Overall, partial or complete responders' combined rate comprised 86% and 86.2% in groups A and B, respectively. There were no reported side effects by patients treated with rifaximin and the multi-strain probiotic for both protocols. Conclusion: The addition of probiotics, both concomitantly or sequentially, to the treatment regimen acts synergistically with rifaximin to improve outcomes. According to our study, there were no statistical differences between the two regimens. In conclusion, the extension of probiotics in the sequential regimen provided a more prolonged clinical response rate.

Prolonged clinical response is possible with regorafenib in refractory osteosarcoma: A case report

<b>Background:</b> Treatment options for metastatic unresectable osteosarcoma are limited, and there is no standard approach after the failure of first-line chemotherapy. Conventional chemotherapy in the second and subsequent lines typically yield a median progression-free survival (PFS) of less than 4 months, with objective response rates ranging from 3 to 29%. The activity of anti-vascular endothelial growth factor receptor multi-tyrosine kinase inhibitors (TKIs) in bone sarcomas has been demonstrated. We present a case of metastatic osteosarcoma exhibiting a durable response to regorafenib treatment.<br /> <b>Case: </b>We discuss a 30-year-old male with metastatic osteosarcoma who had extensive bone and lung metastases and was ineligible for metastasectomy. The patient had received all active chemotherapy regimens in the early and metastatic stages except ifosfamide. Next generation sequencing analysis of resected tumor tissue revealed a possibly pathogenic missense mutation (P.G472E) in NOTCH1 gene. Due to the presence of heart failure with a reduced ejection fraction, chemotherapy was not considered, and regorafenib was initiated. After four cycles of regorafenib, a partial metabolic response was achieved. The patient was followed up without progression under regorafenib for 15 months, without requiring dose reduction. Unfortunately, the treatment had to be interrupted for an extended period due to challenges with recurrent tumor infection and the necessity for repeated surgeries. Following successful wound site control, we restarted full-dose regorafenib and achieved a metabolic partial response again.<br /> <b>Conclusion: </b>To our knowledge, this case represents the longest achieved PFS with regorafenib in metastatic osteosarcoma. TKIs can provide a durable clinical response in metastatic osteosarcoma patients. Clinical and molecular biomarkers are required to determine which patients are most likely to benefit from these treatments.

Sustained depression of B cell counts in lupus nephritis after treatment with rituximab and/or belimumab is associated with fewer disease flares.

To study the risk of lupus nephritis flare (LNF) or severe lupus flare (SLF) as a function of B cell count kinetics in lupus nephritis (LN) patients after they achieve at least a partial renal response (PRR) with induction treatment that includes rituximab (RTX) and/or belimumab (BLM). We performed a retrospective analysis of a cohort of 19 patients with severe LN that received a B cell agent (BCA), RTX and/or BLM, as part of an initial treatment regimen for an LN flare and had subsequent CD19+ B cell measurements in peripheral blood. We then characterized the follow-up periods, after B cell depressions occurred and PRR were achieved, by the corresponding trajectories of B cell counts (BCC). Time periods with sustained low BCC were type 1 (T1) episodes, while those with repletion of BCC>100 cells/μL were called type 2 (T2) episodes. Time periods with rapid BCC repletion, defined as >50 cells/μL in ≤6months, were called T2b episodes. Corresponding C3, C4, and anti-dsDNA levels were recorded for each episode. The time from PRR until an event, either a LNF or SLF, or to censoring, either at the end of the study period or the end of available patient follow-up, was assessed for each episode type. Kaplan-Meier survival analysis was used to compare time to flare between T1 and T2 episodes. There were 26 episodes of B cell depression. Seventeen (65%) were T1 and 9 (35%) were T2. Compared to T1 episodes, T2 episodes were 9.0 times more likely to result in flare over the follow-up period (hazard ratio (HR) = 9.0, 95% CI for HR = 2.2-36.7); this risk was even larger for T2b vs T1 episodes. Median BCC was 14 cells/μL in T1 and 160 cells/μL in T2 episodes. Both C3 and C4 levels significantly increased over the duration of the episode in T1 episodes only. Sustained low BCC was associated with prolonged serologic and clinical response, whereas repletion, and particularly rapid repletion, of B cells after treatment with BCA was associated with subsequent disease flare.

Lenvatinib, gemcitabine, and oxaliplatin for 67 patients with fibrolamellar carcinoma.

e16151 Background: Fibrolamellar Carcinoma (FLC) is a rare form of primary liver cancer affecting teenagers and young adults without any underlying liver disease. It typically presents at an advanced stage with a mix of symptoms attributed to other causes. Currently R0 resection is the only cure. One-half of patients are unresectable at presentation with short life expectancies. An effective neoadjuvant therapy that could increase resectable patients and a sustained response. Although a few FLC-specific clinical trials have been ongoing for several years, there are no published results yet, nor expected for several years. Gemcitabine-oxaliplatin-lenvatinib (GOL) was selected based on case reports of GO success and trials using GO with sorafenib (SOR), but with LEN substituted for SOR based on superior efficacy and lower toxicity. This the largest cohort of FLC patients receiving the same systemic therapy reported. Methods: After approval (#IRB00003999) and consent (NCT03793088), data was collected on all GOL subjects from April 15, 2019 to Jan. 31, 2024. Response was measured using RECIST 1.1 and volume estimates. Results: Sixty-five GOL courses, 60 patients (30F), 5 retreated, median age at diagnosis/start of GOL (19/21), 58 unresectable, previous surgeries/relapses/therapies (1/2/2), stage I/II/III/IV (0/1/4/60) were given GOL cycles (median 10) of G:1000mg/m2,O:100mg/m2,L:8mg daily, 98% neoadjuvantly. Excluding the 14 on GOL, 3 with planned and 3 who refused surgery, 28 of 39 (72%) have had surgery (R0=20, R2=6, transplant=2), leaving 11 still unresectable. Twelve had > 6 lymph nodes examined with 75% showing < 1 positive for microscopic disease. The median time to best response was 4.7 months and 9.8 cycles with RECIST and volume best responses of: -21% and -41%. Complete/partial/stable/progressive responses by RECIST and volume were 1/12/45/1 and 2/18/38/1, for an overall response/disease control rate of: 22% / 98% and 34%/97%. Circulating DNA prospectively followed had an average drop of -93%, with one-third achieving 0.0 at completion of GOL. The 6,12,18 and 24 month overall survival from the start of GOL is (%): 97/87/73/65. To date, 38 have failed GOL, including: death (37%), infection (5%), or alive post relapse (19%) at a median time from start of GOL of 12 months. Although these are high-risk patients (median 3 relapses) 67% had their longest disease-free interval. The most common toxicities were neuropathy (39%), cytopenias (10%), and nausea (10%), mostly (95%) NIH grade 1 or 2. Conclusions: Our retrospective study of high-risk FLC, most multiply relapsed, pretreated, stage 4 and unresectable, showed that a prolonged and meaningful clinical response and acceptable quality of life with a chance for curative surgery is possible for many young patients thought to be incurable. Prospective trials are needed to confirm these results.

Immune-Related Adverse Events Due to Cancer Immunotherapy: Immune Mechanisms and Clinical Manifestations.

The landscape of cancer treatment has undergone a significant transformation with the introduction of Immune Checkpoint Inhibitors (ICIs). Patients undergoing these treatments often report prolonged clinical and radiological responses, albeit with a potential risk of developing immune-related adverse events (irAEs). Here, we reviewed and discussed the mechanisms of action of ICIs and their pivotal role in regulating the immune system to enhance the anti-tumor immune response. We scrutinized the intricate pathogenic mechanisms responsible for irAEs, arising from the evasion of self-tolerance checkpoints due to drug-induced immune modulation. We also summarized the main clinical manifestations due to irAEs categorized by organ types, detailing their incidence and associated risk factors. The occurrence of irAEs is more frequent when ICIs are combined; with neurological, cardiovascular, hematological, and rheumatic irAEs more commonly linked to PD1/PD-L1 inhibitors and cutaneous and gastrointestinal irAEs more prevalent with CTLA4 inhibitors. Due to the often-nonspecific signs and symptoms, the diagnosis of irAEs (especially for those rare ones) can be challenging. The differential with primary autoimmune disorders becomes sometimes intricate, given the clinical and pathophysiological similarities. In conclusion, considering the escalating use of ICIs, this area of research necessitates additional clinical studies and practical insights, especially the development of biomarkers for predicting immune toxicities. In addition, there is a need for heightened education for both clinicians and patients to enhance understanding and awareness.

Ivosidenib for Patients with Clonal Cytopenia of Undetermined Significance and Mutations in IDH1

Background Myeloid neoplasms (MN), including acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS), are hematologic malignancies that are highly resistant to therapy and confer a poor prognosis. Recent studies have revealed that hematopoietic stem cells and progenitor cells carrying preleukemic mutations, defined as clonal hematopoiesis (CH), are the cells of origin in MN. CH can occur many years before the diagnosis of MN. Multiple mutations, mutations with a high variant allele frequency (VAF), and mutations in TP53, spliceosome genes, and isocitrate dehydrogenase 1/2 ( IDH1/2) have been identified as high-risk features for CH progression to MN. Individuals with cytopenias who harbor acquired mutations in their blood yet do not meet criteria for hematologic malignancy, an entity called clonal cytopenia of undetermined significance (CCUS), have an even higher risk of developing MN (estimated at 95% over 10 years of follow-up). Thus, despite being almost inevitably destined for progression to malignancy, there are no established preventative therapies for patients with CCUS. The IDH1 inhibitor ivosidenib has been extensively evaluated in clinical studies and has been shown to effectively inhibit the gain-of-function activity of the mutated protein. Clinical data has shown that ivosidenib is safe and well-tolerated with excellent response rates even in patients with relapsed or refractory AML. Individuals with lower co-mutational burden are more likely to have a clinical response and achieve molecular remission with ivosidenib. Since CCUS is characterized by a lower mutation burden compared to AML or MDS, we hypothesize that the use of ivosidenib in IDH1-mutant CCUS will result in a higher and more prolonged clinical response. Study Design and Methods NCT05030441 is a decentralized open label, multicenter pilot study exploring the efficacy of ivosidenib in patients with IDH1-mutant CCUS. The study is offered as a decentralized trial (DCT) where patients across the US can participate with study procedures occurring in the patient's home using telemedicine, mobile phlebotomy services and with local providers. By reducing barriers to trial participation, we expect that the DCT design will improve accessibility for this rare patient population. This represents an important step toward making personalized medicine available to a socio-economically diverse patient population and enables rare mutations to be studied at scale. Patients with CCUS harboring the IDH1 R132 mutation are considered eligible if they do not have any concurrent active malignancy requiring treatment. Patients must have unexplained cytopenia lasting ≥6 months, defined as hemoglobin <10 g/dL, absolute neutrophil count <1.8 × 10 9/L and platelets <100 × 10 9/L, as well as adequate baseline organ function including renal and liver function, as per the National Institutes of Health Common Terminology Criteria for Adverse Events (NCI CTCAE) grading. Recruitment and data collection will be coordinated with local providers for patients that enroll remotely. A total of 15 patients will be accrued to receive ivosidenib 500 mg daily for up to 18 cycles. The primary endpoint is rate of improvement in hematologic parameters using specific cutoffs for erythroid, platelet and neutrophil responses based on the MDS response criteria. The study will be considered positive if at least 6 out of the 15 patients have a hematologic improvement. Secondary endpoints include change in mutant IDH1 VAF, measured at baseline and every 3 cycles on peripheral blood samples, safety of ivosidenib, and AML/MDS-free survival which will be evaluated by descriptive statistics and Kaplan-Meier methodology. Enrollment opened in one US center and by decentralized structure in April 2022, with 3 patients accrued, and is expected to open in other US centers in 2023. If the study endpoints are met, our aim is to expand to a larger population with the goal of determining whether ivosidenib can prevent the development of hematologic malignancy in patients with IDH1-mutant CCUS.

Mogamulizumab for Refractory CD3-CD4+ Lymphocytic-Variant Hypereosinophilic Syndrome

OCS Introduction. Lymphocytic hypereosinophilic syndrome (L-HES) is an indolent T-cell lymphoproliferative disorder characterized by chronic blood hypereosinophilia and eosinophil-related organ damage secondary to the production of eosinophilopoietic cytokines (including interleukin-5) by clonal T cells, among which CD3-CD4+ T cells are the most frequent subset. Both high exposure to oral corticosteroids (OCS), failure and/or toxicity of OCS-sparing therapies and the risk of progression to AITL (up to 5 - 10% of patients) underscore the unmet need for novel treatments targeting the clonal T-cells (and not only eosinophils). We previously reported that peripheral CD3-CD4+ T cells express C-C chemokine receptor 4 (CCR4). We hypothesized that mogamulizumab, an afucosylated monoclonal antibody targeting CCR4-positive cells through antibody-dependent cellular cytotoxicity, could be beneficial for refractory L-HES patients. Methods. We assessed both the expression of CCR4 by clonal CD3-CD4+ T cells in the skin and lymph nodes as well as theability of mogamulizumab to induce ADCC in vitro on sorted CD3-CD4+ T cells from two L-HES patients, using homologous sorted NK cells as effector cells. We then set up a compassionate use program of intravenous mogamulizumab (1.0 mg/kg weekly for the first 28-day cycle, then on days 1 and 15 from subsequent cycles) for refractory L-HES patients despite treatment with immunosuppressants and/or biologics targeting the IL-5 pathway. Complete blood response was defined as complete if the subset of CD3-CD4+ T cells was <0.5% of all lymphocytes, or as partial if the number of CD3-CD4+ T cells decreased by >50% without reaching complete response at the time of the last perfusion. Results. Significant CCR4 expression on tissue CD4+ T cells was evidenced, and NK cells indeed led to the lysis of CD3-CD4+ T-cells coated with mogamulizumab (10 μg/ml). Four patients with refractory L-HES (despite treatment with high-dose OCS, n=4; pegylated interferon alpha 2a; n=3; or mepolizumab, a single patient) and active disease entered the compassionate use program (Table 1). Despite substantial tapering in OCS doses, all cases showed clinical response. Blood responses (either partial or complete, two patients each) and sharp decrease in absolute eosinophil counts (AEC) were reported in all patients ( Figure 1). Both patients with lymph node enlargement rapidly improved. Although prolonged blood and clinical responses have been observed after discontinuation of mogamulizumab, relapses still occurred preceded by an increase in T-cell clone size and absolute eosinophil count (AEC). Rechallenging a relapse with a short course of mogamulizumab resulted in a complete remission for a further 12 months in case #1. In terms of safety, mogamulizumab was discontinued in two patients due to adverse events: one for recurrent infusion-related reactions and one for infectious events. Lymphopenia was reported in 3/4 cases but was preexisting in the 3 cases. Case #4 reported a serious adverse event related to a tumor lysis syndrome leading to the massive release of IL-5 and subsequent rebound of AEC. Hence lower doses of mogamulizumab, transient use of OCS and/or mepolizumab should be considered in patients with very high number of CD3-CD4+ T cells who are about to start mogamulizumab. Discussion. Mogamulizumab represents a new therapeutic option for L-HES patients with severe refractory HES, T-cell clone related symptoms and/or large or rapidly increasing clonal T-cell counts. In patients who achieve complete remission under mogamulizumab, whether fixed repeated (e.g., every 6 months) infusions could be beneficial to prevent relapses and transformation into high-grade lymphoma remains to be investigated. Figure legend. Hematological responses to mogamulizumab in four refractory lymphocytic HES patients. oral corticosteroids; pINF-α: pegylated interferon alpha; MEPO: mepolizumab; MOGA: mogamulizumab.

An Allogeneic Multiple Myeloma GM-CSF-Secreting Vaccine with Lenalidomide Induces Long-term Immunity and Durable Clinical Responses in Patients in Near Complete Remission.

This proof-of-principle clinical trial evaluated whether an allogeneic multiple myeloma GM-CSF-secreting vaccine (MM-GVAX) in combination with lenalidomide could deepen the clinical response in patients with multiple myeloma in sustained near complete remission (nCR). Fifteen patients on lenalidomide were treated with MM-GVAX and pneumococcal conjugate vaccine (PCV; Prevnar) at 1, 2, 3, and 6 months. Eight patients (53.3%) achieved a true CR. With a median follow-up of 5 years, the median progression-free survival had not been reached, and the median overall survival was 7.8 years from enrollment. MM-GVAX induced clonal T-cell expansion and measurable cytokine responses that persisted up to 7 years in all patients. At baseline, a higher minimal residual disease was predictive of early relapse. After vaccination, a lack of both CD27-DNAM1-CD8+ T cells and antigen-presenting cells was associated with disease progression. MM-GVAX, along with lenalidomide, effectively primed durable immunity and resulted in long-term disease control, as suggested by the reappearance of a detectable, fluctuating M-spike without meeting the criteria for clinical relapse. For patients in a nCR, MM-GVAX administration was safe and resulted in prolonged clinical responses.

Fractional carbon dioxide laser versus carbon-assisted Q-switched Nd: YAG laser in the treatment of dilated facial pores.

The treatment of dilated facial pores is difficult, and the ideal modality is not established yet. Different ablative and nonablative lasers have been used in the treatment of dilated pores with variable outcomes. To evaluate and compare the efficacy of fractional CO2 laser versus carbon-assisted Q-switched Nd: YAG laser in dilated facial pores. The study included 80 patients with dilated pores divided into two groups each containing 40 patients. Group (A) had fractional CO2 laser treatment, and group (B) received Q-switched Nd: YAG laser treatment after the application of a carbon solution on the face. The treatment was repeated monthly for a total of 3 sessions. Objective and subjective assessments of the clinical outcome were performed. Both modalities significantly improved the dilated pores; however, the clinical response was statistically higher and the improvement was maintained for a longer duration of time in the factional laser group compared with the carbon-assisted Q-switched Nd: YAG laser group (p=0.01). The downtime was significantly lower in the Q-switched Nd: YAG laser group, and the patients' satisfaction rates were comparable in both groups. The two laser systems appear to be effective, safe, and well-tolerated in the treatment of dilated pores. The fractional CO2 laser was associated with a significantly higher and more prolonged clinical response.

Negative Minimal Residual Disease Associated with Extended Response to Moxetumomab Pasudotox in Patients with Relapsed/Refractory Hairy Cell Leukemia: Long-Term Follow-up of Bone Marrow Immunohistochemistry Analyses from a Phase 1 Study

The clinical significance of minimal residual disease (MRD) in patients with relapsed/refractory hairy cell leukemia (r/r HCL) who have achieved complete response (CR) has not been demonstrated. In other hematologic malignancies, MRD eradication may be associated with prolonged clinical response (Hourigan et al. Leukemia 2017;31:1482-90; Lahuerta et al. J Clin Oncol 2017;epub ahead of print). Moxetumomab pasudotox (formerly CAT-8015), a recombinant immunotoxin fusion protein that specifically binds to B lymphocyte-specific surface antigen CD22, has been shown by flow cytometry to eradicate MRD in a significant (P= 0.04) percentage of patients with r/r HCL (Kreitman et al. ASCO 2015). However, a detailed study of MRD by bone marrow immunohistochemistry (IHC) was not previously presented. We analyzed data from a phase 1 dose escalation study of moxetumomab pasudotox in r/r HCL patients to test the hypothesis that eradication of MRD in bone marrow, assessed by IHC, may be associated with prolonged remission.CAT-8015-1001 (NCT00586924) was a phase 1 study evaluating the safety and efficacy of moxetumomab pasudotox in patients with r/r HCL who previously had received at least 2 courses of treatment, at least 1 of which included a purine analog; initial results from the dose escalation phase in 28 patients have been reported (Kreitman et al. J Clin Oncol 2012;30:1822-8). Moxetumomab pasudotox was administered on days 1, 3, and 5 of each 28-day cycle until 2 cycles past complete remission (CR), disease progression, unacceptable toxicity, or neutralizing antibodies. In the dose escalation phase, 28 patients received moxetumomab pasudotox 5, 10, 20, 30, 40, or 50 µg/kg. An additional 21 patients were enrolled in the 50-µg/kg cohort.Bone marrow samples were obtained at baseline and at multiple time points during and after treatment. A central pathology laboratory performed hematoxylin and eosin and IHC staining for HCL/B-cell antigens CD20, CD79a, Annexin A1, DBA.44, and PAX-5. A blinded independent central pathologist reviewed (BICR) and assessed stained slides as IHC MRD+ or IHC MRD− for each time point.The best BICR IHC MRD response was compared with the best investigator-reported (IR) disease response. Duration of CR, duration of response (DOR), progression-free survival (PFS), and overall survival were evaluated for patients with a best response of BICR IHC MRD+ vs MRD−.Thirty-seven patients were evaluated for BICR IHC MRD; posttreatment bone marrow biopsies were not available for 11 patients, and biopsies from one patient were non-evaluable. The BICR IHC MRD status appears to be associated with the IR response; 17 of 18 BICR IHC MRD− patients had a best response of CR vs 9 of 19 MRD+ patients. Among patients found to be BICR IHC MRD− at 1 or more posttreatment evaluations, median duration of CR and median PFS were not reached after 84 months of follow-up vs 13.08 and 82.07 months, respectively, for patients who were consistently MRD+ at all time points. DOR was 82.7 vs 54.7 months for the BICR IHC MRD− and MRD+ groups, respectively.Cladribine monotherapy and cladribine followed by rituximab eliminated IHC MRD in some newly diagnosed HCL patients (Sigal et. al, Blood 2010;115:1893-6; Ravandi et. al Blood 2011;118:3818-23). Although vemurafenib demonstrated 96% to 100% overall response rates and 35% to 42% CR rates in patients with r/r HCL, all CR patients were IHC MRD+, and duration of MRD+ CRs was 19 months (Tiacci et al. N Engl J Med 2015;373:1733-47). Moxetumomab pasudotox is, to our knowledge, the only non-chemotherapy regimen shown to eradicate MRD in a meaningful percentage of patients with r/r HCL. Here, BICR findings confirmed elimination of IHC MRD in 49% of evaluable patients. MRD− patients experienced a statistically significantly longer duration of CR (P=0.0002) and PFS (P=0.0031) vs MRD+ patients.Based on the results of this retrospective analysis, together with observations made in the vemurafenib study, BICR IHC MRD− vs MRD+ status is associated with extended DOR and PFS in patients with r/r HCL treated with moxetumomab pasudotox. If this finding can be replicated in additional clinical studies, including the phase 3 pivotal study of moxetumomab pasudotox, IHC MRD determinations may be useful in evaluating the efficacy of therapies in the r/r HCL population. [Display omitted] DisclosuresKreitman:NIH: Patents & Royalties: Co-inventor on pending Moxetumomab Pasudotox patent owned by NIH. Robak:Akari Therapeutics Plc: Research Funding; Pharmacyclics LLC, an AbbVie Company: Research Funding; Janssen: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Research Funding. Coutre:Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding; Janssen: Consultancy; Novartis: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Gilead: Consultancy, Research Funding. Marshall:MedImmune: Employment. Yang:MedImmune: Employment, Equity Ownership, Other: Travel expenses. Pastan:NIH: Patents & Royalties: Pastan is an inventor on several patents on immunotoxins that have all been assigned to the NIH. Yao:MedImmune: Employment, Equity Ownership.

Inflammatory bowel disease in Hermansky-Pudlak syndrome: a retrospective single-centre cohort study.

Knowledge about inflammatory bowel disease (IBD) in patients with Hermansky-Pudlak syndrome (HPS), a rare autosomal recessive disorder characterized by defective biogenesis of lysosome-related organelles, could provide insights into IBD in general. To expand the understanding of IBD in patients with HPS. Retrospective review of records from patients with HPS evaluated at the National Institutes of Health Clinical Center from 1995 to 2019 was conducted. Clinical features of IBD, genotyping results and histologic findings of colectomy specimens were analysed. IBD affected 37 (14.2%; 12 male, 25 female) of 261 patients with HPS. Median age of onset was 17years; range was 1 to 52years. The most common symptoms of HPS IBD were hematochezia, abdominal pain and loose stools. Fistulae or extra-intestinal manifestations developed in 30% or 22%, respectively. Genotyping showed that patients with biallelic variants in HPS1, HPS3, HPS4 or HPS6 were diagnosed with IBD. Six children had very early-onset IBD. Patients with HPS-3 had mild manifestations of IBD. Medical therapy and bowel resection were utilized to treat 73% and 35% of patients with HPS IBD, respectively; 7 of 13 patients receiving anti-tumor necrosis factor alpha therapy had prolonged clinical responses. Active cryptitis, chronic inflammatory changes, granulomas and ceroid lipofuscinosis were histopathologic findings in three colectomy specimens. IBD resembling Crohn's disease affects some patients with HPS; genetic heterogeneity is a feature of HPS IBD. HPS3 is a new gene associated with human IBD. Very early-onset IBD can develop in HPS.

Tumor Associated Antigen Specific T Cells Given in Combination with Nivolumab for the Treatment of Hodgkin Lymphoma

Background: Hodgkin Lymphoma (HL) Reed Sternberg cells express tumor associated antigens (TAA) that are potential targets for cellular therapies. We recently demonstrated that TAA specific T cells (TAA-T) targeting WT1, PRAME and Survivin were safe and associated with prolonged time to progression in solid tumors (Hont JCO 2019). Hence, we evaluated whether TAA-T cells are safe and elicit anti-tumor effects in patients with relapsed/refractory (rel/ref) HL. We further evaluated the safety of Nivolumab following the TAA-T infusion and its effect on the persistence of the TAA-T cells in vivo. Methods: TAA-T products were generated from patients or healthy donors on 2 trials (NCT02203903; NCT03843294). Thirteen patients underwent procurement for product generation and 10 patients (2 allogeneic; 8 autologous) were infused TAA-T for rel/ref HL or as consolidation after autologous hematopoietic stem cell transplant (HSCT) at cumulative doses ranging from 0.5 X107 to 4 X107cells/m2. Patients were monitored for six weeks for safety and for response until disease progression. Seven patients received Nivolumab starting at 8 weeks after the first TAA-T infusion until disease progression or unacceptable toxicity. Results: TAA-T products (n=10) were polyclonal CD3+ T cells (Median 97%; 80.9-99.5%), comprised predominantly of CD4+ helper T cells (Median 10.5%; 1.74-20%) and CD8+ cytotoxic T cells (Median 70%; 29.3-87.5%). Specificity of TAA-T products was tested using Interferon-ϒ(INFϒ)-enzyme-linked immunospot (ELIspot) assay and defined as ≥ 2x spot-forming cells (SFC)/2.5X105cells against the tumor antigen as compared to irrelevant control antigen Actin(Figure 1). The median TAA specificity of the products was 2 antigens (range 0-3). All products were polyfunctional secreting INF-ϒ and TNF-α upon restimulation with tumor antigens (Fig 1). Median age of patients was 36yrs (range16-53). Patients had received a median 6 lines of therapy including HSCT prior to receiving TAA-T. Median follow-up post TAA-T#1 was 6 months (range 32 days-2.5yrs). There were no dose limiting toxicities observed within the 6 week safety monitoring period. In patients receiving Nivolumab post TAA-T, there were no increased immune related events over expected. One patient had Grade 3 seizures, possibly related to Nivolumab, 2 patients developed hypothyroidism requiring thyroid supplements and one patient developed myositis and discontinued Nivolumab after 5 months. The 2 patients who received TAA-T (1 donor derived and one autologous) as consolidation post HSCT achieved a continued complete remission (CCR) for 2+ years. Of the 8 patients with rel/ref HL at the time of infusion, 1 had disease progression at 6 weeks. He then received Nivolumab off protocol and achieved complete remission (CR) but developed Grade 4 GVHD. The remaining 7 patients had stable disease (SD) at 6 weeks. At a median follow-up of 6 months (32 days-2.5 years), 1 patient had progressive disease(PD) at 3 months, 1 patient had a complete metabolic response at 6 months and proceeded to allogeneic HSCT for definitive cure. 2 patients had PD at 6 months and the other 2 patients continue with SD at 6 months and remain on Nivolumab (Fig 1). All patients with objective responses (stable disease or better) recovered functional TAA-T cells in the peripheral blood at 3 months as detected by anti-Interferon-ϒ ELISPOT and reported as mean SFC/1 X105 cells for WT1(14±SD18.1); PRAME (17.4±15.3) and Survivin (4.5±7) compared to those with progressive disease with mean SFC/1 X105 cells for WT1 1.4(±2.3); PRAME (6.7±15.5) and Survivin (0.8±1.2). To evaluate TAA-T persistence, unique T cell receptor clonotypes defined in the TAA-T product and not present at baseline were detected in the peripheral blood 6 weeks post TAA-T, long-term persistence data and evaluating the effect on the TCR repertoire when adding nivolumab are pending. Conclusion: TAA-T cells given in combination with Nivolumab were safe when administered to patients with rel/ref HL with prolonged clinical responses (ranging from SD to CCR) observed in multiply relapsed patients. Disclosures Glenn: Genentech: Research Funding. Hanley:Mana Therapeutics: Honoraria, Other: Board Member; Cellevolve: Honoraria, Other: Board(Scientific Advisory Board). Bollard:Mana Therapeutics: Other: IP.

Response of mTOR inhibitor associated with mutation of FBXW7 gene identified by comprehensive genomic profiling in cervical squamous cell carcinoma supports additional therapy opportunity for select patients with treatment-refractory, recurrent disease

Objective: More than 90% of patients with recurrent cervical squamous cell carcinoma (cSCC) die within 5 years. We describe 2 cases of prolonged clinical response of advanced recurrent cSCC to mTOR inhibitor (mTORi) monotherapy after genomic tumor testing indicated susceptibility. The FoundationOne tumor genomic database was queried to identify the frequency of such mutations in advanced cSCC.

P0283LONG-TERM FOLLOW-UP OF CRYOGLOBULINEMIC SYNDROME WITH RENAL INVOLVEMENT AFTER DAA

Background and Aims To date, the literature shows that HCV eradication with DAA leads to remission from HCV-related cryoglobulinemic syndrome (CS). The goal of our study is to evaluate the effect of DAA treatment on cryoglobulinemic kidney disease. Method Since 2015, 58 patients (pts) have been treated in our Centre; among them we have selected 12 pts with active kidney disease at the time of treatment. Clinical manifestations, renal function and immunological tests were monitored during follow-up (range 6-48 months). Results General characteristics of the population are shown in Table 1. At the time of treatment 6 pts had nephritic syndrome (sdr), 1 had nephrotic sdr and 5 pts had mixed nephritic-nephrotic sdr. It should be noted that 8/12 pts had been treated with Rituximab (RTX) in the 6 months preceding the DAA; despite that they had active disease at baseline. Ten out of 12 pts went into complete remission after HCV-eradication, 1 went into partial remission. One pt, never treated, did not respond clinically to HCV eradication and therefore underwent RTX therapy. Other 2 pt with a recent diagnosis of cryoglobulinemic syndrome came to our attention with a clinical picture of nephritic sdr: they’d never been treated with immunosuppressive therapy and get remission only whit HCV eradication. One pt, although complete CS remission, started hemodialysis for ESRD secondary to ADPKD. During follow-up 3 pts underwent CS relapse: 2 pts, one with lymphoma, were retreated with RTX after 12 and 48 months respectively; 1 pt, with type I cryoglobulinemia and clinical manifestation of vasculitis, died of acute disease reactivation in Cameroon after 9 months from the end of DAA. By evaluating the overall population there is a rapid and prolonged clinical response to DAA therapy, in particular a complete resolution of skin ulcers (Tab 2). Cryocrit decreases and C3 and C4 increase early and persistently after treatment; vice versa the rheumatoid factor does not undergo significant variations. Proteinuria is reduced at the end of the treatment (EOT) and shows a decreasing trend also afterwards; urinary sediment is drastically reduced at EOT and further decreases during follow-up up to the presence of only isolated urinary anomalies in almost all patients (Tab 3). Conclusion The eradication of HCV, and therefore the removal of the immunological stimulus underlying the cryogloblinemic syndrome, appears to be crucial in the control of cryoglobulinemic glomerulonephritis, also after failure of RTX treatment. However, relapses at variable interval from DAA therapy do not allow us to lose these patients to follow-up even after several years from disease remission.

SUN-440 RENAL DISEASE PRESENTATION IN MIXED CRYOGLOBULINEMIA TYPE 2 A CASE REPORT AND A LITERATURE REVIEW

Mixed cryoglobulinemia (MC) results of cryoprecipitable immunocomplexes. In type II MC, a combination of polyclonal and monoclonal immunoglobulin is found. Renal involvement (RI) is one of the most serious complications in MC and may affect the overall prognosis. Case presentation: A diagnosis of essential mixed cryoglobulinemia (EMC) was established in a 36-year-old female patient. Eight years earlier, shedevelopedpurpuraof the lower extremities, arthralgia, peripheral neuropathy andpulmonary renal syndrome. A skin biopsy revealed a leukocytic vasculitis.A mixed cryoglobulin and hypocomplementemia were found. Urinary protein excretion was at 12 g per 24h. Initial treatment included pulse methylprednisolone followed by prednisone (1 mg/kg daily). Despite the clinical improvement in the renal disease, palpable purpuric lesions with arthralgia recurred periodically. So methotrexate was introduced but was rapidly interrupted owing to liver toxicity. On June 2019, she was admitted for pneumonia. An outbreak of her disease with dermal, peripheral nerve and renal involvement was objectified. Urinary protein excretion was at 3 g per 24h. A mixed cryoglobulin with monoclonal IgM Kappa and polyclonal immunoglobulin persisted. A Renal biopsy (RB) was done in July 2019, revealed diffuse endocapillary proliferation with granular IgM, C3 deposits. Plasmapheresis with twice exchanges per weak was conducted. Five days after the initiation of therapy, her purpura disappeared and serum complement values returned to normal. Review of the literature: The results of a long-term prospective, randomized controlled trial of rituximab (RTX) monotherapy in patients with cryoglobulinemia vasculitis (CV). RTX was found to be superior to standard immunosuppressive therapy for severe CV over the long term. A multicenter retrospective study included 14 patients with EMC who were successfully treated with lenalidomide. A study, included 21 patients with severe type II EMC unresponsive to immunosuppressive regimens, showed that IFN-a, as a single agent, is able to determine a response rate as high as 77%. A case report demonstrated that 2-Chlorodeoxyadenosine (2CdA) induced a dramatic and prolonged clinical response for a patient with progressive, symptomatic cryoglobulinemia, in whom corticosteroid and alkylating therapy failed. Some studies suggest that plasma exchange alone might be indicated in the treatment of a rapidly progressive glomerulonephritis complicating MC. We presented this case of EMC with renal involvement. The clinical presentation is characterized by a normal kidney function without nephrotic syndrome with membranoproliferative glomerulonephritis (MPGN) at the renal biopsy. This case reveals the importance of RB for the diagnosis of MPGN even in front of an atypical clinical picture.

1224P - Phase Ib, open-label, dose-escalation study of M9241 (NHS-IL12) plus avelumab in patients (pts) with advanced solid tumours

BackgroundM9241 is a tumor-targeting immunocytokine composed of IL-12 heterodimers fused to a monoclonal antibody targeting DNA in necrotic tumor regions. Avelumab is a human anti–PD-L1 IgG1 monoclonal antibody with clinical activity in various tumor types. Preclinical data predicted a potential drug-drug interaction (DDI) between M9241 and avelumab. We report an interim analysis of safety and PK/PD from the dose-escalation part of JAVELIN IL-12 (NCT02994953), a phase Ib study of M9241 and avelumab in pts with locally advanced, unresectable, or metastatic solid tumors. MethodsAt data cutoff (20 Aug 2018), 29 pts in dose levels (DLs) 1-4 received M9241 4, 8, 12, or 16.8μg/kg SC every 4 weeks (Q4W) and avelumab 10mg/kg IV every 2 weeks (Q2W). Three pts in DL5 received 12-week induction with avelumab 800mg IV once weekly (Q1W) and M9241 16.8μg/kg SC Q4W and then continuation treatment with avelumab 800mg IV Q2W and M9241 16.8μg/kg SC Q4W. The primary endpoint was overall safety and dose-limiting toxicities (DLTs). ResultsDLs 1-4 were well tolerated. One DLT occurred at DL3 (grade 3 autoimmune hepatitis), but no DLTs occurred at other DLs. Maximum tolerated dose was not reached. PK analyses suggested a DDI at DLs 1-4, evidenced by decreased avelumab exposure concurrent with increased IFN-γ levels; therefore, DL5 was introduced. At DL5, PK data showed no evidence of a DDI. DL5 was also well tolerated and showed a similar safety profile to DL4, with treatment-emergent adverse events limited to grade 1/2. Prolonged clinical responses (CR/PR) were seen, including in a checkpoint inhibitor–refractory pt. ConclusionsCombining avelumab 800mg IV Q1W and M9241 16.8μg/kg SC Q4W as 12-week induction followed by avelumab 800mg IV Q2W and M9241 16.8μg/kg SC Q4W as continuation treatment had an acceptable safety and tolerability profile and was therefore declared as recommended phase II dose (RP2D). The observed DDI is likely driven by M9241-mediated IFN-γ induction, causing PD-L1 upregulation in the periphery and tumor and target-mediated clearance of avelumab. Based on available data, this DDI mechanism is likely saturated at the RP2D. This trial continues recruitment into expansion cohorts at the RP2D. Clinical trial identificationNCT02994953. Editorial acknowledgementClinicalThinking, funded by Merck Healthcare KGaA and Pfizer Inc. Legal entity responsible for the studyMerck Healthcare KGaA. FundingMerck Healthcare KGaA and Pfizer Inc. DisclosureJ. Strauss: Research grant / Funding (institution): EMD Serono; Licensing / Royalties, Patent: dual blockade of PD-L1 and TGF beta for HPV+ cancer: Not applicable. Y. Vugmeyster: Full / Part-time employment: EMD Serono; Shareholder / Stockholder / Stock options: EMD Serono; Shareholder / Stockholder / Stock options: Alexion; Licensing / Royalties: EMD Serono; Licensing / Royalties: Wyeth; Licensing / Royalties: Pfizer. M. Sznol: Advisory / Consultancy: Bristol-Myers Squibb; Advisory / Consultancy: Genentech/Roche ; Advisory / Consultancy: AstraZeneca/MedImmune ; Advisory / Consultancy: Kyowa Hakko Kirin ; Advisory / Consultancy: Nektar; Advisory / Consultancy: Novartis; Advisory / Consultancy: Lilly; Advisory / Consultancy: Merck Sharp & Dohme; Advisory / Consultancy: Biodesix; Advisory / Consultancy: Adaptimmune; Advisory / Consultancy: Theravance; Advisory / Consultancy: Modulate Pharma; Advisory / Consultancy: Omniox; Advisory / Consultancy: Seattle Genetics; Advisory / Consultancy: Inovio Pharmaceuticals; Advisory / Consultancy, Shareholder / Stockholder / Stock options: Torque; Shareholder / Stockholder / Stock options: Amphivena Therapeutics; Shareholder / Stockholder / Stock options: Intensity Therapeutics; Shareholder / Stockholder / Stock options: Adaptive Biotechnologies ; Shareholder / Stockholder / Stock options: Actym Therapeutics; Advisory / Consultancy: Pierre Fabre; Advisory / Consultancy: Newlink Genetics; Advisory / Consultancy: Molecular Partners; Advisory / Consultancy: Genmab; Advisory / Consultancy: AbbVie; Advisory / Consultancy: Allakos; Advisory / Consultancy: Hinge; Advisory / Consultancy: Symphogen; Advisory / Consultancy: Pieris Pharmaceuticals; Advisory / Consultancy: Gritstone Oncology; Advisory / Consultancy: Innate Pharma; Advisory / Consultancy: Celldex; Advisory / Consultancy: Incyte; Advisory / Consultancy: Almac Diagnostics; Advisory / Consultancy: immunocore; Advisory / Consultancy: Array BioPharma. R.K. Pachynski: Advisory / Consultancy: EMD Serono; Advisory / Consultancy: Bristol-Myers Squibb; Advisory / Consultancy: Pfizer; Advisory / Consultancy: Sanofi; Advisory / Consultancy: Jounce Therapeutics; Speaker Bureau / Expert testimony: Dendreon; Speaker Bureau / Expert testimony: Merck; Speaker Bureau / Expert testimony, Travel / Accommodation / Expenses: Genentech/Roche; Speaker Bureau / Expert testimony: AstraZeneca; Speaker Bureau / Expert testimony: Sanofi; Speaker Bureau / Expert testimony: Genomic Health; Research grant / Funding (institution): Janssen Oncology. K. Trang: Travel / Accommodation / Expenses, Shareholder / Stockholder / Stock options, Full / Part-time employment: Merck KGaA/EMD Serono. S. Chennoufi: Full / Part-time employment: Merck KGaA. J.L. Gulley: Research grant / Funding (institution): EMD Serono; Research grant / Funding (institution): Bavarian Nordic; Research grant / Funding (institution): Astellas Medivation; Research grant / Funding (institution): Pfizer; Research grant / Funding (institution): NantBioScience, Inc.; Research grant / Funding (institution): Bristol-Myers Squibb; Research grant / Funding (institution): Merck.

P1.14-43 A Novel Patient Derived Synchronous Cell Pair with Different Mutations in an ALK-Rearranged Lung Adenocarcinoma Underlines Tumor Heterogeneity

ALK targeted therapy can provide prolonged clinical response rates in ALK-rearranged lung adenocarcinoma (ADC) patients. However, most tumors relapse within a few years of treatment pressure due to a variety of resistance mechanisms, including intratumoral heterogeneity. Understanding these mechanisms is of utmost importance to more precisely tailor future targeted therapies. We established a novel synchronous ALK-translocated lung ADC cell pair from the malignant pleural effusion (PF240-PE) and the pleural carcinosis (PF240-PC) of a 38-year-old female patient following sequential ALK targeted therapy. Immunohistochemistry and mutational analyses were executed in pleural carcinosis tissue specimens and in the tumor cell lines. SRB assays were performed for viability testings following different generations ALK inhibitor treatment alone and combined with SAHA, a pan-HDAC inhibitor. As positive control for all treatment lines we used PF521, another newly established ALK-rearranged but treatment naïve lung ADC cell line. In vivo tumorigenicity was evaluated by performing subcutaneous xenografts. We identified two distinct resistance mutations in both tissue specimens: a so far non-characterized E1161K and the already described L1152R. Strikingly, PF240-PC harbored E1161K and PF240-PE carried L1152R. Immunohistochemistry showed changes from epithelial/carcinomatous to mesenchymal/sarcomatous differentiation following resistance acquisition. In vitro testing revealed that both cell lines were significantly different in morphology and sensitivity to different generation ALK inhibitors including crizotinib, alectinib and lorlatinib. However, the novel tyrosine kinase inhibitor entrectinib was effective in both E1161K and L1152R mutant cells. Importantly, combination treatment of crizotinib or alectinib plus pan-HDAC inhibitor SAHA yielded strong synergism. Of note, both novel cell lines were highly tumorigenic in vivo. In vivo treatment response profiles are currently under evaluation. This is the first evidence of the synchronous establishment of two highly distinct patient-derived ALK translocated lung ADC cell lines carrying different resistant mutations. This concept supports the paramount significance of spatiotemporal intratumoral heterogeneity under targeted therapy. Furthermore, our findings showed that HDAC inhibition could enhance sensitivity of resistant tumor cells to ALK targeted therapy in vitro. Altogether, our findings provide strong evidence for the synchronous emergence of multiple resistance mechanisms and emphasize the importance of multiple site re-biopsies to better identify acquired resistance mechanisms under targeted therapy.

Intrinsic resistance to EGFR-Tyrosine Kinase Inhibitors in EGFR-Mutant Non-Small Cell Lung Cancer: Differences and Similarities with Acquired Resistance.

Activating mutations in the epidermal growth factor receptor gene occur as early cancer-driving clonal events in a subset of patients with non-small cell lung cancer (NSCLC) and result in increased sensitivity to EGFR-tyrosine-kinase-inhibitors (EGFR-TKIs). Despite very frequent and often prolonged clinical response to EGFR-TKIs, virtually all advanced EGFR-mutated (EGFRM+) NSCLCs inevitably acquire resistance mechanisms and progress at some point during treatment. Additionally, 20–30% of patients do not respond or respond for a very short time (<3 months) because of intrinsic resistance. While several mechanisms of acquired EGFR-TKI-resistance have been determined by analyzing tumor specimens obtained at disease progression, the factors causing intrinsic TKI-resistance are less understood. However, recent comprehensive molecular-pathological profiling of advanced EGFRM+ NSCLC at baseline has illustrated the co-existence of multiple genetic, phenotypic, and functional mechanisms that may contribute to tumor progression and cause intrinsic TKI-resistance. Several of these mechanisms have been further corroborated by preclinical experiments. Intrinsic resistance can be caused by mechanisms inherent in EGFR or by EGFR-independent processes, including genetic, phenotypic or functional tumor changes. This comprehensive review describes the identified mechanisms connected with intrinsic EGFR-TKI-resistance and differences and similarities with acquired resistance and among clinically implemented EGFR-TKIs of different generations. Additionally, the review highlights the need for extensive pre-treatment molecular profiling of advanced NSCLC for identifying inherently TKI-resistant cases and designing potential combinatorial targeted strategies to treat them.