Background

The management of R/M NPC remains a challenge worldwide due to its poor prognosis and limited treatment option after prior chemotherapy. Camrelizumab, a humanized anti–PD-1 antibody, had shown favorable anti-tumor activity and manageable toxicities in R/M NPC in previous phase I trial (Fang et al. Lancet Oncol 2018). We conducted this phase II trial (CAPTAIN) to further assess the efficacy and safety of camrelizumab in R/M NPC.

Methods

Patients with histologically confirmed R/M NPC (stage IVb) who had progressed on ≥2 lines of chemotherapy were enrolled and received camrelizumab at 200 mg IV q2w. The primary endpoint was ORR assessed by independent review committee (IRC) per RECIST v1.1.

Results

From Aug 14, 2018 to Dec 30, 2019, 156 eligible patients were enrolled and received camrelizumab treatment. As of data cutoff on Mar 31, 2020, the median follow-up time was 9.2 months (range 0.7–19.1). Of the 156 patients, 44 (28.2%, 95% CI 21.3–36.0) patients had an objective response assessed by IRC, including one complete response and 43 partial responses. Median DoR was not reached (95% CI 7.4–not estimable), and the 12-month DoR rate was 53.7% (95% CI 30.9–72.0). Median PFS per IRC was 3.7 months (95% CI 2.0–3.9) and median OS was 17.1 months (95% CI 15.2–not estimable). Treatment-related adverse events (TRAEs) of any grade were observed in 151 (96.8%) of the 156 patients. TRAEs of ≥3 grade occurred in 22 (14.1%) patients, with the most common ones being increased gamma-glutamyl transferase (3.2%) and anaemia (3.2%). Treatment interruption and discontinuation due to TRAEs occurred in 18 (11.5%) and one (0.6%) patients, respectively. Seventeen (10.9%) patients had serious TRAEs, and one death was considered as drug-related. Plasma Epstein-Barr virus DNA and evaluable tumor samples for biomarker analysis were obtained and the result will be presented at the meeting.

Conclusions

Camrelizumab demonstrated promising anti-tumor activity and favorable safety profile in patients with R/M NPC who had progressed on ≥2 lines of chemotherapy, thus could represent a novel treatment option for this patient population.

Clinical trial identification

NCT03558191; CTR20180865.

Legal entity responsible for the study

Jiangsu Hengrui Medicine Co., Ltd.

Funding

Jiangsu Hengrui Medicine Co., Ltd.

Disclosure

Q. Yang, B. Zhang: Full/Part-time employment: Jiangsu Hengui Medicine Co., Ltd. All other authors have declared no conflicts of interest.

Background

Nasopharyngeal carcinoma (NPC) survivors have an increased risk of second primary cancer (SPC) after definitive radiotherapy. It has been speculated that the routine use of intensity-modulated radiotherapy (IMRT) further increases the risk of radiation-associated SPC, but long-term clinical data with reference to population cancer incidences are lacking.

Methods

This is a territory-wide multicentered study. Consecutive NPC patients (n=3166) who underwent definitive IMRT in all six public oncology centers in Hong Kong between 2001 and 2010 were included. SPC risks were quantified by standardized incidence ratios (SIR) and absolute excess risks (AER), estimated from age-, sex- and calendar year-specific population cancer incidence data from the Hong Kong Cancer Registry. Predictive factors for SPC occurrence were analyzed by Cox regression. SPC-specific mortality was estimated using competing risk model.

Results

With a median follow-up of 10.8 years, 290 SPCs were observed with a crude incidence of 9.2%. Cancer risk in NPC survivors was 90% higher than that in general population (SIR, 1.9; 95% CI, 1.7–2.2), with an AER of 52.1 (95% CI, 36.8–67.3) per 10,000 person-years at risk. Significant excess cancer risks were observed for oral cavity (SIR, 26.3; 95% CI, 19.1–33.6), soft tissue or bone sarcoma (SIR, 15.2; 95% CI, 9.3–21.2), oropharynx (SIR, 11.4; 95% CI, 4.0–18.9), paranasal sinus (SIR, 8.6; 95% CI, 1.7-25.1), salivary gland (SIR, 6.8; 95% CI, 1.4-20.0), non-melanoma skin (SIR, 3.6; 95% CI, 1.5–5.7), thyroid (SIR, 3.4; 95% CI, 1.2–5.6) and lung (SIR, 1.8; 95% CI, 1.3–2.3). Advanced age, smoking, hepatitis B status and re-irradiation were independent predictive factors for SPC occurrence. SPC constituted 9.4% of all deaths during study period, the 5-year and 10-year SPC-specific mortality were 0.9% and 3.4% respectively. Median overall survival after SPC occurrence was 2.4 years.

Conclusions

Second cancer risk after IMRT for NPC was substantial within the irradiated head and neck regions. Relative risk of SPC after IMRT was comparable with historical reports in the conventional 2-dimensional radiotherapy era. SPC impairs long-term survival of NPC patients, close surveillance is warranted as part of survivorship care.

Legal entity responsible for the study

The authors.

Funding

Health and Medical Research Fund, The Government of the Hong Kong Special Administrative Region.

Disclosure

All authors have declared no conflicts of interest.

Background

Chemo-radiation (CRT) with high dose cisplatin (Cis) 100 mg/m² q3w (3 cycles) is the standard of care (SOC) in LA-HNSCC. Cumulative delivered dose of Cis is prognostic of survival, even beyond 200 mg/m² (P Strojan 2016) but high toxicity compromises its delivery. Fractionated dose of Cis allows decreasing the serum concentration peak and toxicity. No direct comparison was done of SOC vs. fractionated high dose Cis (FHD Cis) leading the GORTEC to conduct a randomized phase II.

Methods

The trial, stratified on postoperative or definitive CRT, compares SOC to FHD Cis (25 mg/m²/d d1-4 q3w (3 cycles)) concomitantly to definitive (70 Gy/7 weeks) or postoperative (66 Gy/6.5 weeks) RT. The primary endpoint was the cumulative delivered Cis dose.

Results

A total of 124 patients (pts) were randomized at 10 sites in France: 65 in SOC arm and 59 in FHD Cis arm. Median age: 60, Male: 85%, ECOG 0: 50%, Stage IV: 77%, definitive CRT: 58%, oropharynx: 51% (p16+: 43%), smoking history 89% of pts (median of 40 pack-years), all well balanced between the 2 arms. The median cumulative Cis dose was 291 mg/m² (interquartile [IQ]: 256-298) for FHD Cis vs. 280 mg/m² (IQ: 199-295) for SOC (p=0.03). 84% of pts with FHD Cis received the third cycle of Cis vs. 67% with SOC (p=0.03). Overall, 50 (35%) grade III-IV acute toxicities occurred with FHD Cis vs. 91 (65%) with SOC (p<0.001) leading to 19 SAEs with FHD Cis vs. 32 with SOC, including one toxic death with pneumonitis and febrile neutropenia (p=0.07). With a median follow-up of 2.2 years (yrs) (0-3.4), the 2-yr loco-regional failure-free survival (LRFFS) was 61% with FHD Cis vs. 58% with SOC (hazard ratio [HR]=0.97, 95%CI: 0.54-1.74, p=0.91). The 2-yr progression-free and overall survival FHD Cis / SOC were: 54%/ 54% (HR=1.05, 95%CI: 0.60-1.81, p=0.87) and 69%/ 68% (HR=0.88, 95%CI: 0.48-1.66, p=0.67) respectively.

Conclusions

FHD Cis allowed significantly more Cis to be delivered, with significantly lower toxicity, when compared to SOC. LRFFS, PFS and OS were not significantly different between the two arms. FHD Cis concomitantly with RT is a treatment option which deserves further consideration.

Clinical trial identification

EudraCT: 2015-001928-29.

Legal entity responsible for the study

GORTEC Group.

Funding

GORTEC Group.

Disclosure

C. Borel: Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses: Merck; Honoraria (self), Advisory/Consultancy: BMS; Honoraria (self), Advisory/Consultancy, Travel/Accommodation/Expenses: AstraZeneca; Honoraria (self): MSD. X. Sun: Honoraria (self), Travel/Accommodation/Expenses: Novartis; Honoraria (self): Merck; Advisory/Consultancy: BMS. A. Coutte: Honoraria (self): Merck; Honoraria (self): Takeda; Honoraria (self): BMS; Honoraria (self): Roche; Honoraria (self): Sanofi. G. Bera: Advisory/Consultancy, Travel/Accommodation/Expenses: Sanofi; Advisory/Consultancy, Travel/Accommodation/Expenses: Astellas; Advisory/Consultancy, Travel/Accommodation/Expenses: Janssen; Advisory/Consultancy, Travel/Accommodation/Expenses: BMS. S. Zanetta: Travel/Accommodation/Expenses: Ipsen. M. Alfonsi: Honoraria (self), Advisory/Consultancy: Merck; Honoraria (self), Advisory/Consultancy: Novartis; Advisory/Consultancy: BMS; Advisory/Consultancy: EMD Serono. G. Janoray: Advisory/Consultancy: BMS. T. Chatellier: Advisory/Consultancy, Travel/Accommodation/Expenses: Roche; Advisory/Consultancy, Travel/Accommodation/Expenses: BMS. N. Etienne-Selloum: Honoraria (self): Lilly. J. Bourhis: Advisory/Consultancy: Merck; Advisory/Consultancy: MSD; Advisory/Consultancy: AstraZeneca; Advisory/Consultancy: BMS. All other authors have declared no conflicts of interest.

Background

In the phase III KEYNOTE-048 study, pembro significantly prolonged OS vs E in patients (pts) with PD-L1 combined positive score (CPS) ≥20 and CPS ≥1 and had noninferior OS in the total population (pop). Pembro+C significantly prolonged OS vs E in the PD-L1 CPS ≥20, CPS ≥1, and total pops. Safety was favorable for pembro vs E and comparable for pembro+C vs E. Results with 4y follow-up are shown.

Methods

Pts with locally incurable R/M HNSCC were randomized to 1L pembro 200 mg Q3W for 24 mo, pembro+C, or E. Pts in the pembro or pembro+C arms who stopped pembro with stable disease or better and then had PD could receive a second course of pembro if eligible. Follow-up was defined as time from randomization to database cutoff. Efficacy was analyzed in the ITT pop; safety was analyzed in all randomized pts who received ≥1 dose of study drug.

Results

Median study follow-up (March 25, 2020) was 46.2 mo for pembro vs E and 45.6 mo for pembro+C vs E. Pembro and pembro+C improved OS vs E in the CPS ≥20, CPS ≥1, and total pops (Table). Pembro 48-mo OS was 21.6%, 16.7%, and 15.4% in the CPS ≥20, CPS ≥1, and total pops, respectively, vs 8.0%, 5.9%, and 6.6% for E. Pembro+C 48-mo OS was 28.6%, 21.8%, and 19.4% in the CPS ≥20, CPS ≥1, and total pops, respectively, vs 6.6%, 4.1%, and 4.5% for E. OS, PFS, ORR, and DOR data are shown in the table. Treatment-related grade 3-5 AEs: 17.0% for pembro, 71.7% for pembro+C, and 69.3% for E. In all, 11 pts (pembro, 6; pembro+C, 5) received a secondcourse of pembro; ORR for second course was 36.4% (CR, 1; PR, 3).

Conclusions

Long-term follow-up confirmed the statistically significant improvement in OS established at the protocol-specified interim and final analyses for pembro vs E in pts with PD-L1 CPS ≥20 and CPS ≥1 and for pembro+C vs E in pts with PD-L1 CPS ≥20 and CPS ≥1, and total pop. Safety was favorable for pembro vs E and comparable for pembro+C vs E Table: 915MO

Clinical trial identification

NCT02358031; February 6, 2015.

Editorial acknowledgement

Medical writing and editorial assistance was provided by Doyel Mitra, PhD, CMPP, and Jo Bairzin, PhD, of the ApotheCom pembrolizumab team (Yardley, PA, USA). This assistance was funded by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.

Legal entity responsible for the study

Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.

Funding

Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.

Disclosure

R. Greil: Advisory/Consultancy: Celgene, Novartis, Roche, Bristol-Myers Squibb, Takeda, AbbVie, AstraZeneca, Janssen, MSD, Merck, Gilead Sciences, Daiichi Sankyo; Travel/Accommodation/Expenses: Rocher, Amgen, Janssen-Cilag, AstraZeneca, Novartis, MSD, Celgene, Gilead Sciences, Bristol-Myers Squibb; Honoraria (self): Celgene, Roche, Merck, Takeda, AstraZeneca, Novartis, Amgen, Bristol-Myers Squibb, MSD, Sandoz, AbbVie, Gilead Sciences, Daiichi Sankyo; Research grant/Funding (institution): Celgene, Merck, Takeda, AstraZeneca, Novartis, Amgen, Bristol-Myers Squibb, MSD, Sandoz, Gilead Sciences, Roche. D. Rischin: Travel/Accommodation/Expenses: Merck; Research grant/Funding (self): Genentech/Roche, Merck, Regeneron, Bristol-Myers Squibb, GlaxoSmithKline, Sanofi. K.J. Harrington: Honoraria (institution), Advisory/Consultancy: AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Merck Serono, MSD, Oncolys, Pfizer, Replimune; Research grant/Funding (institution): AstraZeneca, Boehringer Ingelheim, MSD, Replimune. D. Soulières: Advisory/Consultancy: Merck, Pfizer, Ipsen; Honoraria (self): Merck, Novartis, Pfizer, AstraZeneca, Ipsen, Bristol-Myers Squibb, Eisai, Adlai-Nortye; Research grant/Funding (institution): Novartis, Pfizer, Merck, Roche/Genentech, Bristol-Myers Squibb, Lilly. M. Tahara: Advisory/Consultancy: Ono Pharmaceutical, MSD, Pfizer, Bristol-Myers Squibb, Celgene, Amgen, Rakuten Medical, Bayer; Honoraria (self): Merck Serono, Bristol-Myers Squibb, Eisai, Ono Pharmaceutical MSD, AstraZeneca; Research grant/Funding (institution): Merck Sharp & Dohme, AstraZeneca, Ono Pharmaceutical, Novartis, Pfizer, Bristol-Myers Squibb, Loxo, Rakuten Medical, Bayer. G. de Castro: Advisory/Consultancy: Teva, Boehringer Ingelheim, Pfizer, Bayer, Roche, Merck Sharp & Dohme, Bristol-Myers Squibb, AstraZeneca, Yuhan; Speaker Bureau/Expert testimony: AstraZeneca, Bayer, Novartis, Roche, Merck Serono, Bristol-Myers Squibb, Merck Sharp & Dohme, Boehringer Ingelheim, Pfizer; Travel/Accommodation/Expenses: Merck Sharp & Dohme, Novartis, Pfizer, Roche, AstraZeneca, Boehringer Ingelheim, Bayer, Bristol-Myers Squibb; Honoraria (self): AstraZeneca, Pfizer, Merck Sharp & Dohme, Bristol-Myers Squibb, Novartis, Roche, Boehringer Ingelheim. A. Psyrri: Advisory/Consultancy: AstraZeneca, MSD Oncology, Pfizer, Bristol-Myers Squibb, Amgen, Rakuten; Travel/Accommodation/Expenses: Roche, MSD Oncology, Ipsen, Bristol-Myers Squibb, Ipsen; Honoraria (self): Merck Serono, Roche, Bristol-Myers Squibb, MSD Oncology, Genesis Pharmaceuticals, Bayer, Rakuten, AstraZeneca, Pfizer; Research grant/Funding (self): Kura, Bristol-Myers Squibb, Roche, Amgen, Boehringer Ingelheim, Pfizer, Demo Pharmaceutical, Pharmaten; Non-remunerated activity/ies: AstraZeneca. N. Baste: Advisory/Consultancy: Bristol-Myers Squibb, Merck Serono, Nanobiotix; Travel/Accommodation/Expenses: Bristol-Myers Squibb, Merck Serono, Nanobiotix, AstraZeneca, GlaxoSmithKline, MSD. P. Neupane: Advisory/Consultancy: Pfizer/EMD Serono; Research grant/Funding (self): Merck Sharp & Dohme, Bristol-Myers Squibb. T. Fuereder: Honoraria (self): MSD, Merck Darmstadt, Roche, Bristol-Myers Squibb, Accord Healthcare, Sanofi, Boehringer Ingelheim; Advisory/Consultancy: MSD, Merck Darmstadt, Amgen, Pfizer, Sanofi; Research grant/Funding (institution): MSD, Merck Darmstadt, Bristol-Myers Squibb; Travel/Accommodation/Expenses: Roche, MSD, Bristol-Myers Squibb. B.G.M. Hughes: Advisory/Consultancy: MSD Oncology, Bristol-Myers Squibb, Roche, Pfizer, Boehringer Ingelheim, AstraZeneca, Eisai; Research grant/Funding (institution): Amgen. R. Mesia, Sr.: Advisory/Consultancy: Bristol-Myers Squibb, MSD, Merck KGaA, Roche, AstraZeneca, Nanobiotix; Speaker Bureau/Expert testimony: Bristol-Myers Squibb, Merck KGaA; Travel/Accommodation/Expenses: Merck KGaA, Bristol-Myers Squibb, Roche. N. Ngamphaiboon: Advisory/Consultancy: Roche, MSD, Amgen, Novartis, Boehringer Ingelheim, Taiho Pharmaceutical; Speaker Bureau/Expert testimony: Roche, AstraZeneca, Eisai, Amgen, MSD, Novartis; Travel/Accommodation/Expenses: Roche, MSD, Amgen, Novartis, Merck, Eisai, Taiho Pharmaceutical; Honoraria (self): Roche, AstraZeneca, Eisai, Amgen, MSD, Novartis; Research grant/Funding (self): MSD, Pfizer, Roche, AstraZeneca. T. Rordorf: Advisory/Consultancy: MSD, Bristol-Myers Squibb. W.Z. Wan Ishak: Honoraria (self): MSD Ltd, Eisai Korea, Eisai Malaysia, Mundipharma, Merck Serono, Roche Myanmar, Eli Lilly Malaysia, Roche Malaysia, Pfizer Malaysia, Amgen Malaysia; Advisory/Consultancy: Eli Lilly Malaysia, Merck Serono Malaysia, Roche Malaysia, Mundi Pharma Malaysia, Boehringer Ingelheim Malaysia; Speaker Bureau/Expert testimony: Roche Malaysia, Eli Lilly Malaysia, Boehringer Ingelheim Malaysia; Research grant/Funding (institution): Roche, Amgen, Merck; Travel/Accommodation/Expenses: MSD Ltd, Eisai Korea, Disai Malaysia, Mundipharma, Merck Serono, Roche Myanmar, Eli Lilly Malaysia, Roche Malaysia, Pfizer Malaysia, Amgen Malaysia, Amgen Malaysia, Eli Lilly Malaysia, Merck Serono Malaysia, Mundi Pharma Malaysia, Boehringer Ingelheim Mal. J. Lin: Full/Part-time employment: Merck. R.F. Swaby, B. Gumuscu: Shareholder/Stockholder/Stock options, Full/Part-time employment: Merck. B. Burtness: Advisory/Consultancy: Merck, Debiopharm Group, AstraZeneca, Bristol-Myers Squibb, Alligator Bioscience, Aduro Biotech, GlaxoSmithKline, Celgene, CUE Biopharma, Maverick therapeutics, Rakuten, Nanobiotix, Macrogenics, ALX Oncology; Travel/Accommodation/Expenses: Merck, Debiopharm Group, Boehringer Ingelheim; Honoraria (self): AstraZeneca; Research grant/Funding (institution): Merck, Aduro Biotech, Formation Biologics, Bristol-Myers Squibb, Exelixis. All other authors have declared no conflicts of interest.

Background

Immunotherapy targeting programmed death protein 1 (PD-1) or its ligand (PD-L1) offers clinical benefit in HNSCC, but combination treatments are needed to improve outcomes. Here we report initial safety and efficacy of the anti-PD-L1 durvalumab plus MEDI0457, a DNA immunotherapeutic vaccine expressing HPV 16/18 E6/E7 proteins and IL-12, in pts with HPV+ R/M HNSCC.

Methods

This phase Ib/IIa, open-label, multicenter study (NCT03162224) enrolled pts with incurable, histologically/cytologically confirmed R/M HPV+ HNSCC, who had ≥1 prior platinum-containing regimen or other approved therapy if platinum-ineligible. MEDI0457 at a dose of 7 mg IM (weeks 1, 3, 7, then Q8W after week 12) and durvalumab 1500 mg IV Q4W were given until disease progression or unacceptable toxicity. Primary objectives included safety and efficacy by objective response rate (ORR; RECIST v1.1). Exploratory endpoints included induction of antibodies and HPV-specific T cells peripherally. Tumor-infiltrating T cells were measured.

Results

In July 2017 to Aug 2019, 35 pts were enrolled. Most were male (97.1%) with oropharyngeal primary (82.9%); 31.4% had PD-L1 ≥25%. At the interim data cutoff (DCO; 22 Nov 2019), therapy was ongoing in 13 pts (37.1%) and 27 were response-evaluable. Treatment-related adverse events (TRAEs) occurred in 77.1% of pts, mostly of Grade 1–2 severity. Fatigue (37.1%) and injection site pain (34.3%) were most common. Five pts (14.3%) had Grade 3 TRAEs and 1 pt (2.9%) had 3 serious Grade 3 TRAEs (AST and ALT increased and myocarditis causing discontinuation). No pts had Grade 4/5 TRAEs. ORR was 22.2% with 3 complete responses (all ongoing at DCO) and 3 partial responses (2 ongoing at DCO). Peripheral HPV-specific T cells and tumoral CD8+ T cells were increased. Table: 916MO

Conclusions

MEDI0457 plus durvalumab was well tolerated and showed clinical benefit. The study is active but not recruiting.

Clinical trial identification

NCT03162224.

Editorial acknowledgement

Medical writing support was provided by James Holland, PhD, of Cirrus Communications, an Ashfield company, and was funded by AstraZeneca.

Legal entity responsible for the study

AstraZeneca.

Funding

AstraZeneca.

Disclosure

C. Aggarwal: Advisory/Consultancy: AstraZeneca; Advisory/Consultancy: Bristol-Myers Squibb; Advisory/Consultancy: Celgene; Advisory/Consultancy: Eli Lilly; Advisory/Consultancy: Merck; Advisory/Consultancy: Roche. N.F. Saba: Advisory/Consultancy: Merck; Advisory/Consultancy: Bristol-Myers Squibb; Advisory/Consultancy: Rakuten; Advisory/Consultancy: Biontech; Advisory/Consultancy: Aduro; Advisory/Consultancy: Pfizer; Advisory/Consultancy: GlaxoSmithKline. A.P. Algazi: Research grant/Funding (institution): AstraZeneca; Research grant/Funding (institution): GlaxoSmithKline; Research grant/Funding (institution): Novartis; Advisory/Consultancy, Travel/Accommodation/Expenses, Shareholder/Stockholder/Stock options: OncoSec; Advisory/Consultancy, Shareholder/Stockholder/Stock options: Valitor; Honoraria (self), Research grant/Funding (institution): Regeneron; Honoraria (self): Array; Research grant/Funding (institution): Acerta; Research grant/Funding (institution): Amgen; Research grant/Funding (institution): Bristol-Myers Squibb; Research grant/Funding (institution): Dynavax; Research grant/Funding (institution): Genentech; Research grant/Funding (institution): Idera Pharma; Research grant/Funding (institution): Incyte; Research grant/Funding (institution): ISA; Research grant/Funding (institution): Loxo Oncology; Research grant/Funding (institution): Merck; Research grant/Funding (institution): Pfizer; Research grant/Funding (institution): Sensei; Research grant/Funding (institution): Tessa. A. Sukari: Shareholder/Stockholder/Stock options: Immunomedics; Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (institution): Eisai; Advisory/Consultancy: Bayer; Speaker Bureau/Expert testimony: Merck. T. Seiwert: Advisory/Consultancy: AstraZeneca. M. Haigentz: Advisory/Consultancy: Amgen; Advisory/Consultancy: Genentech; Advisory/Consultancy: Takeda; Advisory/Consultancy: AstraZeneca. M. Porosnicu: Research grant/Funding (institution), I have an investigator initiated clinical trial: AstraZeneca. J. Boyer: Shareholder/Stockholder/Stock options, Full/Part-time employment: Inovio. N. Durham, R. Kumar, K. Laubscher, M. Gong, N. Ceaicovscaia, A. Gascó Hernández: Shareholder/Stockholder/Stock options, Full/Part-time employment: AstraZeneca. All other authors have declared no conflicts of interest.

Background

In the randomized phase III Study CA209141, Nivolumab (N) demonstrated significant overall survival (OS) benefit with favorable safety profile for platinum refractory R/M SCCHN and is now approved for these patients (pts). The objectives of the current study were to provide additional insights into the frequency of high-grade adverse events (AEs) related to N and the efficacy of N in real life.

Methods

From 08/2017 to 11/2018, 343 pts were treated in the multicenter phase II TOPNIVO. The main inclusion criteria were pts with platinum refractory R/M SCCHN, ECOG 0-2. Pts received N 3mg/kg every 2 weeks intravenously. We report safety and efficacy (OS, progression free survival (PFS), overall response rate (ORR)).

Results

Median age was 62 yr (73 pts ≥ 70 yr), 81% male, 85% ECOG 0-1, 15% ECOG 2. Cancer primary site was oropharynx 40%, oral cavity 24%, hypopharynx 20%, larynx 15%. 37% had loco regional (LR) relapse, 30% metastatic disease and 33% both. 51% had received one prior line of chemotherapy and 27% two prior lines before inclusion. Median number of N administrations was 6 (from 1 to 63). 233 pts (68%) experienced ≥ 1 AE grade ≥3. On the 434 AEs grade 3-4, 53 (mainly pneumopathy, lipase increase, endocrine disorders and asthenia) were related to N and occurred in 36 pts (10%). On the 89 AEs grade 5, 5 were considered related to N (3 pneumonitis, 1 hepatitis, 1 cardiac arrest). Median follow-up was 23.5 months (mo). 268 pts died. OS, PFS and ORR are reported in the table. Sex, ECOG, type of relapse and number of prior lines were significantly associated with OS in multivariate analysis. Sex and type of relapse were significantly associated with PFS and ORR in multivariate analysis. Table: 917MO

Conclusions

The final analysis of the TOPNIVO study shows no additional toxicities of N compared to what has been described previously, confirms the previous results in terms of efficacy with new data for prognostic factors.

Clinical trial identification

NCT03226756.

Legal entity responsible for the study

Unicancer.

Funding

BMS.

Disclosure

C. Even: Advisory/Consultancy: BMS; Advisory/Consultancy: Innate Pharma; Advisory/Consultancy: MSD; Advisory/Consultancy: Merck Serono. A. Daste: Advisory/Consultancy, Travel/Accommodation/Expenses: BMS; Advisory/Consultancy, Travel/Accommodation/Expenses: AstraZeneca; Advisory/Consultancy, Travel/Accommodation/Expenses: Merck Serono; Advisory/Consultancy: MSD. J. Fayette: Advisory/Consultancy: MSD; Advisory/Consultancy: BMS; Advisory/Consultancy: AstraZeneca; Advisory/Consultancy: Roche; Advisory/Consultancy: Servier; Advisory/Consultancy: Merck Serono. E. Saada-Bouzid: Advisory/Consultancy, Travel/Accommodation/Expenses: BMS; Advisory/Consultancy, Travel/Accommodation/Expenses: MSD; Advisory/Consultancy, Travel/Accommodation/Expenses: AstraZeneca. C. Toullec: Honoraria (self), Travel/Accommodation/Expenses: Merck Serono; Honoraria (self), Travel/Accommodation/Expenses: Sanofi; Honoraria (self), Travel/Accommodation/Expenses: MSD; Honoraria (self), Travel/Accommodation/Expenses: Ipsen; Honoraria (self), Travel/Accommodation/Expenses: Amgen; Honoraria (self), Travel/Accommodation/Expenses: Servier; Honoraria (self), Travel/Accommodation/Expenses: BMS. A.C. Johnson: Travel/Accommodation/Expenses: BMS. C. Le Tourneau: Advisory/Consultancy: MSD; Advisory/Consultancy: BMS; Advisory/Consultancy: Merck Serono; Advisory/Consultancy: Roche; Advisory/Consultancy: AstraZeneca; Advisory/Consultancy: Seattle Genetics; Advisory/Consultancy: Rakuten; Advisory/Consultancy: Nanobiotix; Advisory/Consultancy: GSK. J. Guigay: Advisory/Consultancy, Research grant/Funding (institution): Merck Serono; Advisory/Consultancy, Research grant/Funding (institution): BMS; Advisory/Consultancy: Innate Pharma; Advisory/Consultancy: AstraZeneca. All other authors have declared no conflicts of interest.

Background

Effective systemic therapies are lacking for mSGT and no standard EMA-approved agents are available. Molecular alterations can guide targeted therapeutics, but the value of comprehensive genomic/proteomic profiling to detect clinically relevant targeteable alterations (TA) as per ESCAT remains to be studied.

Methods

We analyzed all mSGT pts treated at VHIO phase I Unit from 2016 to 2019. Clinicopathological features, molecular alterations and treatment modalities were correlated with outcomes (objective response rates [ORR] and progression-free survival [PFS]). Clinical actionability of multigene panel testing (NGS) and immunohistochemistry (IHC) was defined as per ESCAT scale.

Results

In total 107 pts with baseline NGS were identified, median age was 56.7 years, 93 pts (86.9%) ECOG ≤1, primary tumor histology was adenoid cystic carcinoma in 47%, salivary duct carcinoma in 13%, myoepithelial carcinoma in 8%, other in 32%. Median number of treatment lines was 1.5 (range 0-10), median overall survival was 51.5 months (m) (95%CI 33.9-NA) and median follow-up 25.5 m. On IHC, HER2 overexpression in 7%, Androgen Receptor (AR) in 43% and Estrogen/Progesterone Receptor (ER/PR) in 12%. On NGS, PIK3CA mut in 7%, NOTCH1 mut in 6%, FGFR1-3 mut in 5%, NTRK fusion in 4%. Out of 11 samples with tumor mutation burden assessed, all were low (median=2.5 mut/Mb, range 0-5). According to ESCAT, 48 pts (45%) showed at least one TA and 29 (27%) were treated accordingly. In total, 20 ESCAT levels 1/2 therapies (1 NTRK, 6 HER2, 13 RA) and 13 ESCAT levels 3/4 therapies (2 RE/RP, 5 PIK3CA, 3 FGFR, 1 EGFR, 2 NOTCH) were tested. ORR was 30%, with a trend for higher ORR in level 1/2 vs. 3/4 (Odds ratio 9.8, p= 0.058). Median PFS on TA was 5 months (CI95% 3.45-19.04), not different as per ESCAT levels (3.4 months vs. 12.4 months, hazard ratio 0.6, p= 0.23).

Conclusions

In our cohort, molecularly-guided TA have promising activity in pts with mSGT. These results suggest that MGT and IHC tests are of potential value in selected populations. Response rates are higher with therapies matched to ESCAT level 1/2 alterations, but long-term disease control can also be achieved with more emerging actionability markers levels 3/4.

Legal entity responsible for the study

Vall d´Hebron Institute of Oncology.

Funding

Comprehensive Program of Cancer Immunotherapy and Immunology (CAIMI) supported by the Banco Bilbao Vizcaya Argentaria Foundation (BBVA Foundation) (grant 89/2017). -La Caixa Foundation (LCF/PR/CEO7/50610001). Cellex Foundation providing research facilities and equipment.

Disclosure

A. Hernando-Calvo: Travel/Accommodation/Expenses: Kyowa Kirin. A.B. Azaro Pedrazzoli: Advisory/Consultancy: Orion Pharma; Advisory/Consultancy, Research grant/Funding (self): Amcure GmbH. M. Vieito: Advisory/Consultancy: Debio; Advisory/Consultancy, Travel/Accommodation/Expenses: Roche; Advisory/Consultancy: TFS; Travel/Accommodation/Expenses: Merck Serono. O. Saavedra Santa Gadea: Travel/Accommodation/Expenses: MSD; Travel/Accommodation/Expenses: Kyowa Kirin. R. Dienstmann: Advisory/Consultancy, Speaker Bureau/Expert testimony: Roche; Advisory/Consultancy: Boehringer Ingelheim; Speaker Bureau/Expert testimony: Ipsen; Speaker Bureau/Expert testimony: Amgen; Speaker Bureau/Expert testimony: Servier; Speaker Bureau/Expert testimony: Sanofi; Speaker Bureau/Expert testimony: Merck Sharp and Dohme; Research grant/Funding (institution): Merck; Research grant/Funding (institution): Pierre Fabre. E. Felip: Advisory/Consultancy: Guardant Health; Advisory/Consultancy: Janssen; Speaker Bureau/Expert testimony: Medscape; Advisory/Consultancy: Merck KGaA; Advisory/Consultancy: Novartis; Advisory/Consultancy: Pfizer; Speaker Bureau/Expert testimony: priME Oncology; Advisory/Consultancy: Roche; Advisory/Consultancy: Samsung; Advisory/Consultancy: Takeda; Speaker Bureau/Expert testimony: Touchime; Advisory/Consultancy: GSK; Advisory/Consultancy: Bayer; Research grant/Funding (institution): Grant for Oncology Innovation (GOI); Research grant/Funding (institution): Fundación Merck Salud. E. Garralda: Research grant/Funding (institution): Novartis; Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (institution): Roche; Speaker Bureau/Expert testimony, Research grant/Funding (institution): Thermo Fisher; Advisory/Consultancy: F. Hoffmann La Roche; Advisory/Consultancy: Ellipses Pharma; Advisory/Consultancy: Neomed Therapeutics1 Inc; Advisory/Consultancy: Boehringer Ingelheim; Advisory/Consultancy: Janssen Global Services; Advisory/Consultancy: SeaGen; Advisory/Consultancy: TFS; Advisory/Consultancy: Alkermes; Advisory/Consultancy: Thermo Fisher; Advisory/Consultancy, Travel/Accommodation/Expenses: Bristol-Myers Squibb; Speaker Bureau/Expert testimony: Merck Sharp and Dohme. I. Braña: Advisory/Consultancy, Leadership role: Orion Pharma; Speaker Bureau/Expert testimony, Leadership role: BMS; Speaker Bureau/Expert testimony, Leadership role, Travel/Accommodation/Expenses: AstraZeneca; Speaker Bureau/Expert testimony, Travel/Accommodation/Expenses: Merck Serono; Advisory/Consultancy, Leadership role: Rakutan Pharma; Speaker Bureau/Expert testimony: Roche; Leadership role: Celgene; Leadership role: Gliknik; Leadership role: GSK; Leadership role: Janssen; Leadership role: KURA; Leadership role: MSD; Leadership role: Novartis; Leadership role: Pfizer; Leadership role: Shattuck; Leadership role: Northern Biologics; Leadership role: Nanobiotics. All other authors have declared no conflicts of interest.

Background

Notch signaling plays a key role in ACC tumorigenesis. AL101, an investigational γ-secretase inhibitor, blocks Notch signaling and inhibits tumor in ACC patient-derived xenograft models with Notch^mut (AACR ‘19, Abstr 4885). Notch^mut are found in ∼20% of ACC tumors these tumors are aggressive with a poor prognosis (Ferrarotto 2016, Ho 2019). No therapies are approved for R/M ACC. Updated results (n = 45) will be provided.

Methods

ACCURACY is an open-label, multicenter study of AL101 (4 and 6 mg IV QW) in R/M ACC subjects (bone-only disease allowed) with known Notch1-4^mut (ASCO ‘19, Abstr TPS6098). Subjects require evidence of disease progression within 6 months of entry or newly diagnosed metastatic disease and an ECOG PS of <2. Primary endpoint: ORR by RECIST v1.1 (or modified MD Anderson bone criteria), by investigator. Secondary endpoints: ORR by central review, duration of response and safety. The study was amended, based on the safety and activity in the 4 mg cohort, to add a cohort of 42 subjects at 6mg. The study will provide at least 80% power to detect an increase of the response rate from 8% to 25% using a type I error of 5%.

Results

45 subjects were enrolled at 4 mg QW; 39 are evaluable for efficacy. Table: 919MO

Disposition and baseline characteristics of subjects treated with the investigational new drug AL101-4 mg

Conclusions

Investigational AL101 has clinical activity in R/M Notch mutant ACC and appears to be well tolerated. The trial was amended to enroll additional subjects at 6 mg QW.

Clinical trial identification

NCT03691207; EudraCT 2019-000309-64.

Legal entity responsible for the study

Ayala Pharmaceuticals.

Funding

Ayala Pharmaceuticals.

Disclosure

R. Ferrarotto: Advisory/Consultancy: Regeneron-Sanofi; Advisory/Consultancy: Ayala Pharmaceuticals; Advisory/Consultancy: Klus Pharmaceuticals; Advisory/Consultancy: Medscape; Advisory/Consultancy: Carevive; Advisory/Consultancy: Prelude; Advisory/Consultancy: Carevive; Honoraria (institution), Clinical Trials: Merck; Honoraria (institution), Clinical Trials: Genentech; Honoraria (institution), Clinical Trials: Pfizer; Honoraria (institution), Clinical Trials: Oropharynx Program Stiefel; Honoraria (self): ASCO Career Development; Honoraria (self): MD Anderson Khalifa Award. L.J. Wirth: Advisory/Consultancy: Bayer; Advisory/Consultancy: Blueprint; Advisory/Consultancy: Cue Biopharma; Advisory/Consultancy: Exelixis; Advisory/Consultancy: Genentech; Advisory/Consultancy: Loxo Oncology; Advisory/Consultancy: Merck; Advisory/Consultancy: Rakuten; Advisory/Consultancy: Eisai; Advisory/Consultancy: Lilly. C.P. Rodriguez: Advisory/Consultancy: Cue Biopharma; Speaker Bureau/Expert testimony: Clinical Care Options. B. Xia: Advisory/Consultancy: AstraZeneca; Advisory/Consultancy: Genentech. C.A. Perez: Advisory/Consultancy: Regeneron; Advisory/Consultancy: Kimera Labs. E. Winquist: Honoraria (self): Amgen; Honoraria (self): AstraZeneca; Honoraria (self): Bayer; Honoraria (self): Eisai; Honoraria (self): Merck; Honoraria (self): Roche. S.J. Hotte: Research grant/Funding (institution): Ayala Pharmaceuticals. R. Metcalf: Advisory/Consultancy: AstraZeneca; Advisory/Consultancy, Travel/Accommodation/Expenses: BMS; Advisory/Consultancy: Bayer; Advisory/Consultancy: Roche. C. Even: Advisory/Consultancy: Bristol-Myer Squibb; Advisory/Consultancy: Merck Sharpe and Dohme; Advisory/Consultancy: Innate; Advisory/Consultancy: Merck Serono. G.B. Gordon: Shareholder/Stockholder/Stock options, Full/Part-time employment: Ayala Pharmaceuticals; Advisory/Consultancy: Molecular Templates; Advisory/Consultancy: Intellia. G. Gordon: Advisory/Consultancy, Full/Part-time employment: Ayala Pharmaceuticals; Advisory/Consultancy: Agios; Advisory/Consultancy: Heron; Advisory/Consultancy: Jounce; Advisory/Consultancy: Brickell; Advisory/Consultancy: Onkure; Advisory/Consultancy: Aethlon; Advisory/Consultancy: Zenatlis; Advisory/Consultancy: Prevacept. A. Ho: Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: Ayala Pharmaceuticals; Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: Merck; Research grant/Funding (institution): Novartis; Research grant/Funding (institution): Eisai; Advisory/Consultancy, Research grant/Funding (institution): Bristol Meyer Squibb; Advisory/Consultancy, Research grant/Funding (institution): AstraZeneca; Advisory/Consultancy, Research grant/Funding (institution): Genentech/Roche; Research grant/Funding (institution): Celldex; Research grant/Funding (institution): Bayer; Research grant/Funding (institution): Lilly; Research grant/Funding (institution): Astellas; Research grant/Funding (institution): Daichi; Research grant/Funding (institution): Allos; Research grant/Funding (institution): Pfizer; Honoraria (self): Sanofi Genzyme; Honoraria (self): Sun Pharma; Honoraria (self): Regeneron; Research grant/Funding (institution), Travel/Accommodation/Expenses: TRM; Research grant/Funding (institution), Travel/Accommodation/Expenses: Kura; Travel/Accommodation/Expenses: Ignyta; Travel/Accommodation/Expenses: Jansen; Advisory/Consultancy: Curevac; Speaker Bureau/Expert testimony: Medscape. All other authors have declared no conflicts of interest.