Search

Through elucidating the genetic mechanisms of drug sensitivity, precision medicine aims to improve patient selection and response to therapy. Exceptional responders are patients that exhibit exquisite and durable responses to targeted therapy, providing a rare opportunity to identify the molecular basis of drug sensitivity. We identified an exceptional responder to everolimus, an oral inhibitor of the mammalian target of rapamycin (mTOR) pathway, in a patient with advanced renal cell carcinoma. Through whole-exome sequencing on pretreatment and metastatic tumor DNA, we identified alterations in several mTOR pathway genes, with several mutations implicated in mTOR activation. Importantly, these alterations are currently not included in commercially available next-generation sequencing panels, suggesting that precision medicine is still limited in its ability to predict responses to mTOR-targeted therapies. Further research to discover and validate predictive biomarkers of response to everolimus and other targeted therapies is urgently needed. Given the rarity of patients with exceptional responses to targeted agents, cooperative efforts to understand the molecular basis for these phenotypes are essential.

Objective To examine whether blocking multiple points of the angiogenesis pathway by addition of sorafenib, a multi-kinase inhibitor against VEGFR2/3, Raf, c-Kit, and PDGFR, to bevacizumab would yield clinical activity in ovarian cancer (OvCa). Methods This phase II study tested bevacizumab plus sorafenib in two cohorts; bevacizumab-naive and bevacizumab-exposed patients. Bevacizumab (5 mg/kg IV every 2 weeks) was given with sorafenib 200 mg bid 5 days-on/2 days-off. The primary objective was response rate using a Simon two-stage optimal design. Progression-free survival (PFS) and toxicity were the secondary endpoints. Exploratory correlative studies included plasma cytokine concentrations, tissue proteomics and dynamic contrast-enhanced-magnetic resonance imaging (DCE-MRI). Results Between March 2007 and August 2012, 54 women were enrolled, 41 bevacizumab-naive and 13 bevacizumab-prior, with median 5 (2–9) and 6 (5–9) prior systemic therapies, respectively. Nine of 35 (26%) evaluable bevacizumab-naive patients attained partial responses (PR), and 18 had stable disease (SD) ≥ 4 months. No responses were seen in the bevacizumab-prior group and 7 (54%) patients had SD ≥ 4 months, including one exceptional responder with SD of 27 months. The overall median PFS was 5.5 months (95%CI: 4.0–6.8 months). Treatment-related grade 3/4 adverse events (≥5%) included hypertension (17/54 [31%]; grade 3 in 16 patients and grade 4 in one patient) and venous thrombosis or pulmonary embolism (5/54 [9%]; grade 3 in 4 patients and grade 4 in one patient). Pretreatment low IL8 concentration was associated with PFS ≥ 4 months (p = .031). Conclusions The bevacizumab and sorafenib combination did not meet the pre-specified primary endpoint although some clinical activity was seen in heavily-pretreated bevacizumab-naive OvCa patients with platinum-resistant disease. Anticipated class toxicities required close monitoring and dose modifications.

Purpose: We pursued genomic analysis of an exceptional responder with non–small cell lung cancer (NSCLC) through a multi-platform effort to discover novel oncogenic targets. Experimental Design: In this open-label, single-arm phase II study (NCT01829217), an enriched cohort of patients with advanced NSCLC was treated with the multi-kinase inhibitor sunitinib. The primary endpoint was objective response rate. Tissue was collected for multi-platform genomic analysis of responders, and a candidate oncogene was validated using in vitro models edited by CRISPR-Cas9. Results: Of 13 patients enrolled, 1 patient (8%), a never smoker, had a partial response lasting 33 months. Genomic analysis of the responder identified no oncogenic variant using multi-platform DNA analysis including hotspot allelotyping, massively parallel hybrid-capture next-generation sequencing, and whole-exome sequencing. However, bulk RNA-sequencing (RNA-seq) revealed a novel fusion, TMEM87A–RASGRF1, with high overexpression of the fusion partners. RASGRF1 encodes a guanine exchange factor which activates RAS from GDP-RAS to GTP-RAS. Oncogenicity was demonstrated in NIH/3T3 models with intrinsic TMEM87A–RASGRF1 fusion. In addition, activation of MAPK was shown in PC9 models edited to express this fusion, although sensitivity to MAPK inhibition was seen without apparent sensitivity to sunitinib. Conclusions: Sunitinib exhibited limited activity in this enriched cohort of patients with advanced NSCLC. Nonetheless, we find that RNA-seq of exceptional responders represents a potentially underutilized opportunity to identify novel oncogenic targets including oncogenic activation of RASGRF1.

Background In a recent individual patient data meta-analysis, acupuncture was found to be superior to sham and non-sham controls in patients with chronic pain. It has been suggested that a subgroup of patients has an exceptional response to acupuncture. We hypothesized the presence of exceptional acupuncture responders would lead to a different distribution of pain scores in acupuncture versus control groups, with the former being skewed to the right. Methods This individual patient data meta-analysis included 39 high-quality randomized trials of acupuncture for chronic headache, migraine, osteoarthritis, low back pain, neck pain and shoulder pain published before December 2015 (n = 20,827). In all, 25 involved sham acupuncture controls (n = 7097) and 25 non-acupuncture controls (n = 16,041). We analyzed the distribution of change scores and calculated the difference in the skewness statistic—which assesses asymmetry in the data distribution—between acupuncture and either sham or non-acupuncture control groups. We then entered the difference in skewness along with standard error into a meta-analysis. Findings Control groups were more right-skewed than acupuncture groups, although this difference was very small. The difference in skew was 0.124 for non-acupuncture-controlled trials (p = 0.047) and 0.141 for sham-controlled trials (p = 0.029). In a pre-specified sensitivity analysis excluding three trials with outlying results known a priori, the difference in skew between acupuncture and sham was no longer statistically significant (p = 0.2). Conclusion We did not find evidence to support the notion that there are exceptional acupuncture responders. The challenge remains to identify features of chronic pain patients that can be used to distinguish those that have a good response to acupuncture treatment.

Enzastaurin (ENZA, DB102) is an oral serine/threonine kinase inhibitor targeting the protein kinase C (PKC) and phosphoinositide 3-kinase (PI3K)/AKT pathways to inhibit tumor cell proliferation, induce tumor cell apoptosis, and suppress tumor-induced angiogenesis. We report the long-term clinical response of a GBM patient treated with ENZA who has survived for 15 years from initial diagnosis, despite tumor recurrence 5 years ago. In 2006, the 44-year-old man was diagnosed with GBM and underwent surgical resection of the tumor. He subsequently enrolled in a Phase I/II trial evaluating ENZA in newly diagnosed GBM and gliosarcoma (NCT00402116), in September 2006. He was treated with radiation and concurrent temozolomide (TMZ) + ENZA, followed by adjuvant TMZ + ENZA, which he tolerated well. He stopped treatment electively in November 2010, after 51 adjuvant cycles, in the setting of stable imaging without evidence of tumor activity. The patient did well until January 2016, when a serial MRI scan showed tumor progression; he underwent a second surgical resection (pathology: recurrent GBM, IDH1 R132H neg, ATRX retained, EGFR amplified, MGMT methylated) followed by re-irradiation with concurrent TMZ. Given the patient’s prior prolonged disease control, he started a compassionate treatment of ENZA in combination with adjuvant TMZ in April 2016. TMZ was stopped in June 2018 after 28 cycles; he continues single agent ENZA to date, with no evidence of tumor progression as of May 2021. Consistent with DGM1 (Denovo Genomic Marker 1) being an ENZA efficacy predicting biomarker, the patient is DGM1 positive. This case provides clinical evidence that the addition of ENZA to standard of care may provide substantial long-term benefit in DGM1 positive patients with GBM. A Phase 3 study of ENZA in DGM1 positive newly diagnosed GBM patients is currently ongoing (ENGAGE study, NCT03776071).

In a pilot study, we evaluated the feasibility of real-time deep analysis of serial tumor samples from triple negative breast cancer patients to identify mechanisms of resistance and treatment opportunities as they emerge under therapeutic stress engendered by poly-ADP-ribose polymerase (PARP) inhibitors (PARPi). In a BRCA-mutant basal breast cancer exceptional long-term survivor, a striking tumor destruction was accompanied by a marked infiltration of immune cells containing CD8 effector cells, consistent with pre-clinical evidence for association between STING mediated immune activation and benefit from PARPi and immunotherapy. Tumor cells in the exceptional responder underwent extensive protein network rewiring in response to PARP inhibition. In contrast, there were minimal changes in the ecosystem of a luminal androgen receptor rapid progressor, likely due to indifference to the effects of PARP inhibition. Together, identification of PARPi-induced emergent changes could be used to select patient specific combination therapies, based on tumor and immune state changes.

Introduction: Since the advent of anti-cancer therapies, physicians have observed that certain patients experience deep, durable responses to these agents (exceptional responders). The application ...

NRG1 rearrangements are oncogenic drivers that are enriched in invasive mucinous adenocarcinomas (IMA) of the lung. The oncoprotein binds ERBB3–ERBB2 heterodimers and activates downstream signaling, supporting a therapeutic paradigm of ERBB3/ERBB2 inhibition. As proof of concept, a durable response was achieved with anti-ERBB3 mAb therapy (GSK2849330) in an exceptional responder with an NRG1-rearranged IMA on a phase I trial (NCT01966445). In contrast, response was not achieved with anti-ERBB2 therapy (afatinib) in four patients with NRG1-rearranged IMA (including the index patient post-GSK2849330). Although in vitro data supported the use of either ERBB3 or ERBB2 inhibition, these clinical results were consistent with more profound antitumor activity and downstream signaling inhibition with anti-ERBB3 versus anti-ERBB2 therapy in an NRG1-rearranged patient-derived xenograft model. Analysis of 8,984 and 17,485 tumors in The Cancer Genome Atlas and MSK-IMPACT datasets, respectively, identified NRG1 rearrangements with novel fusion partners in multiple histologies, including breast, head and neck, renal, lung, ovarian, pancreatic, prostate, and uterine cancers. Significance: This series highlights the utility of ERBB3 inhibition as a novel treatment paradigm for NRG1-rearranged cancers. In addition, it provides preliminary evidence that ERBB3 inhibition may be more optimal than ERBB2 inhibition. The identification of NRG1 rearrangements across various solid tumors supports a basket trial approach to drug development. Cancer Discov; 8(6); 686–95. ©2018 AACR. See related commentary by Wilson and Politi, p. 676. This article is highlighted in the In This Issue feature, p. 663

Optimal treatment for advanced cervical cancer after first line chemotherapy remains undefined. Immune checkpoint inhibition with pembrolizumab, a programmed cell death protein 1(PD-1) inhibitor, is under investigation. We analyzed the micro-environmental and molecular genetic profile of tumors from 4 patients with metastatic cervical cancer treated with off-label second-line pembrolizumab in an effort to identify predictive biomarkers. All patients received 2 mg/kg of pembrolizumab, 3-weekly until disease progression. Immunohistochemistry(IHC) for PD-1, PD-L1, CD3 and CD8, as well as next generation sequencing (NGS) for 50 cancer-related genes were performed on tumor samples. All patients tolerated treatment well with no discontinuation of treatment due to toxicity. One patient experienced dramatic and prolonged partial response, and remains stable on pembrolizumab with a progression free survival (PFS) of 21 months at the time of reporting of this series. Three patients experienced disease progression as best response. In the exceptional responder, there was no tumoral expression of PD-L1, however, combined positive score (CPS) for PD-L1 was 1 and we identified somatic mutations in ERBB4(R612W), PIK3CA(E542K) and RB1(E365K). In 2 patients, despite progressive disease defined by RECIST v1.1, symptom stabilization on pembrolizumab was observed. The tumors of both patients had PD-1 expression in ≥1% of stromal lymphocytes. All patients with response or clinical benefit had CPS for PD-L1 ≥ 1. NGS revealed PIK3CA mutations in 3 tumors. Pembrolizumab is a promising therapeutic option in advanced cervical cancer. Further evaluation of biomarkers may guide optimal patient selection., Highlights • 1 of 4 patients receiving second line pembrolizumab, experienced dramatic and durable response. • All patients with response or clinical benefit had CPS for PD-L1 ≥ 1. • Germline BRCA1 mutation was detected in 1 patient, but she was a non-responder. • All tumors had somatic mutation in PIK3CA or PTEN.

The transcription factor GATA-3, highly expressed in many cutaneous T-cell lymphoma (CTCL) and peripheral T-cell lymphomas (PTCL), confers resistance to chemotherapy in a cell-autonomous manner. As GATA-3 is transcriptionally regulated by NF-κB, we sought to determine the extent to which proteasomal inhibition impairs NF-κB activation and GATA-3 expression and cell viability in malignant T cells. Proteasome inhibition, NF-κB activity, GATA-3 expression, and cell viability were examined in patient-derived cell lines and primary T-cell lymphoma specimens ex vivo treated with the oral proteasome inhibitor ixazomib. Significant reductions in cell viability, NF-κB activation, and GATA-3 expression were observed preclinically in ixazomib-treated cells. Therefore, an investigator-initiated, single-center, phase II study with this agent in patients with relapsed/refractory CTCL/PTCL was conducted. Concordant with our preclinical observations, a significant reduction in NF-κB activation and GATA-3 expression was observed in an exceptional responder following one month of treatment with ixazomib. While ixazomib had limited activity in this small and heterogeneous cohort of patients, inhibition of the NF-κB/GATA-3 axis in a single exceptional responder suggests that ixazomib may have utility in appropriately selected patients or in combination with other agents.

The immune response is a dynamic multistep process with a complex system regulation. Identification of predictive biomarkers is therefore challenging. Deep investigation of an exceptional responder to pembrolizumab in ovarian cancer identifies a new mechanism of response and highlights the interest of individualized medicine strategy. Clin Cancer Res; 24(14); 3233–5. ©2018 AACR. See related article by Bellone et al., p. 3282

Background. Exceptional responders to immune checkpoint inhibitors in metastatic non-small-cell lung cancer (NSCLC) are rare. Furthermore, the optimal duration of immunotherapy in patients who achieve complete remission and the benefit of rechallenge after recurrence remain unknown. Studying the clinical course of exceptional responders can help identify potential predictors of response to immunotherapy and further fine-tune our management algorithms in the absence of standard of care in challenging scenarios. Case Presentation. We highlight the case of a 73-year-old Vietnam War Veteran with active tobacco dependence who achieved complete response with nivolumab for metastatic NSCLC after four prior lines of chemotherapy. Nivolumab was discontinued after 10 cycles due to immune-mediated hepatitis that resolved with steroids. He remained in complete remission for 14 months while off therapy. Then, his tumor recurred twice locally in the mediastinum and he again achieved complete and durable responses after each recurrence with radiotherapy. Due to recurrence in both lungs one year later, he was rechallenged with nivolumab and achieved partial response after two months of therapy. He continues to do well five and a half years since his initial diagnosis of de novo metastatic NSCLC. Conclusion. Optimal management of exceptional responders to immune checkpoint inhibitors in metastatic NSCLC is largely unknown. Our case report adds to the limited data supporting the use of localized therapy for oligometastatic recurrences and rechallenge with immunotherapy for widespread disease in achieving disease control and long-term survival.

Widely available molecular profiling technology, including next-generation sequencing has changed the landscape of drug development in cancer. An increasing number of clinical trials in early drug development require patient selection based on molecular alterations. Concurrently, efforts to identify molecular alterations in tumors that exhibited exceptional response after systemic treatment with standard or investigational agents have been published or are in progress. These discoveries may ultimately serve as predictive markers or "actionable mutations" for future therapies. To test the feasibility of collecting the archival tissues from proposed exceptional responder patients and successful subsequent molecular profiling, the National Cancer Institute opened a nationwide exceptional responder initiative protocol in 2014. In addition, an increasing number of exceptional responder cases have been identified and published from academia institutions. The Network of Enigmatic Exceptional Responders study uses crowdsourcing to identify exceptional responders and will molecularly profile tumors to discern molecular correlates with exceptional response. In this review, we discuss the potential role of exceptional responder molecular analysis in new biomarker discovery efforts to further advance precision medicine in oncology therapeutics.

Immunotherapy is the treatment that either boosts the patient’s immune system or uses human-made versions of the normal parts of the immune system to kill lymphoma cells or slow their growth. A forty-eight-year-old lady with neck nodes, axillary nodes, weight loss and fever diagnosed to have Diffuse Large B-Cell Lymphoma (DLBCL) in December 2009 was treated with 6 cycles of R-CHOP, and her treatment was completed in May 2010. After 2 years in July 2012, the patient developed similar symptoms and received salvage chemotherapy with R-DHAP, and her treatment was completed in January 2013. After one and a half years, in August 2014, the patient again had relapsed DLBCL. She was treated with R-ICE 4-cycles and rendered disease-free following allogeneic HSCT in June 2015. But in December 2016, the patient again developed isolated axillary lymphadenopathy and relapsed DLBCL was confirmed by HPR and IHC. This time, the patient was unwilling to go on chemotherapy, but after counselling about the new drug, Nivolumab, she became convinced, and her treatment was started with 3mg per kg every 2 weeks. After 4 cycles, she had a complete response and is now being treated with the same treatment without any symptoms of the disease or any adverse drug reactions. Nivolumab was well tolerated and exhibited antitumor activity in extensively pretreated patients with relapsed or refractory B- cell lymphomas. Additional studies are ongoing to learn more about the use of Nivolumab in these diseases.

A small fraction of cancer patients with advanced disease survive significantly longer than patients with clinically comparable tumors. Molecular mechanisms for exceptional responses to therapy have been identified by genomic analysis of tumor biopsies from individual patients. Here, we analyzed tumor biopsies from an unbiased cohort of 111 exceptional responder patients using multiple platforms to profile genetic and epigenetic aberrations as well as the tumor microenvironment. Integrative analysis uncovered plausible mechanisms for the therapeutic response in nearly a quarter of the patients. The mechanisms were assigned to four broad categories���DNA damage response, intracellular signaling, immune engagement, and genetic alterations characteristic of favorable prognosis���with many tumors falling into multiple categories. These analyses revealed synthetic lethal relationships that may be exploited therapeutically and rare genetic lesions that favor therapeutic success, while also providing a wealth of testable hypotheses regarding oncogenic mechanisms that may influence the response to cancer therapy. Profiling multi-platform genomics of 110 cancer patients with an exceptional therapeutic response, Wheeler et al. identify putative molecular mechanisms explaining this survival phenotype in ���23% of cases. Therapeutic success is related to rare molecular features of responding tumors, exploiting synthetic lethality and oncogene addiction.

BACKGROUND. The combination of multikinase VEGF inhibitor regorafenib and anti-EGFR antibody cetuximab overcomes intrinsic and acquired resistance in both EGFR-sensitive and EGFR-resistant preclinical models of colorectal cancer (CRC). METHODS. Utilizing a standard 3+3 design, a phase I study was designed to determine safety, maximum tolerated dose (MTD), and dose-limiting toxicities (DLTs) of the regorafenib plus cetuximab combination among patients with advanced cancer including CRC. Comprehensive genomic profiling was performed on the exceptional responder. RESULTS. Among the 27 patients enrolled the median age was 54 years. None of 19 patients treated at dose level 1 (cetuximab i.v. 200 mg/m2 followed by 150 mg/m2 weekly + regorafenib 80 mg daily) experienced a DLT, and 2 of 5 patients treated at dose level 2 (cetuximab i.v. 200 mg/m2 followed by 150 mg/m2 weekly + regorafenib 120 mg daily) experienced a DLT (grade 3 thrombocytopenia [n = 1] and grade 3 intra-abdominal bleed [n = 1]). Most common adverse events were grade 1 or 2 rash (20 patients). Of 24 evaluable patients, 11 (46%) patients had clinical benefit (stable disease > 6 cycles or partial response [PR]) (CRC n = 8, one patient each with head and neck cancer, carcinoma of unknown primary, and glioblastoma). A CRC patient, who progressed on anti-EGFR and regorafenib, achieved a PR (46% decrease per RECIST v1.1) lasting 15 months. Genomic profiling of an exceptional responder with response for over 27 cycles revealed hypermutated genotype with microsatellite instability (MSI). CONCLUSION. Regorafenib 80 mg daily plus cetuximab 200 mg/m2 loading dose, followed by 150 mg/m2 every week is the MTD/recommended phase II dose. The combination demonstrated early signals of activity in wild-type CRC, including 1 exceptional responder with MSI high. TRIAL REGISTRATION. clinicaltrials.gov {"type":"clinical-trial","attrs":{"text":"NCT02095054","term_id":"NCT02095054"}}NCT02095054 FUNDING. The University of Texas MD Anderson Cancer Center is supported by the NIH Cancer Center Support Grant CA016672. This work was supported in part by the Cancer Prevention Research Institute of Texas grant RP110584 and National Center for Advancing Translational Sciences grant UL1 TR000371 (Center for Clinical and Translational Sciences).

BackgroundThis case represents an exceptional response to pembrolizumab in a patient with epithelioid mesothelioma with a further response on rechallenge.Case presentationA 77-year-old woman with advanced epithelioid mesothelioma extensively pretreated with chemotherapy demonstrated a prolonged response of 45 months to 52 cycles of pembrolizumab. On rechallenge with pembrolizumab, further disease stability was achieved. Serial biopsies and analysis by immunohistochemistry and immunofluorescence demonstrated marked immune infiltration and documented the emergency of markers of immune exhaustion. Whole exome sequencing demonstrated a reduction in tumor mutational burden consistent with subclone elimination by immune checkpoint inhibitor (CPI) therapy. The relapse biopsy had missense mutation in BTN2A1.ConclusionThis case supports rechallenge of programme death receptor 1 inhibitor in cases of previous CPI sensitivity and gives molecular insights.

MDS and AML are generally not considered curable in older patients (pts) outside of allogeneic transplant. Hypomethylating agents (HMAs) have clinical activity and survival benefit in these diseases, although responses are typically not durable. Maakaron et al previously reported 4 AML super-responders to decitabine (DAC) at ASH 2018. There is no consensus on what defines an exceptional responder. Maakaron et al defined "super-responders" as those in CR >2 years (yrs). Other groups, working in solid tumors, have variably defined exceptional responders using median duration of response (14-17.5 mos), >1 yr in CR or 3 yrs with stable disease, or sustained response ≥3 times the expected median duration of response. Considering these definitions, we screened for pts seen at Sylvester Comprehensive Cancer Center since 2014 with MDS or AML who had a working group response or stable disease to HMA therapy for >2 yrs. We excluded pts who received allo-transplant. We collected clinical, pathologic, and molecular data for review. For mutations, only pathogenic variants are reported. Survival and other outcomes were measured from the start of HMA therapy. We identified 15 pts with MDS or AML as potential exceptional responders to HMA-based therapy. 11 pts were treated with azacitidine (AZA) (5 on trial with pevonedistat) and 4 with DAC. HMA was the initial therapy in all but 1 pt. 8 pts had AML (6 de novo, 2 prior MPN); 2 had MDS-related changes. 7 pts had MDS (46.6%), 1 therapy-related. 8 pts (53.3%) identified as White/Non-Hispanic, 6 (40%) as White/Hispanic, and 1 (6.7%) as Black/Non-Hispanic. Median age was 70 yrs (range 49-80). Median blast count for all pts was 25% (range 1-70%), AML 31.5% (25-70%), and MDS 2% (1-11%). Mean blast count was 21.4%. Of the MDS pts, 28.6% were high-risk and 42.6% intermediate-risk by IPSS-R (2 had monosomy 7). Per ELN criteria, 6 AML pts (75%) were intermediate risk and 1 pt (33.3%) was adverse risk. 1 pt (12.5%) had refractory AML (failed 2 inductions). TET2 was the most common mutation (41.67%) in the 12 pts with NGS done, followed by ZRSR2, SF3B1, and JAK2 (all 16.7%). The overall mutation burden was low in both MDS and AML, with 3 pts (3 AML) having no mutations or karyotypic abnormalities. The median number of mutations was 1.5 (range 0-3). 11 pts had a normal karyotype, 3 had abnormal karyotype, and 1 had del(X)(q24) (likely germline). The median duration on HMA for all pts was 2.66 yrs (range 0.45-8.17), for AML was 2.31 yrs (0.45-8.17), and for MDS was 3.31 yrs (1.60-6.81). 10 pts (67%) had an objective response (best response: 6 CR, 2 CRi, 1 marrow CR w/ HI-E, 1 PR), and 5 pts had stable disease (SD) (2 AML and 3 MDS; 2 MDS SD pts had HI). In the 10 responders, median duration of response was 3.34 yrs. The median time from start of HMA to death or last contact for all pts was 3.33 yrs (range 1.62-13.11), for AML was 3.38 yrs (2.46-13.11), and for MDS was 3.33 yrs (1.62-7.69). Median OS and PFS were not reached for MDS or AML, and there was no difference in survival between the 2 groups [Figure 1]. 12 pts were alive at last contact (1 lost to follow up) and 2 died of other causes. 3 AML pts (37.5%) relapsed (1 died of metastatic urothelial cancer and 2 are alive on subsequent therapy), 3 (37.5%) are alive in clinical remission (1 has residual MPN and 1 has persistent mutations), and 2 (25%) are alive with prolonged SD. 2 MDS pts (40%) are alive in remission, 1 alive with SD, 1 progressed to AML (with prolonged survival on HU), and 1 died of ESRD. When we examined the 10 responders vs. 5 SD pts, median OS/PFS were not reached in responders and median OS and PFS were 3.15 yrs in SD pts. There was no difference in PFS between responders and SD pts, but there was a trend toward longer OS in responders (p=0.06) We examined 15 AML and MDS pts with exceptional survival on HMA therapy, with a median follow-up of 3.33 yrs. Most notably, despite a range of clinical responses including SD, no pts died of disease progression (2 died of other causes). It is unclear if any of these pts may be cured, but 3 pts (2 MDS and 1 AML) remain in molecular CR for >3 yrs, and 1 refractory AML pt has survived for >10 yrs (HMA stopped after 8 years). Although the numbers are small, for the AML exceptional responders: TET2, epigenetic/splicing mutations, normal karyotype, intermediate risk, lower blast count, low number of total mutations, and lack of kinase mutations appear to be enriched. Larger, multicenter reviews might shed more light on the characteristics of exceptional responders. Figure 1 Disclosures Bradley: AbbVie: Other: Advisory Board. Watts:Pfizer: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees; Takeda: Research Funding.

Introduction: Advanced stage squamous cell carcinoma of the head and neck carries an overall poor prognosis, and survivorship gains have remained relatively stagnant compared to other malignancies due to its complex tumor biology and lack of proven effective targeting agents. Methods: We present a case of an exceptional responder to molecular-targeted therapy for metastatic oropharyngeal squamous cell carcinoma using a chemotherapeutic agent FDA approved for breast cancer and targeting the HER2/Neu receptor in order to discuss the larger clinical implications. Results: The National Cancer Institute (NCI) has recently instituted the Exceptional Responders Initiative in order to identify such patients with unexpected outcomes in order to expedite the development of additional targeted therapies. This case illustrates the opportunity for cure using targeted oncogene identification in a scenario of recurrent squamous cell carcinoma with lung metastasis typically considered fatal. Conclusions: Molecular tumor analysis is an infrequently utilized tool in head and neck squamous cell carcinoma; however, as understanding of biologic mechanisms improves, additional molecular targets will become available and expand treatment opportunities such as HER2/Neu targeting. The Exceptional Responders Initiative is a unique strategy with potential to expedite progress.

Traditional approaches to evaluating antitumor agents using human tumor xenograft models have generally used cohorts of 8 to 10 mice against a limited panel of tumor models. An alternative approach is to use fewer animals per tumor line, allowing a greater number of models that capture greater molecular/genetic heterogeneity of the cancer type. We retrospectively analyzed 67 agents evaluated by the Pediatric Preclinical Testing Program to determine whether a single mouse, chosen randomly from each group of a study, predicted the median response for groups of mice using 83 xenograft models. The individual tumor response from a randomly chosen mouse was compared with the group median response using established response criteria. A total of 2,134 comparisons were made. The single tumor response accurately predicted the group median response in 1,604 comparisons (75.16%). The mean tumor response correct prediction rate for 1,000 single mouse random samples was 78.09%. Models had a range for correct prediction (60%–87.5%). Allowing for misprediction of ± one response category, the overall mean correct single mouse prediction rate was 95.28%, and predicted overall objective response rates for group data in 66 of 67 drug studies. For molecularly targeted agents, occasional exceptional responder models were identified and the activity of that agent confirmed in additional models with the same genotype. Assuming that large treatment effects are targeted, this alternate experimental design has similar predictive value as traditional approaches, allowing for far greater numbers of models to be used that more fully encompass the heterogeneity of disease types. Cancer Res; 76(19); 5798–809. ©2016 AACR.

The paper by Zafeiriou et al . (1) describes exceptionally prolonged remission ranging from 3 to 15 years observed in three cases with homologous DNA repair mutations in metastatic castrate resistant prostate cancer (CRPC). The exceptional response has always been the most intriguing part of the clinical practice of medicine. Every physician sees at least one unexpected/exceptional responder during their medical practice careers.

e15161Background: Analyzing anti-cancer immune responses can offer insights into the mechanisms that underlie successful cancer therapies. We studied the B and T cell responses of 11 metastatic bre...

This is the case of an 84-year-old woman diagnosed with Stage IVb colon adenocarcinoma (CRC) metastatic to the liver, retroperitoneum, anastomotic site, and distal rectal sigmoid colon. She experienced intolerable side effects to systemic chemotherapy with 5-fluorouracil and bevacizumab, as well as disease progression. Next generation sequencing of her tumor was ordered, and further discussion of her malignancy’s genomic information took place at a multidisciplinary molecular tumor board. The patient had mutations in KRAS (Kirsten rat sarcoma viral oncogene homolog) which made her ineligible for epidermal growth factor receptor (EGFR) inhibitors; however, a KDR p.R961W c.2881C>T mutation was noted as a variant of unknown significance (VUS). KDR (kinase insert domain receptor) is the human gene encoding for vascular endothelial growth factor receptor 2 (VEGFR-2). She was then considered a suitable candidate for regorafenib, which she could only tolerate at a low dose of 40 mg daily, with the intent of prolonging her survival and to optimize her quality of life. We report her excellent tolerance and exceptional response to low dose regorafenib, including symptomatic, tumor marker, and sustained partial metabolic radiological improvement. In the largest Phase III trial of regorafenib in CRC, only five patients (1%) of 760 experienced a partial response (versus one patient, 0.4%, receiving placebo). KDR R961W mutation has been described but no functional data has been reported. This mutation occurs in the tyrosine kinase domain of the VEGFR-2. Regorafenib targets VEGFR-2 (KDR). Hereby we hypothesize KDR mutation as a novel predictive biomarker to exceptional response to regorafenib in metastatic colorectal cancer. To our knowledge, this is the first reported case of the potential correlation between KDR mutation and regorafenib use for the successful management of a patient with advanced CRC, leading to what is considered an exceptional response. Further studies based on this preliminary data are warranted.

Targeted therapies have changed the landscape of cancer treatment, although they fail too many patients with advanced cancer. Still, insight gained from an exceptional responder has the power to identify new biomarkers of sensitivity that can unlock subsets of patients across anatomic disease sites who may also derive benefit and facilitate development of novel therapeutic strategies that may overcome resistance. The use of large-scale genomic profiling is a promising first step.

This is the case of a 47-year-old woman diagnosed with chemotherapy and radiation-refractory BRAF V600E mutant, poorly differentiated intrahepatic cholangiocarcinoma (ICC), with multiple metastatic lesions within the liver, lungs, pleura, and bone, stage IV. Discussion of her malignancy’s next-generation sequencing genomic information at a multidisciplinary molecular tumour board took place. The patient was considered a suitable candidate for dual BRAF and MEK inhibition, with the intent to prolong her survival and optimize the quality of life. We report her excellent tolerance and exceptional response to dual therapy with dabrafenib and trametinib, including symptomatic and sustained near-complete radiological improvement. We also briefly review the current knowledge of the genomics of cholangiocarcinoma with a focus on BRAF mutations, and make a point of the importance of the establishment of a molecular tumour board for personalized genomic medicine approaches. To our knowledge, this is the first reported case of the use of personalized genomic information for the successful management of a patient with ICC, and it is also the first description of dual BRAF and MEK targeted therapy in this malignancy, leading to what is considered an exceptional response.

Metastatic solid tumors are almost invariably fatal. Patients with disseminated small-cell cancers have a particularly unfavorable prognosis, with most succumbing to their disease within two years. Here, we report on the genetic and functional analysis of an outlier curative response of a patient with metastatic small-cell cancer to combined checkpoint kinase 1 (CHK1) inhibition and DNA-damaging chemotherapy. Whole-genome sequencing revealed a clonal hemizygous mutation in the Mre11 complex gene RAD50 that attenuated ATM signaling which in the context of CHK1 inhibition contributed, via synthetic lethality, to extreme sensitivity to irinotecan. As Mre11 mutations occur in a diversity of human tumors, the results suggest a tumor-specific combination therapy strategy in which checkpoint inhibition in combination with DNA-damaging chemotherapy is synthetically lethal in tumor cells but not normal cells with somatic mutations that impair Mre11 complex function.Strategies to effect deep and lasting responses to cancer therapy in patients with metastatic disease have remained difficult to attain, especially in early-phase clinical trials. Here, we present an in-depth genomic and functional genetic analysis identifying RAD50 hypomorphism as a contributing factor to a curative response to systemic combination therapy in a patient with recurrent, metastatic small-cell cancer.

Background Hormone-refractory breast cancer metastatic to bone is a clinically challenging disease associated with high morbidity, poor prognosis, and impaired quality of life owing to pain and skeletal-related events. In a preclinical study using a mouse model of breast cancer and bone metastases, Ra-223 dichloride was incorporated into bone matrix and inhibited proliferation of breast cancer cells and differentiation of osteoblasts and osteoclasts (all P values

The US National Cancer Institute is launching an 'exceptional responder' programme to see whether outliers from failed cancer trials can open up new drug development avenues.

Understanding molecular mechanisms of response and resistance to anticancer therapies requires prospective patient follow-up and clinical and functional validation of both common and low frequency mutations. We describe an evidence-based precision medicine program designed to bring whole exome sequencing (WES) into clinical practice and illustrate how this can be utilized to identify novel predictive biomarkers associated with exceptional systemic response. Metastatic and treatment-resistant cancer patients are prospectively enrolled for paired metastatic tumor and normal WES. Using a comprehensive computational pipeline, point mutations, indels and copy number alterations are detected. Mutations are categorized as Category I-III based on actionability and a report is generated and discussed in tumor board. Patients are followed prospectively for correlation of molecular information with clinical response and patient outcomes. A rapid response functional team follows on key findings to expand actionability based on the WES results. In the first year, 154 tumor-normal pairs from 97 patients were sequenced, with an average coverage of 95X of over 21,000 genes and 16 somatic alterations detected on average per patient. In total, 16 mutations were Category I, 98 were Category II, and 1474 were Category III. Tumor purity ranged from 14 to near 100%. Among unexpected findings, a prostate cancer exceptional responder was identified that harbored a somatic hemizygous deletion of the DNA repair gene FANCA and likely loss of function of the second allele through germline missense variant. Follow-up experiments established that loss of FANCA function was associated with platinum hypersensitivity both in vitro and in patient-derived xenografts, thus providing biologic rationale and functional evidence for his extreme clinical response. The establishment of a clinical program for whole exome sequencing of metastatic tumors with prospective follow-up of patients can help identify candidate predictive biomarkers of response. Citation Format: Mark A. Rubin. Towards the next clinical option: Experience from a precision cancer medicine trial. [abstract]. In: Proceedings of the AACR Special Conference on Translation of the Cancer Genome; Feb 7-9, 2015; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2015;75(22 Suppl 1):Abstract nr IA19.

Background: Understanding molecular mechanisms of response and resistance to anticancer therapies requires prospective patient follow-up and clinical and functional validation of both common and low frequency mutations. We describe an evidence-based precision medicine program designed to bring whole exome sequencing into clinical practice and illustrate how this can be utilized to identify novel predictive biomarkers associated with exceptional systemic response. Methods: Metastatic and treatment-resistant cancer patients are prospectively enrolled under an IRB approved protocol for paired metastatic tumor and normal WES through our Precision Medicine Clinic. Using a comprehensive computational pipeline, point mutations, indels and copy number alterations are detected. Mutations are categorized as Category I-III based on actionability and a report is generated and discussed in tumor board. Patients are followed prospectively for correlation of molecular information with clinical response and patient outcomes. A rapid response functional team follows on key findings to expand actionability based on the WES results. Results: In the first year, 154 tumor-normal pairs from 97 patients were sequenced, with an average coverage of 95X of over 21,000 genes and 16 somatic alterations detected on average per patient. In total, 16 mutations were Category I, 98 were Category II, and 1474 were Category III. Tumor purity ranged from 14 to near 100%. Among unexpected findings, a prostate cancer exceptional responder was identified that harbored a somatic hemizygous deletion of the DNA repair gene FANCA and likely loss of function of the second allele through germline missense variant. Follow-up experiments established that loss of FANCA function was associated with platinum hypersensitivity both in vitro and in patient-derived xenografts, thus providing biologic rationale and functional evidence for his extreme clinical response. Conclusions: The establishment of a clinical program for whole exome sequencing of metastatic tumors with prospective follow-up of patients can help identify candidate predictive biomarkers of response. Citation Format: Himisha Beltran, Kenneth Eng, Juan Miguel Mosquera, Alexandros Sigaras, Alessandro Romanel, Hanna Rennart, Myriam Kossai, Chantal Pauli, Bishoy Faltas, Jacqueline Fontugne, Brian Robinson, David M. Nanus, Scott T. Tagawa, Jenny Z. Xiang, Francesca Demichelis, David Rickman, Andrea Sboner, Olivier Elemento, Mark A. Rubin. Precision cancer medicine program for whole-exome sequencing of metastatic tumors reveals biomarkers of response. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4745. doi:10.1158/1538-7445.AM2015-4745

Aims Advanced biliary tract carcinomas (ABC) are malignancies with limited effective therapies for advanced disease. There is little published evidence of outcomes of ABC patients participating in phase I clinical trials. Materials and methods Patient characteristics, treatment details and outcomes of ABC patients treated at a dedicated phase I unit were captured and analysed from case and trial records. Results In total, 123 ABC patients were included in the study, of which 48 patients participated in 41 different phase I trials; 75 (61%) did not participate due to rapid disease progression or patient choice. Molecular characterisation of tumours using a targeted panel was conducted in 15 (31%), yielding several potentially actionable mutations, including BRCA , PIK3CA , FGFR , AKT and PTEN loss. Of the 39 evaluable patients there was one exceptional responder. Eighteen (46%) other patients achieved stable disease as their best response, with a clinical benefit rate at 4 months of 10%. Treatment was generally well tolerated with grade 3 or 4 adverse events only observed in eight patients (17 %), of which six were drug related and led to trial discontinuation in one (3%), with no toxicity-related deaths. Conclusion Carefully selected ABC patients have been found to tolerate experimental phase I clinical trials without excess toxicity. The aggressive nature of this disease warrants consideration of early referral to a phase I unit. Future work will require comprehensive molecular profiling in an attempt to understand the biology underlying the exceptional responders and to match patients in real-time to targeted therapies.

Background Germ cell tumors (GCT) are the most common solid tumors in adolescent and young adult males (age 15 and 35 years) and remain one of the most curable of all solid malignancies. However a subset of patients will have tumors that are refractory to standard chemotherapy agents. The management of this refractory population remains challenging and approximately 400 patients continue to die every year of this refractory disease in the United States. Methods Given the preclinical evidence implicating vascular endothelial growth factor (VEGF) signaling in the biology of germ cell tumors, we hypothesized that the vascular endothelial growth factor receptor (VEGFR) inhibitor sunitinib (Sutent) may possess important clinical activity in the treatment of this refractory disease. We proposed a Phase II efficacy study of sunitinib in seminomatous and non-seminomatous metastatic GCT’s refractory to first line chemotherapy treatment (ClinicalTrials.gov Identifier: NCT00912912). Next generation targeted exome sequencing using HiSeq 2000 (Illumina Inc., San Diego, CA, USA) was performed on the tumor sample of the unusual responder. Results Five patients are enrolled into this Phase II study. Among them we report here the clinical course of a patient (Patient # 5) who had an exceptional response to sunitinib. Next generation sequencing to understand this patient’s response to sunitinib revealed RET amplification, EGFR and KRAS amplification as relevant aberrations. Oncoscan MIP array were employed to validate the copy number analysis that confirmed RET gene amplification. Conclusion Sunitinib conferred clinical benefit to this heavily pre-treated patient. Next generation sequencing of this ‘exceptional responder’ identified the first reported case of a RET amplification as a potential basis of sensitivity to sunitinib (VEGFR2/PDGFRβ/c-kit/ FLT3/RET/CSF1R inhibitor) in a patient with refractory germ cell tumor. Further characterization of GCT patients using biomarkers for clinical response and patient selection is warranted. Trial registration ClinicalTrials.gov Identifier: NCT00912912