Prospects in the management of patients with follicular lymphoma beyond first-line therapy

The management of patients with relapsed or refractory follicular lymphoma has evolved markedly in the last decade, with the availability of new classes of agents (phosphoinositide 3-kinase inhibitors, immunomodulators, epigenetic therapies, and chimeric antigen receptor T cells) supplementing the multiple approaches already available (cytotoxic agents, anti-CD20 antibodies, radiation therapy, radioimmunotherapy, and autologous and allogeneic transplants). The diversity of clinical scenarios, the flood of data derived from phase II studies, and the lack of randomized studies comparing treatment strategies preclude firm recommendations and require personalized decisions. Patients with early progression require specific attention given the risk of histological transformation and their lower response to standard therapies. In sequencing therapies, one must consider prior treatment regimens and the potential need for future lines of therapy. Careful evaluation of risks and expected benefits of available options, which vary depending on location and socioeconomics, should be undertaken, and should incorporate the patient’s goals. Preserving quality of life for these patients is essential, given the likelihood of years to decades of survival and the possibility of multiple lines of therapy. The current landscape is likely to continue evolving rapidly with other effective agents emerging (notably bispecific antibodies and other targeted therapies), and multiple combinations being evaluated. It is hoped that new treatments under development will achieve longer progression-free intervals and minimize toxicity. A better understanding of disease biology and the mechanisms of these different agents should provide further insights to select the optimal therapy at each stage of disease.

Combination Therapy for HIV-Associated Cryptococcal Meningitis—A Success Story

Cryptococcal meningitis is the leading cause of adult meningitis in patients with HIV, and accounts for 15% of all HIV-related deaths in sub-Saharan Africa. The mainstay of management is effective antifungal therapy, despite a limited arsenal of antifungal drugs, significant progress has been made developing effective treatment strategies by using combination regimens. The introduction of fluconazole as a safe and effective step-down therapy allowed for shorter courses of more fungicidal agents to be given as induction therapy, with higher doses achieving more rapid CSF sterilisation and improved treatment outcomes. The development of early fungicidal activity (EFA), an easily measured surrogate of treatment efficacy, has enabled rapid identification of effective combinations through dose ranging phase II studies, allowing further evaluation of clinical benefit in targeted phase III studies. Recent clinical trials have shown that shorter course induction regimens using one week of amphotericin paired with flucytosine are non-inferior to traditional two-week induction regimens and that the combination of fluconazole and flucytosine offers a viable treatment alternative when amphotericin is unavailable. Access to drugs in many low and middle-income settings remains challenging but is improving, and novel strategies based on single high dose liposomal amphotericin B promise further reduction in treatment complications and toxicities. This review aims to summarise the key findings of the principal clinical trials that have led to the success story of combination therapy thus far.

Clinical Studies on Ultrafractionated Chemoradiation: A Systematic Review

AimThe efficacy of low-dose fractionated radiotherapy (LDFRT) and chemotherapy (CHT) combination has large preclinical but little clinical evidence. Therefore, the aim of this review was to collect and analyze the clinical results of LDRT plus concurrent CHT in patients with advanced cancers.MethodsA systematic literature search was conducted on PubMed using the PRISMA methodology. Only studies based on the combination of LDFRT (< 1 Gy/fraction) and CHT were included. Endpoints of the analysis were tumor response, toxicity, and overall survival, with particular focus on any differences between LDFRT-CHT and CHT alone.ResultsTwelve studies (307 patients) fulfilled the selection criteria and were included in this review. Two studies were retrospective, one was a prospective pilot trial, six were phase II studies, two were phase I trials, and one was a phase I/II open label study. No randomized controlled trials were found. Seven out of eight studies comparing clinical response showed higher rates after LDFRT-CHT compared to CHT alone. Three out of four studies comparing survival reported improved results after combined treatment. Three studies compared toxicity of CHT and LDFRT plus CHT, and all of them reported similar adverse events rates. In most cases, toxicity was manageable with only three likely LDFRT-unrelated fatal events (1%), all recorded in the same series on LDFRT plus temozolomide in glioblastoma multiforme patients.ConclusionNone of the analyzed studies provided level I evidence on the clinical impact of LDFRT plus CHT. However, it should be noted that, apart from two small series of breast cancers, all studies reported improved therapeutic outcomes and similar tolerability compared to CHT alone. Systematic Review Registrationwww.crd.york.ac.uk/prospero/, identifier CRD42020206639.

Most ASH Abstracts Reporting Phase II Studies Lead to Peer-Reviewed Publications, but Less Than 50% of "Positive" Abstracts Lead to Phase III Investigations: An Analysis of 371 Abstracts 2013 - 2015

Reports of "positive" results in early phase trials as presented at ASH presumably herald therapeutic advances, or at a minimum, a larger, potentially confirmatory, randomized trial. However, the predictive value of an ASH abstract reporting positive results in AML for subsequent clinical utility seems low (Estey 2006, ASH). Furthermore, not all results presented at ASH are published in peer-reviewed journals, and selectively publishing positive results leads to publication bias. Moreover, truly negative studies may be scientifically more rigorous and accurate than positive studies given the unequivocal findings. The extent of publication bias is unknown as is the frequency with which positive or negative abstracts lead to subsequent investigation in phase III and the reasons why positive phase II studies might not progress to phase III. We downloaded all 2013 - 2015 ASH abstracts (N = 17,251) and evaluated all abstracts reporting phase II clinical trials (N = 371) of novel drugs and therapeutic regimens presented at ASH in these years, covering investigational treatments of MM, CLL, AML, DLBCL, MDS, NHL, ALL, CML, MCL, SLL, other lymphomas and POEMS. We first scored abstracts "positive", "negative" or "inconclusive". Criteria for a positive abstract were words/phrases such as "encouraging", "promising", "could represent a novel therapeutic option" and "warrants investigation in a randomized trial". Negative abstracts included terms such as "does not support further research" and "demonstrates no clinical activity". The remainder were scored as inconclusive. Using this approach, we scored 296/371 (80%) abstracts as positive, 37/371 (10%) as negative, and 38/371 (10%) as inconclusive. 292/371 abstracts (79%) were published in peer-reviewed journals. The abstract conclusion (positive, negative or inconclusive) was not associated with publication in a peer-reviewed journal. Most frequently, studies were published in Blood (34/292 [11.6%]) and British Journal of Haematology (39/292 [13.4%]) . In Blood, 91% (31/34) of the studies were positive. British Journal of Haematology published significantly more negative studies than Blood (26%, Fisher Exact p = 0.02). Abstracts reporting studies with larger sample sizes tended to be published more often (p = 0.066). Differences exist between the abstract conclusion and later peer-reviewed publications. Of positive ASH abstracts, 6% changed to a negative conclusion in the peer-reviewed publication. Similarly, 6.5% of the initial negative abstract later reversed to a positive conclusion. 53% of positive abstracts did not lead to phase III studies, as registered on clinicaltrials.gov. Subsequently, regimens described in positive peer-reviewed publications did not proceed to phase III research in 48%. To explore why, we sent questionnaires to the first and/or last authors of positive studies not prompting phase III trials. 52% responded. Failure of positive phase II trials to proceed to phase III was due to the decision by the pharmaceutical company to halt clinical investigation (44%), lack of any intent to study the drug in phase III in the first place (40%), insufficient funding (35%), insufficient efficacy (despite the "positive" abstract; 33%) and safety concerns (4%) (Figure). Additional reasons for not proceeding to phase III were the availability of newer regimens, the rarity of the disease, or when regulatory approval had already been obtained after phase II. In conclusion, "positive" and "negative" ASH abstracts are published as full papers equally often, although the positive ones may be published more often in journals with higher "impact factors". More than half of the regimens presented in positive ASH abstracts remain unevaluated in randomized phase III trials. A separate problem is the likely tendency to disproportionately submit (and/or accept) positive, rather than negative, studies to ASH in the first place. We believe our findings raise issues in clinical research that may not be in the best interest of patients. This demands more consideration than it currently receives. Figure 1 Figure 1. Disclosures Ossenkoppele: Astellas: Consultancy, Honoraria; Agios: Consultancy, Honoraria; Abbvie, AGIOS, BMS/Celgene Astellas,AMGEN, Gilead,Servier,JAZZ,Servier Novartis: Consultancy, Honoraria; BMS/Celgene: Consultancy, Honoraria; Jazz: Consultancy, Honoraria; Servier: Consultancy, Honoraria; Gilead: Consultancy, Honoraria. Rowe: Biosight Inc.: Consultancy.

CTNI-37. ISOEFFECTIVE HYPOFRACTIONATION FOR ELDERLY OR FRAIL PATIENTS WITH A NEWLY DIAGNOSED GLIOBLASTOMA: A POOLED INTERNATIONAL STUDY

PURPOSE The standard of care (SOC) for elderly or frail glioblastoma (GBM) patients is 40 Gy in 15 fraction radiotherapy. However, this regimen has a lower BED compared to the Stupp regimen, 60 Gy in 30 fractions. We hypothesize that isoeffective hypofractionated radiation of 52.5 Gy in 15 fractions (BED equivalent to Stupp) will have superior survival compared to standard of care. METHODS Elderly GBM patients treated with 52.5 Gy in 15 fractions were pooled from 2 phase II studies, 1 phase 1 and a prospective observation study. Overall survival (OS) and progression free survival (PFS) were defined as the time elapsed between surgery/biopsy and death from any cause or progression. Univariate and multivariate analyses were performed. RESULTS 62 newly-diagnosed patients were eligible for this analysis. Median follow-up was 10 months. The median OS and PFS was 10.3 and 6.9 mos, respectively. Patients with KPS ≥ 70 and < 70 had a median OS of 15.3 and 9.5 mos. No survival difference was seen between unmethylated and methylated patients with a median OS of 10.2 and 10.3 months, respectively. Multivariable analysis demonstrated that concurrent chemotherapy was an independent prognostic factor for improved PFS and OS. Grade 3 neurologic toxicity was seen in 2 patients (3.2%). CONCLUSION This is the first pooled, prospective analysis of elderly/frail GBM patients treated with dose-escalated hypofractionated radiation. Treatment was well tolerated and demonstrated excellent OS and PFS, exceeding that from prior elderly trials (Roa; 6.5 mo [poor KPS]/Perry; 9.3mo [good KPS]). This treatment regimen gives the elderly population an alternative to Stupp that is not de-escalating therapy. Future prospective trials are needed to validate these results.

Salvage Chemotherapy in Patients with Previously Treated Thymic Carcinoma

Thymic carcinoma is a rare neoplasm, and it is difficult to achieve complete remission with systemic chemotherapy. In advanced or recurrent thymic carcinoma, platinum-based chemotherapy is chosen as the first-line setting; however, it remains unclear which regimen is better to improve its outcome. It remains unknown whether salvage chemotherapy should be administered to patients with platinum-based chemotherapy-refractory thymic carcinoma. Currently, several clinical studies have investigated the efficacy of second-line settings for advanced thymic carcinoma. As cytotoxic agents, S-1, amrubicin, pemetrexed, docetaxel, paclitaxel, and gemcitabine have been reported as prospective phase II studies or retrospective studies. The overall response rates (ORRs) of S-1, amrubicin, and pemetrexed were 25–50%, 11–44.4%, and 9–10%, respectively. Molecular targeting drugs, such as sunitinib, everolimus, and lenvatinib, also provide clinical effectiveness with tolerability after the failure of platinum-based regimens. Based on the results of the prospective phase II study, the ORR, median progression-free survival, and median overall survival were 16.6% and 5.6 months, respectively, in everolimus, 26% and 7.2 months, respectively, in sunitinib, and 38% and 9.3 months, respectively, in lenvatinib. Although it is difficult to compare each study, lenvatinib appears to be better in increasing efficacy as a second-line setting. However, each study had a small sample size, which may have biased the results of their studies. Further investigation is warranted to elucidate the therapeutic significance of salvage chemotherapy in advanced thymic carcinoma in a large-scale study.

RET Inhibitors in Non-Small-Cell Lung Cancer

RET rearrangements are observed in 1–2% of non-small-cell lung cancer (NSCLC) patients and result in the constitutive activation of downstream pathways normally implied in cell proliferation, growth, differentiation and survival. In NSCLC patients, RET rearrangements have been associated with a history of non-smoking, a higher rate of brain metastasis at initial diagnosis and a low immune infiltrate. Traditionally, RET fusions are considered mutually exclusive with other oncogenic drivers, even though a co-occurrence with EGFR mutations and MET amplifications has been observed. Cabozantinib, vandetanib and lenvatinib are the first multi-kinase inhibitors tested in RET-rearranged NSCLC patients with contrasting results. More recently, two selective RET inhibitors, selpercatinib and pralsetinib, demonstrated higher efficacy rates and good tolerability and they were approved for the treatment of patients with metastatic RET fusion-positive NSCLC on the bases of the results of phase II studies. Two ongoing phase III clinical trials are currently comparing selpercatinib or pralsetinib to standard first line treatments and will definitively establish their efficacy in RET-positive NSCLC patients.

Centralised RECIST Assessment and Clinical Outcomes with Lenvatinib Monotherapy in Recurrent and Metastatic Adenoid Cystic Carcinoma

Adenoid cystic carcinoma (ACC) is a rare cancer of secretory glands. Recurrent or metastatic (R/M) ACC is generally considered resistant to cytotoxic chemotherapy. Recent phase II studies have reported improved objective response rates (ORR) with the use of the multi-kinase inhibitor lenvatinib. We sought to evaluate real-world experience of R/M ACC patients treated with lenvatinib monotherapy within the UK National Health Service (NHS) to determine the response rates by Response Evaluation Criteria of Solid Tumour (RECIST) and clinical outcomes. Twenty-three R/M ACC patients from eleven cancer centres were included. All treatment assessments for clinical decision making related to drug therapy were undertaken at the local oncology centre. Central radiology review was performed by an independent clinical trial radiologist and blinded to the clinical decision making. In contrast to previously reported ORR of 12–15%, complete or partial response was not observed in any patients. Eleven patients (52.4%) had stable disease and 5 patients (23.8%) had progression of disease as the best overall response. The median time on treatment was 4 months and the median survival from discontinuation was 1 month. The median PFS and OS from treatment initiation were 4.5 months and 12 months respectively. Multicentre collaborative studies such as this are required to evaluate rare cancers with no recommended standard of care therapy and variable disease courses.

A case report of response to crizotinib in chemotherapy-refractory metastatic gallbladder cancer with met amplification and acquired resistance resulting from the loss of MET amplification

Gallbladder cancer (GBC) is a highly invasive disease and the most prevalent malignancy of the biliary system. Patients with GBC are commonly diagnosed at a late stage and have an unfavorable prognosis. Palliative chemotherapy has been the standard care for recurrent or metastatic disease in the past decades. Recently, several targeted therapies have been investigated in advanced biliary tract cancer (BTC) including inhibitors of genes or pathways such as FGFR2 fusions or rearrangements, IDH1 mutations, and NTRK gene fusions. Also, several clinical studies involving molecular stratification have been performed in defined patient groups, for example, BRAF V600E and HER2. MET encodes a tyrosine kinase receptor and its ligand hepatocyte growth factor (HGF), is a proto-oncogene. Targeting the MET signaling pathway is an effective strategy in numerous cancer types. However, the poor efficacy of MET inhibitors has been demonstrated in several phase II studies but currently no reports have explained the potential mechanisms of resistance to MET inhibitors in BTC. In this article, we report a case of metastatic GBC with MET amplification that exhibited a rapid response to crizotinib after the failure of two lines of chemotherapy. After the patient had progressed and discontinued crizotinib, cabozantinib was introduced. Analysis of circulating tumor DNA (ctDNA) by next-generation sequencing (NGS) indicated a loss of MET amplification status. To our knowledge, this is the first case study demonstrating the use of NGS in ctDNA to monitor the development of acquired resistance during anti-MET treatment in GBC.