Mark Harries

Abstract S3-01: The TNT trial: A randomized phase III trial of carboplatin (C) compared with docetaxel (D) for patients with metastatic or recurrent locally advanced triple negative or BRCA1/2 breast cancer (CRUK/07/012)

Introduction: Subgroups within sporadic triple negative breast cancers (TNBCs) appear to share impaired DNA damage response mechanisms with BRCA1/2 mutation-associated breast cancers. This has been hypothesised to confer particular sensitivity to DNA-damaging platinum chemotherapy. The TNT trial, a randomized phase III trial in women with metastatic or recurrent locally advanced TNBC or BRCA1/2 mutation-associated breast cancer, aimed to test this hypothesis and examine treatment effect in biological subgroups. Patients & Methods: Eligible patients had either ER-, PR-, HER2- breast cancer or were known BRCA1/2 carriers (any ER/PR/HER2). Patients were randomized (1:1) to receive either C (AUC 6 q3wk) or D (100mg/m2 q3wk) for 6-8 cycles or until disease progression if sooner and could cross over to the alternative treatment on confirmed progression. Ineligible patients included those who had ECOG performance status >2, received adjuvant taxane therapy in the last 12 mths, any previous treatment with a platinum chemotherapy, or previous non-anthracycline chemotherapy for metastatic disease. For consenting patients a blood sample and archived tissue samples were obtained for BRCA1/2 genotyping and central biomarker analysis (primary tumour, lymph nodes and recurrent tumour biopsy if available) of subtypes within TNBC and biomarkers of DNA repair deficiency. The primary endpoint was RECIST objective tumour response up to cycle 6 of randomised treatment. Secondary endpoints included toxicity, progression free survival (PFS), time to progression and overall survival. TNT aimed to detect a 15% improvement in ORR with C compared to D, with planned target sample size range of 370-450 depending on assumed ORR in D patients (2-sided α=0.05, power=90%). 376 (188 C, 188 D) were recruited from 74 UK centres between Apr 08 and Mar 14. Results: A snapshot of the data was taken on 30/5/14 at which point 336 (89.4%) patients had experienced a PFS event, with overall median PFS time of 4.4 mths. Median age of patients was 55 yrs (IQR 48-63). 366/376 (97%) patients had TNBC of whom 18 were also known BRCA1/2 mutation carriers, with the remaining 10 patients receptor +ve and BRCA1/2 carriers. 338/376 (90%) had metastatic and 38/376 (10%) recurrent locally advanced disease. 53% had liver or lung metastases affecting the parenchyma and 34% had received previous adjuvant taxane therapy. Median time from initial diagnosis to entering TNT was 2.2 yrs (IQR 1.5-3.5). Primary tumour tissue has currently been received for 277 patients, blood from 286 patients and recurrent tumour tissue from 85 patients. Discussion: TNT will report evidence on the activity of single agent platinum chemotherapy compared with single agent taxane in patients with TNBC and BRCA1/2 associated breast cancer. Correlative analyses of BRCA1/2 mutation status, subtypes and DNA repair biomarkers will also be reported. TNT will be the first randomised trial to report the activity of platinum compared with standard chemotherapy within TNBC subtypes and in relation to BRCA1/2 mutation status and DNA repair biomarkers. Safety, tolerability and response to crossover treatment will also be presented. Citation Format: Andrew Tutt, Paul Ellis, Lucy Kilburn, Cheryl Gilett, Sarah Pinder, Jacinta Abraham, Sophie Barrett, Peter Barrett-Lee, Stephen Chan, Maggie Cheang, Mitch Dowsett, Lisa Fox, Patrycja Gazinska, Anita Grigoriadis, Alexander Gutin, Catherine Harper-Wynne, Matthew Hatton, Sarah Kernaghan, Jerry Lanchbury, James Morden, Julie Owen, Jyoti Parikh, Peter Parker, Nazneen Rahman, Rebecca Roylance, Adam Shaw, Ian Smith, Rose Thompson, Kirsten Timms, Holly Tovey, Andrew Wardley, Gregory Wilson, Mark Harries, Judith Bliss. The TNT trial: A randomized phase III trial of carboplatin (C) compared with docetaxel (D) for patients with metastatic or recurrent locally advanced triple negative or BRCA1/2 breast cancer (CRUK/07/012) [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr S3-01.

IgG4 subclass antibodies impair antitumor immunity in melanoma

Host-induced antibodies and their contributions to cancer inflammation are largely unexplored. IgG4 subclass antibodies are present in IL-10–driven Th2 immune responses in some inflammatory conditions. Since Th2-biased inflammation is a hallmark of tumor microenvironments, we investigated the presence and functional implications of IgG4 in malignant melanoma. Consistent with Th2 inflammation, CD22+ B cells and IgG4+-infiltrating cells accumulated in tumors, and IL-10, IL-4, and tumor-reactive IgG4 were expressed in situ. When compared with B cells from patient lymph nodes and blood, tumor-associated B cells were polarized to produce IgG4. Secreted B cells increased VEGF and IgG4, and tumor cells enhanced IL-10 secretion in cocultures. Unlike IgG1, an engineered tumor antigen-specific IgG4 was ineffective in triggering effector cell–mediated tumor killing in vitro. Antigen-specific and nonspecific IgG4 inhibited IgG1-mediated tumoricidal functions. IgG4 blockade was mediated through reduction of FcγRI activation. Additionally, IgG4 significantly impaired the potency of tumoricidal IgG1 in a human melanoma xenograft mouse model. Furthermore, serum IgG4 was inversely correlated with patient survival. These findings suggest that IgG4 promoted by tumor-induced Th2-biased inflammation may restrict effector cell functions against tumors, providing a previously unexplored aspect of tumor-induced immune escape and a basis for biomarker development and patient-specific therapeutic approaches.

Nanoparticle Albumin–Bound Paclitaxel for Metastatic Breast Cancer

The taxanes, paclitaxel and docetaxel, are among the most important drugs in the modern treatment of metastatic breast cancer. By the mid 1990s, several phase II trials had demonstrated both agents to have considerable activity in the metastatic setting. Phase III trials were then conducted to compare these agents with the then reference agent, doxorubicin. In 1999, a large randomized trial comparing docetaxel with doxorubicin found an improved response rate in patients who received docetaxel (48% v 33%; P .008), though differences in time to progression (26 v 21 weeks) and survival (15 v 14 months) were not statistically significant. A similar study that compared paclitaxel at a dose of 200 mg/m given over 3 hours, with doxorubicin 75 mg/m, showed paclitaxel to have an inferior response rate (25% v 41%; P .003) and time to progression (3.9 v 7.5 months; P .001) but again, overall survival was not statistically different between the two arms (15.6 v 18.3 months), possibly as a result of the preplanned cross-over on progression. Both agents, however, were rapidly adopted for the treatment of metastatic breast cancer, especially for the many women who had received an anthracycline in the adjuvant setting. Trials were subsequently launched to examine taxane combinations in advanced disease, and while some have demonstrated improved efficacy compared with single agents, this benefit has to be balanced against the excess toxicities seen with some of these regimens. This encouraging activity of taxanes in advanced disease led investigators to examine their role in addition to anthracyclines in the adjuvant setting. The first to be reported was CALGB (Cancer and Leukemia Group B) 9344 and the final analysis of this trial showed improvements in 5-year disease-free and overall survival with the addition of four cycles of paclitaxel to four cycles of doxorubicin cyclophosphamide (disease-free survival [DFS] 70% v 65%, P .0023; overall survival [OS] 80% v 77%, P .0064). Other paclitaxel adjuvant studies have shown less convincing benefits. Docetaxel has also been evaluated in several adjuvant trials. In the Breast Cancer International Research Group study (BCIRG 001), six cycles of doxorubicin, docetaxel, and cyclophosphamide (TAC) were found to be associated with superior DFS and OS compared with doxorubicin, fluorouracil, and cyclophosphamide (FAC; DFS 75% v 68%; P .001; OS 87% v 81%, P .008). Taxanes are now commonly used in adjuvant regimens for women with high-risk disease. Parallel to these studies, major advances have been achieved for women with HER-2–overexpressing breast cancer by employing schedules combining taxanes plus trastuzumab in advanced disease and in the adjuvant setting. Despite their widespread use, both docetaxel and paclitaxel are associated with significant toxicities, including alopecia, fatigue, myalgia, nail changes, myelosuppression, neuropathy, and hypersensitivity reactions. Although these adverse effects are manageable for the majority of patients, it has meant there are limitations on the duration of therapy and on combining the taxanes with other agents with overlapping toxicity profiles. Paclitaxel and docetaxel are highly hydrophobic, and therefore have to be delivered in synthetic vehicles. In the case of paclitaxel the vehicle is polyoxyethylated castor oil (Cremophor EL) and ethanol, whereas the combination of polysorbate 80 and ethanol are used for docetaxel. It has become increasingly recognized that the vehicles may be responsible for some of the “taxane-associated toxicity,” particularly fluid retention and hypersensitivity. The experiences from the early phase I and II trials of these drugs found that the incidence of such reactions could be reduced to acceptable levels with the use of premedication schedules containing antihistamines together with moderate to high doses of corticosteroids. It is in large part because of the toxicities associated with the current formulations of taxanes that strategies to JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 23 NUMBER 31 NOVEMBER 1 2005

Adjuvant bevacizumab in patients with melanoma at high risk of recurrence (AVAST-M): Preplanned interim results from a multicentre, open-label, randomised controlled phase 3 study

BACKGROUND Bevacizumab, a monoclonal antibody that targets VEGF, has shown restricted activity in patients with advanced melanoma. We aimed to assess the role of bevacizumab as adjuvant treatment for patients with resected melanoma at high risk of recurrence. We report results from the preplanned interim analysis. METHODS We did a multicentre, open-label, randomised controlled phase 3 trial at 48 centres in the UK between July 18, 2007, and March 29, 2012. Patients aged 16 years or older with American Joint Committee on Cancer stage (AJCC) stage IIB, IIC, and III cutaneous melanoma were randomly allocated (1:1), via a central, computer-based minimisation procedure, to receive intravenous bevacizumab 7.5 mg/kg, every 3 weeks for 1 year, or to observation. Randomisation was stratified by Breslow thickness of the primary tumour, N stage according to AJCC staging criteria, ulceration of the primary tumour, and patient sex. The primary endpoint was overall survival; secondary endpoints included disease-free interval, distant-metastases interval and quality of life. Analysis was by intention-to-treat. This trial is registered as an International Standardised Randomised Controlled Trial, number ISRCTN81261306. FINDINGS 1343 patients were randomised to either the bevacizumab group (n=671) or the observation group (n=672). Median follow-up was 25 months (IQR 16-37) in the bevacizumab group and 25 months (17-37) in the observation group. At the time of interim analysis, 286 (21%) of 1343 enrolled patients had died: 140 (21%) of 671 patients in the bevacizumab group, and 146 (22%) of 672 patients in the observation group. 134 (96%) of patients in the bevacizumab group died because of melanoma versus 139 (95%) in the observation group. We noted no significant difference in overall survival between treatment groups (hazard ratio [HR] 0.97, 95% CI 0.78-1.22; p=0.76); this finding persisted after adjustment for stratification variables (HR 1.03; 95% CI 0.81-1.29; p=0.83). Median duration of treatment with bevacizumab was 51 weeks (IQR 21-52) and dose intensity was 86% (41-96), showing good tolerability. 180 grade 3 or 4 adverse events were recorded in 101 (15%) of 671 patients in the bevacizumab group, and 36 (5%) of 672 patients in the observation group. Bevacizumab resulted in a higher incidence of grade 3 hypertension than did observation (41 [6%] vs one [<1%]). There was an improvement in disease-free interval for patients in the bevacizumab group compared with those in the observation group (HR 0.83, 95% CI 0.70-0.98, p=0.03), but no significant difference between groups for distant-metastasis-free interval (HR 0.88, 95% CI 0.73-1.06, p=0.18). No significant differences were noted between treatment groups in the standardised area under the curve for any of the quality-of-life scales over 36 months. Three adverse drug reactions were regarded as both serious and unexpected: one patient had optic neuritis after the first bevacizumab infusion, a second patient had persistent erectile dysfunction, and a third patient died of a haemopericardium after receiving two bevacizumab infusions and was later identified to have had significant predisposing cardiovascular risk factors. INTERPRETATION Bevacizumab has promising tolerability. Longer follow-up is needed to identify an effect on the primary endpoint of overall survival at 5 years.

Changes in Primary Breast Cancer Heterogeneity May Augment Midtreatment MR Imaging Assessment of Response to Neoadjuvant Chemotherapy

PURPOSE To evaluate whether changes in magnetic resonance (MR) imaging heterogeneity may aid assessment for pathologic complete response (pCR) to neoadjuvant chemotherapy (NACT) in primary breast cancer and to compare pCR with standard Response Evaluation Criteria in Solid Tumors response. MATERIALS AND METHODS Institutional review board approval, with waiver of informed consent, was obtained for this retrospective analysis of 36 consecutive female patients, with unilateral unifocal primary breast cancer larger than 2 cm in diameter who were receiving sequential anthracycline-taxane NACT between October 2008 and October 2012. T2- and T1-weighted dynamic contrast material-enhanced MR imaging was performed before, at midtreatment (after three cycles), and after NACT. Changes in tumor entropy (irregularity) and uniformity (gray-level distribution) were determined before and after MR image filtration (for different-sized features). Entropy and uniformity for pathologic complete responders and nonresponders were compared by using the Mann-Whitney U test and receiver operating characteristic analysis. RESULTS With NACT, there was an increase in uniformity and a decrease in entropy on T2-weighted and contrast-enhanced subtracted T1-weighted MR images for all filters (uniformity: 23.45% and 22.62%; entropy: -19.15% and -19.26%, respectively). There were eight complete pathologic responders. An area under the curve of 0.84 for T2-weighted MR imaging entropy and uniformity (P = .004 and .003) and 0.66 for size (P = .183) for pCR was found, giving a sensitivity and specificity of 87.5% and 82.1% for entropy and 87.5% and 78.6% for uniformity compared with 50% and 82.1%, respectively, for tumor size change for association with pCR. CONCLUSION Tumors become more homogeneous with treatment. An increase in T2-weighted MR imaging uniformity and a decrease in T2-weighted MR imaging entropy following NACT may provide an earlier indication of pCR than tumor size change.

A Phase 1 Study of AS1409, a Novel Antibody-Cytokine Fusion Protein, in Patients with Malignant Melanoma or Renal Cell Carcinoma

Purpose: AS1409 is a fusion protein comprising a humanized antibody BC1 linked to interleukin-12 (IL-12). It is designed to deliver IL-12 to tumor-associated vasculature using an antibody targeting the ED-B variant of fibronectin. Experimental Design: We conducted a phase 1 trial of weekly infusional AS1409 in renal carcinoma and malignant melanoma patients. Safety, efficacy, markers of IL-12–mediated immune response, and pharmacokinetics were evaluated. Results: A total of 11 melanoma and 2 renal cell carcinoma patients were treated. Doses of 15 and 25 μg/kg were studied. Most drug-related adverse events were grade 2 or less, and included pyrexia, fatigue, chills, headache, vomiting, and transient liver function abnormalities. Three dose limiting toxicities of grade 3 fatigue and transaminase elevation were seen at 25 μg/kg. IFN-γ and interferon-inducible protein-10 (IP-10) were elevated in all patients, indicating activation of cell-mediated immune response; this was attenuated at subsequent cycles. Antidrug antibody responses were seen in all patients, although bioassays indicate these do not neutralize AS1409 activity. Plasma half-life was 22 hours and not dose-dependent. Five patients received 6 cycles or more and a best response of at least stable disease was seen in 6 (46%) patients. Partial response was seen in a melanoma patient, and disease shrinkage associated with metabolic response was maintained beyond 12 months in another melanoma patient despite previous rapid progression. Conclusions: The maximum tolerated dose was established at 15 μg/kg weekly. AS1409 is well tolerated at this dose. Evidence of efficacy assessed by RECIST, functional imaging, and biomarker response warrants the planned further investigation using this dose and schedule in malignant melanoma. Clin Cancer Res; 17(7); 1998–2005. ©2011 AACR.

Neoadjuvant Chemotherapy: Not the Best Option in Estrogen Receptor–Positive, HER2-Negative, Invasive Classical Lobular Carcinoma of the Breast?

In 1973, the European Institute of Oncology performed the first prospective neoadjuvant chemotherapy study in locally advanced, inoperable breast cancer. The original purpose was to downstage the primary tumor in order to achieve surgical resection. This approach has subsequently increased in popularity, and in the last 10 years, randomized controlled trials of neoadjuvant chemotherapy have been performed with a view to further downstage the primary tumor and lymph nodes in order to achieve greater rates of breast-conserving surgery and to test whether systemic therapy given earlier would confer a survival benefit. Although the net result of these trials did demonstrate a higher rate of breast conservation, no overall survival benefit was seen. However, in subgroup analysis, there was a significant survival benefit in patients in whom a complete pathologic response (pCR) was achieved. In the National Surgical Adjuvant Breast and Bowel Project B-18 trial of neoadjuvant chemotherapy, at 9 years median follow-up, the overall survival rate for patients achieving a pCR was 85% compared with 73% in those in whom residual cancer was detected on histopathologic examination. For disease-free survival, the respective rates were 75% and 58%. After adjustment for other prognostic factors, achievement of a pCR was associated with a 50% reduction in deaths compared with the group as a whole. Mauri et al evaluated nine randomized studies, with a total of 3,946 patients with breast cancer in whom neoadjuvant therapy was compared with adjuvant systemic therapy. They found no statistically or clinically significant difference between neoadjuvant therapy and adjuvant therapy arms with regard to overall survival, disease progression, or distant disease recurrence. However, they observed that neoadjuvant therapy was associated with an increased risk of locoregional disease recurrence compared with adjuvant therapy, especially in trials where more patients in the neoadjuvant arm received radiation therapy without surgery. In several retrospective studies, the pCR rates in invasive ductal breast carcinoma (no special type) have been shown to be approximately 15% or less, whereas the pCR rates in invasive lobular carcinoma have been shown to be 2% or less. Katz et al reviewed randomized trials of neoadjuvant chemotherapy and noted that the pCR rate was 1.7% in invasive lobular carcinoma and 11.6% in invasive ductal breast carcinoma (no special type). Regarding invasive lobular carcinoma, they concluded: “the benefit from systemic chemotherapy for individuals with this form of breast disease is unclear.” Similarly, two retrospective studies have demonstrated low rates of successful breast conservation for patients with lobular carcinoma who underwent neoadjuvant chemotherapy. In patients who received breast-conserving surgery after neoadjuvant therapy, Soucy et al found surgical margin involvement in 43% of patients with lobular carcinoma compared with 16% of patients with invasive ductal carcinoma (no special type). Another study, from the M. D. Anderson Cancer Center, of 284 consecutive patients diagnosed with pure invasive lobular carcinoma between 1998 and 2006 compared patients who received neoadjuvant chemotherapy with those who received primary surgery as first-line treatment and concluded that neoadjuvant chemotherapy did not increase the rates of breast conservation in this morphologic subtype. It should be noted that the above studies are retrospective, not randomized, trials. In the three randomized trials of neoadjuvant endocrine therapy (P024 conducted by the Letrozole Neoadjuvant Breast Cancer Study Group, IMPACT [Immediate Preoperative Anastrozole, Tamoxifen, or Combined with Tamoxifen], and PROACT [Pre-Operative “Arimidex” Compared to Tamoxifen]) for women with estrogen receptor (ER) –positive disease, none of which carried out analysis of histological tumor type (ie, lobular v ductal [no special type]), a higher rate of breast conservation was observed in women who received preoperative endocrine treatment. The lack of subgroup analysis in these three studies does not allow one to draw conclusions regarding histologic type-specific effectiveness of neoadjuvant endocrine treatment, although classical lobular carcinoma is well recognized as more often being ER positive than ductal tumors (no special type). JOURNAL OF CLINICAL ONCOLOGY COMMENTS AND CONTROVERSIES VOLUME 28 NUMBER 22 AUGUST 1 2010

Sorafenib and dacarbazine as first-line therapy for advanced melanoma: phase I and open-label phase II studies.

Method:The safety of oral sorafenib up to a maximum protocol-specified dose combined with dacarbazine in patients with metastatic, histologically confirmed melanoma was investigated in a phase I dose-escalation study and the activity of the combination was explored in an open-label phase II study.Results:In the phase I study, three patients were treated with sorafenib 200 mg twice daily (b.i.d.) plus 1000 mg m−2 dacarbazine on day 1 of a 21-day cycle and 15 patients had the sorafenib dose escalated to 400 mg b.i.d. without reaching the maximum tolerated dose of the combination. In the phase II study (n=83), the overall response rate was 12% (95% CI: 6, 21): one complete and nine partial, with median response duration of 46.7 weeks. Stable disease was the best response in 37%; median duration was 13.3 weeks. Median overall survival (OS) was 37.0 weeks (95% CI: 33.9, 46.0).Conclusion:Oral sorafenib combined with dacarbazine had acceptable toxicity and some antineoplastic activity against metastatic melanoma.

Routine positron emission tomography and positron emission tomography/computed tomography in melanoma staging with positive sentinel node biopsy is of limited benefit

Positron emission tomography (PET) is increasingly used for the staging and management of melanoma. The aim of this study was to evaluate the role of PET or PET/ computed tomography (CT) as a routine procedure in patients with positive sentinel node biopsy (SNB). Thirty patients with melanoma of Breslow thickness greater than 1 mm who had PET or PET/CT scans performed within 100 days after a positive SNB were reviewed retrospectively. Two patients (6%) had a positive PET scan, none of which were melanoma related. The first patient had a synchronous neuroendocrine thyroid tumour and the second patient had increased uptake in the chest wall, which proved to be old trauma. Lymph node dissection was positive in five cases (16%). With a median follow-up of 24 months, 21 patients remained disease free. In none of the 30 cases did the early PET scan after a positive SNB alter subsequent melanoma management. The role of PET scanning soon after a positive sentinel node biopsy seems to be of limited benefit. It is questionable whether any imaging is beneficial at this stage. The results of this review suggest that PET scanning might not be indicated for this group of patients.

Ipilimumab in the real world: the UK expanded access programme experience in previously treated advanced melanoma patients

Before licensing, ipilimumab was first made available to previously treated advanced melanoma patients through an expanded access programme (EAP) across Europe. We interrogated data from UK EAP patients to inform future clinical practice. Clinicians registered in the UK EAP provided anonymized patient data using a prespecified variable fields datasheet. Data collected were baseline patient characteristics, treatment delivered, toxicity, response, progression-free survival and overall survival (OS). Data were received for 193 previously treated metastatic melanoma patients, whose primary sites were cutaneous (82%), uveal (8%), mucosal (2%), acral (3%) or unknown (5%). At baseline, 88% of patients had a performance status (PS) of 0–1 and 20% had brain metastases. Of the patients, 53% received all four planned cycles of ipilimumab; the most common reason for stopping early was disease progression, including death from melanoma. Toxicity was recorded for 171 patients, 30% of whom experienced an adverse event of grade 3 or higher, the most common being diarrhoea (13%) and fatigue (9%). At a median follow-up of 23 months, the median progression-free survival and OS were 2.8 and 6.1 months, respectively; the 1-year and 2-year OS rates were 31 and 14.8%, respectively. The 2-year OS was significantly lower for patients with poorer PS (P<0.0001), low albumin concentrations (P<0.0001), the presence of brain metastases (P=0.007) and lactate dehydrogenase levels more than two times the upper limit of normal (P<0.0001) at baseline. These baseline characteristics are negative predictors of benefit from ipilimumab and should be taken into consideration before prescription.