A phase 2 clinical trial of axitinib and avelumab in patients with recurrent/metastatic adenoid cystic carcinoma (ACC)

Background: ACC is a heterogeneous neoplasm and there is no standard treatment for patients (pts) with recurrent/metastatic (R/M) disease. Vascular endothelial growth factor receptor inhibitors (VEGFRi) are frequently used to treat R/M ACC rendering mostly disease stabilization. ACC is resistant to PD-1/PD-L1 inhibitors (PD-L1i), consistent with its low mutational burden and uninflamed immune microenvironment. We hypothesized that the immunomodulatory role of VEGFRi (axitinib) would enhance PD-L1i (Avelumab) activity and be a more effective therapy for R/M ACC. Methods: Eligible pts had R/M ACC with radiological or clinical progression within 6 months (mos) of enrollment. Treatment consisted of axitinib 5 mg PO bid and avelumab 10 mg/Kg IV every 2 weeks. Primary endpoint was objective response rate (ORR) per RECIST 1.1;secondary endpoints included duration of response (DOR), progression-free survival (PFS), overall survival (OS), and toxicity. Simon 2-stage design was applied to test the null hypothesis of ORR ≤ 5% versus the alternative ORR ≥ 20%;≥ 4 responses out of 29 pts was required to reject the null hypothesis. Results: 41 pts enrolled from 07/24/19 to 06/29/ 21;28 were evaluable for the primary endpoint (7 screen failures, 6 evaluable for safety only due to loss of insurance/logistics issues related to COVID-19 pandemic);16 pts were treated in first-line. Mutation data was available for 23 of 28 evaluable pts;7 had NOTCH1 activating mutations. The ORR was 17.9% (5/28, 95%CI: 6.1-36.9%). One response was unconfirmed (pt progressed in non-target lesions 2 mos after achieving a PR), for a confirmed ORR of 14.3% (95%CI: 4-32.7%). The median follow-up time for the 15 alive pts was 11.6 mos (min-max: 7.7-29.2 mos). Median PFS was 7.2 mos (95%CI: 3.7-11.7 mos) with a 6-mos PFS rate of 57% (95%CI: 41-79%). Median OS was 17.4 mos (95%CI: 13-NA). 5 pts remain on therapy, 2/5 with a PR. The median DOR for the 5 responders was 5.2 mos (95% CI: 3.7-NA mos). The most common treatment-related adverse events (TRAEs) were fatigue (62%), hypertension (32%), diarrhea (29%), and stomatitis (29%). Serious TRAEs occurred in 8 (24%) pts, all grade 3 and manageable. 4 (15%) pts discontinued avelumab and 9 (32%) underwent axitinib dose reduction due to toxicity. Conclusions: The study reached its primary endpoint with ≥ 4 responses out of 28 evaluable pts (ORR of 17.8%;confirmed ORR of 14.3%). The ORR and 6- mos PFS rate of 57% with axitinib and avelumab compares favorably with single agent axitinib and warrants further study of the combination.

Prescrire's ratings of new drugs in 2021: A brief review

Three new drugs, all based on messenger RNA or small interfering RNA technology, represented a major therapeutic advance in 2021. But the bigger picture is that most of the new authorisations that advanced patient care were adaptations of existing drugs. And that more than half of this year's new authorisations were not advances, and in fact about one-tenth represented a step backwards compared to existing options.

Real-world Adverse Event Data of the Avelumab plus Axitinib combination in Advanced Renal-cell Carcinoma

Introduction: Incidence rates of renal-cell carcinoma have increased by more than a third within the last decade.1 VEGF inhibitors were the mainstay of treatment options in the first-line setting up until the NICE Technology Appraisal in 2020 recommended avelumab plus axitinib combination for untreated advanced RCC within the Cancer Drugs Fund.2 Since then, the use of immunotherapy plus oral VEGF inhibitor has showed promising results in patients with good, intermediate or poor risk disease. The Javelin 101 trial demonstrated progression-free survival was significantly longer with avelumab plus axitinib than with the standard of care, sunitinib, however adverse events occurred in 99.5% of patients who received the combination.3 The complexity lies with the overlap of immunotherapy and VEGF inhibitor adverse events and how to distinguish between the two in order to effectively manage these. With the introduction of pharmacy-led clinics, a major role of the pharmacist has been toxicity management in this cohort of patients. Aim and objectives: To compare and quantify the incidence of common adverse events and resulting dose modifications and treatment delays between the Javelin 101 trial with a real-world cohort of patients treated at Mount Vernon Cancer Centre, MVCC. Methods: Electronic health records were retrospectively scrutinized for all patients who received avelumab plus axitinib treatment at MVCC between June 2020 and June 2021. Patients who commenced treatment in June 2021 or who had 1 cycle or less of treatment were excluded. Clinical data based on dose delays, adverse events and dose modifications was collected, collated and analysed. Results: A total of 36 patients were analysed and 97.2% experienced an adverse event. 52.7% of patients needed dose modifications of axitinib and 5.5% had a dose escalation. Comparatively the Javelin study had 42.2% of patients requiring a dose reduction and 10.8% received 1 dose escalation. Avelumab is given as a flat dose. Most common reasons for dose reductions at MVCC included diarrhoea, stomatitis, rash and palmar-plantar erythema. Dose reductions and dose delays are standard practice for managing toxicities from avelumab and axitinib. Hypothyroidism was the most common adverse event, affecting 50% of patients studied (Female 70%: Male 42%). Patients experienced diarrhoea (42%) throughout their treatment which is largely attributed to axitinib. This was effectively managed through dose delays. Due to Covid-19, patients were reviewed in telephone clinics hence hypertension primarily managed by GPs;hence dose delays due to elevated BP were not seen. Dyspnoea and cough symptoms required further investigation. A significant number of patients ended up with Covid-19 infections resulting in treatment delays. Others had pulmonary embolisms and quickly resumed their treatment once on anticoagulation. Some patients with transaminitis were managed with long term steroids resulting in extended dose delays. Conclusions: The occurrence of the adverse events in real-world data significantly differed in some areas to the Javelin 101 trial. The lack of face-to-face reviews due to the Covid-19 pandemic may have contributed to this. The non-medical prescriber pharmacist led clinics played a major role in managing avelumab and axitinib adverse events.

Avenue - Avelumab in the Frontline Treatment of Advanced Classic Hodgkin Lymphoma - a Window Study

AVENuE - Avelumab in the frontline treatment of advanced classic Hodgkin lymphoma - a window study Background Response adapted ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine) has become a standard of care in many countries for advanced stage classic Hodgkin Lymphoma (cHL), as investigated in the RATHL study: following 2 cycles of ABVD patients with negative (Deauville 1-3) interim PET (iPET2) proceeded to 4 cycles of AVD;those with positive (Deauville 4-5) iPET2 intensified therapy to escalated bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, prednisolone (escBEACOPP) or BEACOPP every 14 days. Overall this strategy was associated with a 3-year progression free survival (PFS) of 82.6%, and outcomes for patients with positive iPET2 were disappointing with 3y progression-free survival (PFS) of 67.5%. More intensive treatment such as upfront use of escBEACOPP has been reported to produce higher PFS (89% at 5 years), but it is unclear whether overall survival (OS) is improved. More intensive treatment is, however, associated with higher risk of toxicity. Inhibitors of programmed cell death protein 1 (PD-1) or programmed death-ligand 1 (PD-L1) have established efficacy in relapsed / refractory cHL with response rates of 55-87%. In the front line setting PD-1 inhibitors have a reported complete metabolic response (CMR) rate of 18-37%. Response to PD-L1 inhibitors in the frontline setting has not been explored. Serial serum TARC (thymus and activation-regulated chemokine) is reported to be prognostic in the frontline treatment of cHL and may aid response assessment because PET interpretation with checkpoint inhibitors is often complex. In the context of PD-1 inhibition, PD-1 expression by immunohistochemistry (IHC) and 9p24.1 copy gain by fluorescence in situ hybridisation (FISH) are reported to correlate with response. Methods AVENuE is a Phase II single-arm multicentre study with sites in the UK and Australia assessing the safety and efficacy of 2 cycles (4 doses) of the PD-L1 inhibitor avelumab for untreated high-risk stage II-IV cHL prior to the iPET2 response adapted approach described above. Eligible patients must be 16-60 years, ECOG 0-1, and have adequate organ function. Patients with;compressive symptoms from lymphoma, autoimmune disorders or immunosuppressive treatment within 2 months are excluded. The primary endpoint is the centrally reviewed PET CMR rate to avelumab. Secondary endpoints are: the safety and tolerability of sequential avelumab and combination chemotherapy as assessed by CTCAE v 5.0;the iPET2 CMR rate after avelumab and 2 cycles of ABVD;PFS and OS at one year. Using a single stage A'hern design, target recruitment is 47 patients to give 90% power at a 0.05% one sided alpha to exclude an overall response rate (ORR) to 2 cycles of avelumab of < 20%;an ORR of 40% would be considered worthy of further study. Recruitment has continued during the COVID-19 pandemic. 29 patients have been enrolled. Exploratory endpoints include correlating disease response with baseline PD-1 copy number by FISH and PD-1 expression by IHC. Serial serum TARC is being explored as an aid to response assessment and changes in peripheral blood immune cell subset are being investigated as possible biomarkers of response. Trial funder: Pfizer Ltd in alliance with Merck KGaA Pfizer Ltd is providing funding as part of an Alliance between Pfizer and Merck KGaA Clinical trials.gov NCT03617666 EUDRACT No.: 2018-002227-42 Disclosures: Hawkes: Roche: Membership on an entity's Board of Directors or advisory committees, Other: Travel and accommodation expenses, Research Funding, Speakers Bureau;Regeneron: Speakers Bureau;Merck KgA: Research Funding;Astra Zeneca: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau;Janssen: Speakers Bureau;Merck Sharpe Dohme: Membership on an entity's Board of Directors or advisory committees;Novartis: Membership on an entity's Board of Directors or advisory committees;Gilead: Membership on an entity's Boa d of Directors or advisory committees;Antigene: Membership on an entity's Board of Directors or advisory committees;Bristol Myers Squib/Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding;Specialised Therapeutics: Consultancy. Barrington: Bristol Myers Squibb international corporation: Research Funding;Pfizer Inc: Research Funding;Amgen Ltd: Research Funding;Takeda Speakers Bureau: Honoraria. McKay: Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees;Gilead: Honoraria, Other: Travel Support;KITE: Honoraria, Membership on an entity's Board of Directors or advisory committees;Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Support;Janssen: Honoraria, Other: Travel Support;Beigene: Honoraria, Membership on an entity's Board of Directors or advisory committees;BMS/Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. Iyengar: Janssen: Other: conference support, Speakers Bureau;Abbvie: Other: conference support;Beigene: Membership on an entity's Board of Directors or advisory committees;Gilead: Membership on an entity's Board of Directors or advisory committees, Other: conference support, Speakers Bureau;Takeda: Membership on an entity's Board of Directors or advisory committees, Other: conference support, Speakers Bureau. Radford: Takeda: Consultancy, Honoraria, Research Funding, Speakers Bureau;AstraZeneca: Current holder of individual stocks in a privately-held company;ADC Therapeutics: Consultancy, Current holder of individual stocks in a privately-held company, Honoraria, Speakers Bureau;BMS: Honoraria. Shah: Abbvie, Janssen and Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees. Clifton-Hadley: Bristol-Myers Squibb Pharmaceuticals Ltd.: Other: The haematology team at the CTC has received funding (which in part pays staff salary) to Sponsor and coordinate clinical trials.;Amgen: Other: The haematology team at the CTC has received funding (which in part pays staff salary) to Sponsor and coordinate clinical trials.;Celgene: Other: The haematology team at the CTC has received funding (which in part pays staff salary) to Sponsor and coordinate clinical trials.;Merck Sharp and Dohme: Other: The haematology team at the CTC has received funding (which in part pays staff salary) to Sponsor and coordinate clinical trials.;Janssen-Cilag: Other: The haematology team at the CTC has received funding (which in part pays staff salary) to Sponsor and coordinate clinical trials.;Pfizer: Other: The haematology team at the CTC has received funding (which in part pays staff salary) to Sponsor and coordinate clinical trials.;Millennium pharmaceutics inc.: Other: The haematology team at the CTC has received funding (which in part pays staff salary) to Sponsor and coordinate clinical trials. Collins: Beigene: Membership on an entity's Board of Directors or advisory committees;Novartis: Honoraria, Speakers Bureau;Pfizer: Honoraria;Celgene: Research Funding;Amgen: Research Funding;AstraZeneca: Honoraria, Research Funding;ADC Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees;Celleron: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding;Merck Sharp & Dohme: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding;Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau;Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau;Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau;Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel expenses, Speakers Bureau. OffLabel Disclosure: Avelumab prior to frontline chemotherapy in advanced stage classic Hodgkin lymphoma.

Avelumab, a PD-L1 Inhibitor, in Combination with Hypofractionated Radiotherapy and the Abscopal Effect in Relapsed Refractory Multiple Myeloma.

LESSONS LEARNED: Despite the initial optimism for using immune checkpoint inhibition in the treatment of multiple myeloma, subsequent clinical studies have been disappointing. Preclinical studies have suggested that priming the immune system with various modalities in addition to checkpoint inhibition may overcome the relative T-cell exhaustion or senescence; however, in this small data set, radiotherapy with checkpoint inhibition did not appear to activate the antitumor immune response. BACKGROUND: Extramedullary disease (EMD) is recognized as an aggressive subentity of multiple myeloma (MM) with a need for novel therapeutic approaches. We therefore designed a proof-of-principle pilot study to evaluate the synergy between the combination of the anti-PD-L1, avelumab, and concomitant hypofractionated radiotherapy. METHODS: This was a single-arm phase II Simon two-stage single center study that was prematurely terminated because of the COVID-19 pandemic after enrolling four patients. Key eligibility included patients with relapsed/refractory multiple myeloma (RRMM) who had exhausted or were not candidates for standard therapy and had at least one lesion amenable to radiotherapy. Patients received avelumab until progression or intolerable toxicity and hypofractionated radiotherapy to a focal lesion in cycle 2. Radiotherapy was delayed until cycle 2 to allow the avelumab to reach a study state, given the important observation from previous studies that concomitant therapy is needed for the abscopal effect. RESULTS: At a median potential follow-up of 10.5 months, there were no objective responses, one minimal response, and two stable disease as best response. The median progression-free survival (PFS) was 5.3 months (95% confidence interval [CI]: 2.5-7.1 months), and no deaths occurred. There were no grade ≥3 and five grade 1-2 treatment-related adverse events. CONCLUSION: Avelumab in combination with radiotherapy for patients with RRMM and EMD was associated with very modest systemic clinical benefit; however, patients did benefit as usual from local radiotherapy. Furthermore, the combination was very well tolerated compared with historical RRMM treatment regimens.