Megan Garlapow, PhD

This study prospectively addressed the role of upfront consolidation in patients newly diagnosed with NDMM. Between February 2011 and April 2014, 1510 patients &le;65 years with symptomatic multiple myeloma were enrolled, of whom 1499 were eligible. Of these, 1211 were first randomized (R1) and stratified by International Staging System (ISS) stage, to 4 cycles of bortezomib/melphalan/prednisone (VMP; n = 505) or high-dose melphalan (HDM) and autologous stem cell transplantation (ASCT; n = 706; 1 or 2 ASCT) as intensification therapy after induction with VCD.

The second randomization (R2) to consolidation therapy (n = 444) with 2 cycles of VRD versus no consolidation (n = 459) was performed after intensification. This was followed by lenalidomide maintenance at 10 mg continuously. Patient characteristics at baseline were similar between the 2 arms. FISH was used at diagnosis to assess cytogenetics, and the FISH status was found to be similar between the 2 arms.

&ldquo;As for the second randomization, we saw no difference in consolidation between patients receiving 1 or 2 transplants,&rdquo; explained Pieter Sonneveld, MD, PhD, at the Department of Hematology, Erasmus MC Cancer Institute, Rotterdam, Netherlands.

PFS from R2 adjusted for R1 was prolonged in patients randomized to VRD (HR, 0.78; 95% CI, 0.61-1.00;

= .045). The benefit of VRD on PFS was retained across predefined subgroups with revised ISS stage III (HR, 0.67;

= .26). This benefit was also retained in patients randomized in R1 to VMP (HR, 0.76;

&ldquo;PFS from second randomization with adjustment for the first randomization was prolonged in patients randomized to consolidation,&rdquo; stated Sonneveld.

The benefit of consolidation, however, was observed in patients with low-risk cytogenetics (HR, 0.68;

= .03), but not in patients with high-risk cytogenetics (del[17p], t[4;14] and/or t[14;16]; HR, 1.03;

&ldquo;The benefit of consolidation was primarily observed in patients with low-risk cytogenetics but not in patients with high-risk cytogenetics, deletion 17p, t(4;14), and t(14;16),&rdquo; Sonneveld explained.

PFS for R2 was 62% in all patients. In other words, PFS was 60% in patients without consolidation and 65% in patients with consolidation. There were 258 events for PFS after R2 reported.

At 3 years, OS was 86% in both arms. Median follow-up from R2 was 25 months (maximum 53).

At the time of R2, 23% experienced a CR or higher, 67% at least a very good partial response, and 93% experienced a partial response or higher.

Toxicity from VRD was limited with 5% Common Terminology Criteria for Adverse Events (CTCAE) grade 4, most of which were hematological. Cytopenia and thrombocytopenia were observed with no other unexpected toxicities.

A central MRD analysis was organized across 4 European countries. The samples were assessed for quality several times. From the MRD analyses, they concluded that main analysis is possible. These results are expected to be present at the 2017 ASCO Annual Meeting and/or the 2017 EHA Annual Congress.

The EMN011 trial established a first relapse protocol after EMN01. This protocol uses pomalidomide (Pomalyst), carfilzomib (Kyprolis), and dexamethasone. This trial is ongoing, and data will be presented in the future.

&ldquo;In conclusion, this is the first analysis of the EMN02 trial and also the first trial that prospectively addressed consolidation treatment versus no consolidation treatment in the transplant setting, and we conclude that in this analysis we see an improvement of CR rates,&rdquo; concluded Sonneveld.

Unrestricted grants from Celgene and Janssen supported this trial.

Sonneveld P, Beksac M, van der Holt B, et al. Consolidation Followed By Maintenance Therapy Versus Maintenance Alone in Newly Diagnosed, Transplant Eligible Patients with Multiple Myeloma (MM): A Randomized Phase 3 Study of the European Myeloma Network (EMN02/HO95 MM Trial). Presented at: the 58th Annual Meeting of the American Society of Hematology; Dec 3-6, 2016; San Diego, California. Abstract 242.

Articles

Consolidation therapy with bortezomib/lenalidomide/dexamethasone (VRD) followed by maintenance with lenalidomide until progression or toxicity showed promising results over maintenance alone for patients with transplant-eligible multiple myeloma (NDMM) up to 65 years old, according to a final analysis of the EMN02 trial.

Consolidation to VRD Improves PFS in Patients With Newly Diagnosed Myeloma

Adding cetuximab (Erbitux) to induction chemotherapy and hyperfractionated or accelerated chemoradiation therapy (CRT) produced long-term control for patients with HPV-negative, locoregionally advanced head and neck squamous cell carcinoma (LA-HNSCC) with a poor prognosis, according to results from a phase II trial.

The randomized study, which was presented at the 2016 Head and Neck Cancer Symposium, enrolled 110 patients who were diagnosed with LA-HNSCC between September 2006 and April 2010. In 103 of these patients, HPV status was evaluated, and 56 were HPV-negative.

These 56 HPV-negative patients were randomized to 2 treatment arms: 32 patients received Cetux-FHX (concurrent cetuximab, 5-FU, hydroxyurea, and 1.5 Gy twice-daily RT every other week to 75 Gy), and 24 patients received Cetux-PX (cetuximab, cisplatin, and accelerated RT with delayed concomitant boost to 72 Gy in 42 fractions). Both arms received 2 cycles of weekly induction chemotherapy.

Previous phase II trials indicated cetuximab was well tolerated and had high response rates when added to induction chemotherapy, though these trials were not randomized. Research has also previously shown that cetuximab increased survival in the metastatic setting when added to cytotoxic chemotherapy and in the curative-intent setting when added to single-modality radiotherapy.

&ldquo;The primary objective for this trial was to assess the tolerability and efficacy of adding cetuximab to induction chemotherapy and chemoradiotherapy. A secondary objective with this trial was to compare 2 chemoradiotherapy platforms,&rdquo; said lead study author James Melotek, MD, a radiation oncology resident at the University of Chicago.

Overall survival (OS) at 5 years for the entire cohort was 80.3% (95% CI, 73.1%-88.3%) and for the HPV-negative subset was 72.5% (95% CI, 61.6%-85.4%). Progression-free survival (PFS) at 5 years was 74.1% (95% CI, 66.3%-82.9%) for the entire cohort and 65.9% (95% CI 54.6%-79.6%) for the HPV-negative group.

No significant difference was found in OS (

= .57) between the two HPV-negative treatment arms. Five-year OS was 71.4% (95% CI, 57.1%-89.1%) for the Cetux-FHX arm and 74.2% (95% CI, 58.4%-94.3%) for the Cetux-PX arm. Median follow-up was 68 months.

PFS at 5 years was 62.1% (95% CI, 47.2%-81.6%) for the Cetux-FHX arm and 70.8% (95% CI, 54.8%-91.6%) for the Cetux-PX arm. Late outcomes in the HPV-negative subset at 5 years were locoregional failure in 26.9% (95% CI, 16.0%-39%) and distant failure in 7.2% (95% CI, 2.3%-16%).

Neither OS nor PFS were affected by tobacco use, alcohol use, or HPV status. For both OS and PFS, however, age was a significant predictor (HR, 1.07; 95% CI, 1.02-1.12;

Patient demographics were comparable between the 2 arms. Median age was 57 years (range, 32-81 years). Most of the patients (84%) were male. Almost all (98%) patients had stage IV carcinomas (61% &ge;T3, 77% &ge;N2b, 54% T4 or N3). The majority (66%) of patients smoked &ge;10 packs per year.

The induction chemotherapy had an overall response rate of 91%. Severe toxicity during induction chemotherapy was limited to rash and myelosuppression. Rash grade &ge;3 occurred in 23% of patients, and neutropenia &ge;3 occurred in 38% of patients.

Each arm had distinct adverse events (AEs) with CRT. The Cetux-FXH arm had increased dermatitis, with grade &ge;3 dermatitis in 81% of patients versus 51% in the Cetux-PX arm (

<.01). The Cetux-PX arm had increased myelosuppression, with grade &ge;3 neutropenia in 38% of patients versus 18% in the Cetux-FHX arm (

= .018), and increased dehydration, with grade &ge;3 dehydration in 17% of patients versus 2% in the Cetux-FHX arm (

<.01). One death (sepsis) occurred on the Cetux-PX arm.

&ldquo;In conclusion, the addition of cetuximab to induction chemotherapy and chemoradiotherapy in this trial was tolerable and produced long-term control of locally advanced head and neck cancer, particularly among poor-prognosis, HPV-negative patients. Both chemoradiotherapy platforms were well tolerated without any significant differences in survival,&rdquo; said Melotek.

He suggested that additional investigation of cetuximab might be merited in the neoadjuvant setting with intensification of treatment in high-risk subgroups and in the concurrent setting with nonplatinum-based CRT.

Melotek JM, Haraf DJ, Blair EA, et al. Final results of a randomized phase 2 trial investigating the addition of cetuximab to induction chemotherapy and accelerated or hyperfractionated chemoradiation therapy for locoregionally advanced head and neck cancer: HPV-negative subset analysis. Presented at: 2016 Multidisciplinary Head and Neck Cancer Symposium; Feb 18-20, 2016; Scottsdale, AZ. Abstract 7.

Adding cetuximab (Erbitux) to induction chemotherapy and hyperfractionated or accelerated chemoradiation therapy produced long-term control for patients with HPV-, locoregionally advanced head and neck squamous cell carcinoma with a poor prognosis.

Cetuximab Improves Long-Term Disease Control in HPV-Negative HNSCC

The trial was recently amended to add nivolumab to the combination of cetuximab and motolimod.

&ldquo;We know that PD-1 and PD-L1 are overexpressed in head and neck cancer, and so it was somewhat irresistible to combine our baseline treatment of cetuximab and motolimod with the PD-L1 inhibition pathway. EGFR itself drives PD-L1, so combining cetuximab with anti-PD-1 inhibitor makes sense. So, we&rsquo;ve amended this trial. We&rsquo;re now accruing to treatment with cetuximab, motolimod, and the antiPD-L1 nivolumab in this trial,&rdquo; said lead author Robert Ferris, MD, PhD, professor, Departments of Otolaryngology, Radiation Oncology, and Immunology, Cancer Immunology Program, University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania.

According to the authors of the data, the rationale for cetuximab plus motolimod as a neoadjuvant therapy was that cetuximab induces cellular immunity that correlates with neoadjuvant clinical response. The phase 1 dose-escalation and safety of the combination had been established (NCT 01334177).

This study of neoadjuvant cetuximab and motolimod had accrued 14 patients with HNSCC that was stage II-IV, resectable, and located in the oropharynx, oral cavity, hypopharynx, or larynx. These patients were biopsied, treated with cetuximab and motolimod for 4 weeks, and then underwent surgery. The endpoints of the trial were the modulation of immune biomarkers.

Interferon-inducible cytokine IP-10 increased after the patients were administered neoadjuvant cetuximab and motolimod (P = .0001). After the neoadjuvant treatment, the peripheral blood lymphocytes had an increased frequency of EGFR-specific CD8 T cells. After the neoadjuvant treatment, regulatory T cells had decreased suppressive receptors and transforming growth factor-&beta;, which induces Foxp3. Also, after the neoadjuvant treatment, circulating MDSCs had decreased PD-L1 (P <.07) and macrophages had increased CD16 expression (P <.07).

After the neoadjuvant treatment with cetuximab and motolimod, genotyping of T-cell receptors showed increased clonality in peripheral blood lymphocytes (P = .003 by Wilcox signed rank test) and tumor-infiltrating lymphocytes (P = .081 by Wilcox signed rank test). Most patients are more oligoclonal than healthy individuals, and some are very clonal with highly prominent expanded clones. Genotyping of T-cell receptors found that clonality was increased by the combination of cetuximab and motolimod compared with treatment with cetuximab alone.

Recent studies have indicated that the PD-1/PD-L1 pathway is upregulated in the HNSCC microenvironment, and that EGFR blockade prevents interferon-&gamma;-mediated upregulation of PD-L1. Thus, this study has been amended to add nivolumab to the adjuvant treatment with cetuximab and motolimod. The endpoints are still the modulation of immune biomarkers.

The aim is to target the tumor microenvironment, such that tumor immune escape is reversed and T cells eliminate HNSCC. Antitumor T cells are reprogrammed to reverse inhibitory signals. Combining the toll-like receptor agonist, motolimod, with cetuximab and with PD-1 pathway inhibitors, such as nivolumab, may enhance the priming and activity of T cells.

&ldquo;Targeting the tumor microenvironment requires understanding as well as reversal of immune escape mechanisms in the cellular compartment. Reprogramming antitumor T cells to reverse inhibitory signals can be done by directly disrupting those inhibitory signals, the so-called checkpoint receptor field, and can be done potentially by combining proinflammatory signals, such as toll-like receptor agonists, to chemo-attract cells into the microenvironment and to create good inflammation to overcome suppressive factors,&rdquo; said Ferris.

Recent findings have shown tremendous promise for nivolumab in head and neck cancer. Bristol-Myers Squibb (BMS) announced in January 2016 that nivolumab improved overall survival versus investigator&rsquo;s choice of therapy for patients with platinum-refractory squamous cell carcinoma of the head and neck in the phase III CheckMate-141 trial. Findings from the study are being discussed with the FDA and other health authorities, according to BMS.

Ferris RL, Kansy BA, Gibson SP, et al. A phase 1b study of neoadjuvant immune biomarker modulation with cetuximab and motolimod in head and neck cancer (HNC). Presented at: 2016 Multidisciplinary Head and Neck Cancer Symposium; Feb 18-20; Scottsdale, AZ. Abstract 8.

A neoadjuvant combination of motolimod plus cetuximab was found to increase the immune responses in both the blood and tumor microenvironment for patients with head and neck squamous cell carcinoma.

Author | Megan Garlapow, PhD

Articles

Consolidation to VRD Improves PFS in Patients With Newly Diagnosed Myeloma

Cetuximab Improves Long-Term Disease Control in HPV-Negative HNSCC

Motolimod Plus Cetuximab Proves Efficacious in Head and Neck Cancer