Background

Outcomes in RAS-mutant metastatic colorectal cancer (mCRC) remain poor and patients have limited therapeutic options. Adavosertib is the first small molecule inhibitor of WEE1 kinase. We hypothesised that aberrations in DNA replication seen in mCRC with both RAS and TP53 mutations would sensitise tumours to WEE1 inhibition.

Methods

Patients with newly diagnosed mCRC were registered into FOCUS4 and tested for TP53 and RAS mutations. Those with both mutations who were stable or responding after 16 weeks of chemotherapy were randomised 2:1 between Adavosertib or active monitoring (AM). The primary outcome was progression-free-survival (PFS).

Results

Between Jul 2017 and Mar 2020 718 patients were registered into FOCUS4; 247 (34%) were RAS/TP53-mutant. 69 patients were randomised from 25 UK hospitals (44 to Adavosertib; 25 to AM) and recruitment terminated early due to COVID-19 and following DMEC review of efficacy data. Adavosertib was associated with a PFS improvement over AM (median 3.61 vs 1.87 months; HR=0.35[95% CI 0.18-0.68], p=0.0022). In pre-specified subgroup analysis, Adavosertib activity was greater in left-sided tumours HR=0.24 [95% CI 0.11–0.51], versus right-sided HR=1.02 [95% CI 0.41–2.56] (interaction p=0.043). Adavosertib activity was limited to tumours with KRAS12/13 mutations, rather than mutations in extended KRAS or NRAS (interaction p=0.01). Overall survival (OS) was not improved with Adavosertib vs AM (median 14.0 vs 12.8 months; HR=0.92[95%CI 0.44-1.94], p=0.93); however in left-sided tumours, median OS was 14.1 vs 11.3 months (HR=0.37 [95%CI 0.15-0.87]) and 6.5 vs 15.5 months in right-sided (HR=2.15 [95%CI 0.72-6.43], interaction p=0.0047). Adavosertib was well tolerated; grade 3 toxicities were diarrhoea (9%), nausea (5%) and neutropenia (7%).

Conclusions

In this phase II randomised trial, Adavosertib improved PFS compared with AM and demonstrates potential as a well-tolerated therapy for RAS/TP53-mutant mCRC. Activity was greater in patients with left-sided tumours, with potential impact on OS. Further testing is required in this sizable population of unmet need.

Clinical trial identification

ISRCTN90061546.

Legal entity responsible for the study

The authors.

Funding

MRC/NIHR, CRUK, AstraZeneca.

Disclosure

J. Seligmann: Financial Interests, Personal, Invited Speaker: Pierre Fabre; Financial Interests, Personal, Invited Speaker: Merck Serono; Financial Interests, Personal, Advisory Board: Pierre Fabre; Financial Interests, Personal, Expert Testimony: Roche Diagnostics; Financial Interests, Personal, Invited Speaker: Servier. T. Maughan: Financial Interests, Personal, Advisory Board: AstraZeneca; Financial Interests, Personal, Advisory Board: Pierre Fabre; Financial Interests, Personal, Advisory Board: Pfizer; Financial Interests, Institutional, Funding: AstraZeneca; Financial Interests, Institutional, Funding: Psioxus; Financial Interests, Institutional, Funding: Merck KGAA. All other authors have declared no conflicts of interest.

Background

T-DXd is an antibody–drug conjugate consisting of an anti-HER2 antibody, a cleavable linker, and a topoisomerase I inhibitor. In primary analyses of DESTINY-CRC01 (NCT03384940), T-DXd showed antitumor activity and a manageable safety profile in HER2+ mCRC pts (Siena ASCO 2020). We present exploratory biomarker data and its relation to response in HER2+ mCRC.

Methods

Pts with centrally confirmed HER2-expressing, RAS wildtype mCRC that progressed after ≥2 prior regimens received 6.4 mg/kg of T-DXd Q3W in 3 cohorts (A: HER2+, IHC3+, or IHC2+/ISH+, n = 53; B: IHC2+/ISH−, n = 15; C: IHC1+, n = 18). Circulating tumor DNA (ctDNA) samples at baseline (BL), cycle 4, day 1, and end of treatment, along with BL serum HER2 extracellular domain (HER2ECD) were analyzed as exploratory biomarkers. To correct for variation in plasma tumor fraction between samples, adjusted plasma ERBB2 copy number (ApCN) was calculated based on the maximum variant allele fraction (Siravegna CCR 2019). Exploratory cutoff values for ApCN in ctDNA and HER2ECD were defined as those with the maximum value of the Youden index for ORR.

Results

In cohort A, higher clinical response to T-DXd was observed with higher tumor or plasma HER2 expression (Table). Antitumor activity of T-DXd was seen in pts with or without ctDNA-detected activating RAS or PIK3CA mutations and was lower in pts with blood TMB high vs low (Table). In paired ctDNA samples collected at BL and disease progression from 30 pts, acquired alterations were observed in several genes, but none was common across pts (n = 12). Table: 386O

ORR by BL Biomarker Group

Conclusions

This exploratory analysis of biomarker data in HER2+ mCRC pts administered T-DXd indicates that antitumor activity appears to be correlated with BL HER2 expression or amplification in tumor and liquid biopsy. Further investigations into potential mechanisms of resistance to and patient selection for T-DXd in HER2+ mCRC are warranted.

Clinical trial identification

NCT03384940.

Editorial acknowledgement

Under the guidance of the authors, assistance in medical writing and editorial support was provided by Alya R. Raphael, PhD, of ApotheCom.

Legal entity responsible for the study

Daiichi Sankyo.

Funding

Daiichi Sankyo and AstraZeneca.

Disclosure

S. Siena: Financial Interests, Personal, Advisory Role, Advisory/consultancy: Amgen, AstraZeneca, Bayer, BMS, CheckmAb, Daiichi Sankyo, Merck, and Seattle Genetics. K. Raghav: Financial Interests, Personal, Other, Honoraria: Bayer, Daiichi, AstraZeneca, Seattle Genetics; Financial Interests, Personal, Advisory Role, Advisory/Consultancy: Bayer, Daiichi, AstraZeneca, Seattle Genetics. T. Masuishi: Financial Interests, Institutional, Research Grant: Daiichi Sankyo. K. Yamaguchi: Financial Interests, Personal, Research Grant: Daiichi Sankyo, Taiho Pharm, Sanofi, Ono, Yakurt Honsha; Financial Interests, Personal, Speaker’s Bureau: Taiho Pharm, Eli Lilly, Takeda, Chugai Pharm, Ono, Bristol Myers Squibb, Bayer, Merck Biopharm. T. Nishina: Financial Interests, Institutional, Research Grant: Daiichi Sankyo, Taiho Pharma, Chugai Pharma, MSD, Ono, Bristol Myers Squibb, Lilly, Dainippon Sumitomo Pharma. E. Elez: Financial Interests, Personal, Other, Honoraria: Amgen, Array Biopharma, Bayer, BristolMyersSquibb, Hoffman La-Roche, Merck Serono, Sanofi, Servier; Financial Interests, Institutional, Advisory Role, Advisory/Consultancy: Amgen, Array Biopharma, Bayer, BristolMyersSquibb, Hoffman La-Roche, Merck Serono, Sanofi, Servier; Financial Interests, Institutional, Research Grant: AbbVie, Amgen, Array Pharmaceuticals, AstraZeneca, Boehringer Ingelheim, BristolMyersSquibb, GlaxoSmithKline, Hoffman La-Roche; Medimmune, Merck Serono, MSD, Novartis, Pierre-Fabre, Sanofi Aventis. I. Chau: Financial Interests, Personal, Advisory Board: Eli Lilly, Bristol Myers Squibb, MSD, Bayer, Roche, Merck-Serono, Five Prime Therapeutics, AstraZeneca, OncXerna, Pierre Fabre, Boehringer Ingelheim, Incyte, Astellas; Financial Interests, Institutional, Research Grant: Eli Lilly, Janssen-Cilag; Financial Interests, Personal, Other, Honoraria: Eli Lilly, Eisai. M. Di Bartolomeo: Financial Interests, Personal, Other, Honoraria: Lilly, MSD, Servier; Financial Interests, Institutional, Other, Honoraria: Lilly; Financial Interests, Personal, Speaker’s Bureau, Speaker Bureau/Expert Testimony: BMS; Financial Interests, Institutional, Research Grant: Lilly. H. Kawakami: Financial Interests, Personal, Other, Honoraria: Bristol-Myers Squibb Co. Ltd., AstraZeneca K.K., Bayer yakuhin Ltd., Eli Lilly Japan K.K., MSD K.K., Ono Pharmaceutical Co. Ltd., Chugai Pharmaceutical Co. Ltd., Daiichi Sankyo Co. Ltd., Takeda Pharmaceutical Co. Ltd., and Taiho Pharmaceutical Co. Ltd.; l; Financial Interests, Personal, Research Grant: Taiho Pharmaceutical Co. Ltd, and Eisai Co. Ltd.; Financial Interests, Institutional, Research Grant: Bristol Myers Squibb Co. Ltd., Ono Pharmaceutical Co. Ltd., and Chugai Pharmaceutical Co. Ltd. F. Suto: Financial Interests, Personal, Full or part-time Employment: Daiichi Sankyo; Financial Interests, Personal, Stocks/Shares: Daiichi Sankyo. K. Kobayashi: Financial Interests, Personal, Full or part-time Employment: Daiichi Sankyo; Financial Interests, Personal, Stocks/Shares: Daiichi Sankyo. M. Koga: Financial Interests, Personal, Full or part-time Employment: Daiichi Sankyo. K. Inaki: Financial Interests, Personal, Full or part-time Employment: Daiichi Sankyo. Y. Kuwahara: Financial Interests, Personal, Stocks/Shares: Daiichi Sankyo Co., Ltd.; Financial Interests, Personal, Full or part-time Employment: Daiichi Sankyo Co., Ltd. I. Takehara: Financial Interests, Personal, Full or part-time Employment: Daiichi Sankyo. A. Grothey: Financial Interests, Institutional, Other, Honoraria: Bayer, Daiichi, Amgen, Regeneron, Merck/ MSD, Mirati, Natera, CARIS, Guardant Health, Boston Biomedicals, Roche/ Genentech, BMS, Foundation Medicine; Financial Interests, Personal, Advisory Role, Advisory/Consultancy: Bayer,Daiichi, Amgen, Regeneron, Merck/ MSD, Mirati, Natera, CARIS, Guardant Health, Boston Biomedicals, Roche/ Genentech, BMS, Foundation Medicine; Financial Interests, Institutional, Research Grant: Bayer, Boston Biomedicals, Natera, Caris, Foundation Medicine, Roche/ Genentech. T. Yoshino: Financial Interests, Personal, Other, Honoraria: Taiho, Chugai, Eli Lilly, Merc Biopharma, Bayer, Ono; Financial Interests, Institutional, Research Grant: Taiho, Sumitomo Dainippon, Ono, Chugai, Amgen, Parexel International, MSD, Daiichi Snakyo, Sanofi. All other authors have declared no conflicts of interest.

Background

FOLFOXIRI/bev is an upfront therapeutic option for selected mCRC pts. Immune checkpoint inhibitors (ICIs) reported remarkable achievements in dMMR but not in pMMR mCRC. The association of cytotoxics and bev may promote the sensitivity to ICIs increasing the exposure of neoantigens, inducing immunogenic cell death, and increasing the immune infiltration in tumor microenvironment while reducing the activity of Tregs.

Methods

AtezoTRIBE was a prospective, open label, phase II, comparative trial in which initially unresectable mCRC patients, irrespective of MMR status, were randomized 1:2 to receive up to 8 cycles of FOLFOXIRI/bev (arm A) or FOLFOXIRI/bev/atezo (arm B), followed by maintenance with 5-FU/bev or 5FU/bev/atezo until disease progression. The primary endpoint was PFS. Assuming a median PFS of 12 months in arm A, 201 patients and 129 events were required to detect a HR of 0.66 in favour of arm B with 1-sided α and β errors of 0.10 and 0.15. Trial info: NCT03721653.

Results

From November 2018 to February 2020, 218 pts were enrolled (arm A/B: 73/145) in 22 Italian sites. Main pts’ characteristics were (arm A/B): right-sided 44%/44%, synchronous metastases 89%/86%, liver-only 22%/22%, RAS mutant 71%/73%, BRAF mutant 14%/8%, dMMR 7%/6%. At a median follow up of 19.9 mos, 159 (arm A/B: 60/99) PFS events were collected. A significant advantage by the addition of atezo was observed in PFS (13.1 vs 11.5 mos, HR 0.69, 80%CI 0.56-0.85, p=0.012), but not in ORR (59% vs 64%, p=0.412). No safety issues were evident. Significant interaction effect between MMR status and treatment arm was found (p=0.010). In the pMMR subgroup (N=199, arm A/B: 67/132), 147 (arm A/B: 54/93) PFS events were collected. Significantly longer PFS was reported in arm B (12.9 vs 11.4 mos, HR 0.78, 80%CI 0.62-0.97, p=0.071).

Conclusions

The primary endpoint was met: the addition of atezo to FOLFOXIRI/bev prolongs PFS of mCRC patients. While the magnitude of benefit is significantly higher in dMMR tumors, signals of efficacy are reported also in the pMMR subgroup. Translational analyses to identify predictive biomarkers are ongoing.

Clinical trial identification

NCT03721653.

Legal entity responsible for the study

G.O.N.O. Group.

Funding

G.O.N.O. Group.

Disclosure

C. Cremolini: Financial Interests, Personal, Advisory Board: Roche; Financial Interests, Personal, Invited Speaker: Bayer; Financial Interests, Personal, Invited Speaker: Servier; Financial Interests, Personal, Advisory Board: MSD; Financial Interests, Personal, Expert Testimony: Amgen; Financial Interests, Institutional, Invited Speaker: Roche; Financial Interests, Institutional, Invited Speaker: Bayer; Financial Interests, Institutional, Invited Speaker: Servier; Financial Interests, Institutional, Invited Speaker: Merck. D. Rossini: Financial Interests, Personal, Invited Speaker: Takeda. F. Pietrantonio: Financial Interests, Personal, Invited Speaker: Amgen; Financial Interests, Personal, Invited Speaker: Merck; Financial Interests, Personal, Invited Speaker: Serono; Financial Interests, Personal, Invited Speaker: Sanofi; Financial Interests, Personal, Invited Speaker: Bayer; Financial Interests, Personal, Invited Speaker: Servier; Financial Interests, Personal, Invited Speaker: Lilly; Financial Interests, Institutional, Funding: Bristol Myers Squibb; Financial Interests, Personal, Advisory Role: Amgen; Financial Interests, Personal, Advisory Role: Merck Serono; Financial Interests, Personal, Advisory Role: Bayer; Financial Interests, Personal, Advisory Role: Lilly; Financial Interests, Personal, Advisory Role: Sanofi; Financial Interests, Personal, Advisory Role: Servier; Financial Interests, Personal, Invited Speaker: AstraZeneca; Financial Interests, Institutional, Funding: AstraZeneca. S. Lonardi: Financial Interests, Personal, Speaker’s Bureau: Amgen; Financial Interests, Personal, Speaker’s Bureau: Merck; Financial Interests, Personal, Speaker’s Bureau: Serono; Financial Interests, Personal, Speaker’s Bureau: Eli Lilly & co; Financial Interests, Personal, Speaker’s Bureau: Merck Serono; Financial Interests, Institutional, Funding: Amgen; Financial Interests, Institutional, Funding: Merck Serono. A. Falcone: Financial Interests, Personal, Invited Speaker: Roche; Financial Interests, Personal, Invited Speaker: Amgen; Financial Interests, Personal, Invited Speaker: Merck Serono; Financial Interests, Personal, Invited Speaker: Celgene; Financial Interests, Personal, Invited Speaker: Bayer; Financial Interests, Personal, Invited Speaker: Sanofi; Financial Interests, Institutional, Funding: Roche; Financial Interests, Institutional, Funding: Amgen; Financial Interests, Institutional, Funding: Merck Serono. All other authors have declared no conflicts of interest.

Background

The activity of TMZ in patients with mCRC is modest, but restricted to those with MSS status and MGMT silencing (negative IHC + MGMT methylation). In this hyperselected population, acquired resistance to TMZ is linked to emergence of mutations in mismatch repair genes and hypermutation. Thus, TMZ may be used as priming agent for immune-sensitization of MSS CRCs.

Methods

MAYA was a multicenter, single-arm phase II trial enrolling patients with pretreated MSS mCRC and MGMT silencing as centrally assessed by IHC + pyrosequencing (NCT03832621). The trial was designed to evaluate the safety and efficacy of 2 priming cycles of TMZ 150 mg/sqm d1-5q4w followed in absence of disease progression by its combination with ipilimumab 1 mg/kg q8w/nivolumab 480 mg q4w. Primary endpoint: 8-month progression-free survival rate (8m PFS). Secondary endpoints: overall survival (OS), overall response rate (ORR), safety, patient-reported outcomes. According to a single-stage design, 27 patients were required to increase 8m PFS from 5% to 20% with α- and β-error of 5% and 20%.

Results

Among 703 patients prescreened from March 2019 to November 2020, 204 (29%) were molecularly eligible and 135 started the priming phase, of whom 33 (24%) reached the second treatment phase. For these, median age: 58 years, M/F 52/48%, RAS mutated/wild-type 76/24% (no BRAF mutated); 1/2/≥3 previous lines 6/45/49%. Overall, 10 were alive and progression free after 8 months, 21 had PFS <8 months (2 too early). The primary endpoint was met: 8m PFS was 32%; median PFS and OS: 7.1 and 18.5 months; ORR 39%, with delayed/gradual responses consistent with efficacy of immunotherapy. The rate of any grade/grade ≥3 immune-related adverse events was 48/6%, all easily manageable with protocol guidelines. On/post-therapy re-biopsies were analyzed in 9 cases with emergence of either TMB>10 mut/mb or MGMT expression, which predicted 8m PFS status.

Conclusions

MAYA study proved the immune-sensitizing role of TMZ in MSS/MGMT silenced mCRC. The safety and efficacy of TMZ priming followed by ipilimumab/nivolumab combo strategy is worthy of further development and extensive biomarker analyses are ongoing.

Clinical trial identification

NCT03832621.

Legal entity responsible for the study

Istituto Nazionale dei Tumori di Milano - Fondazione IRCCS, Milan, Italy.

Funding

Bristol-Myers Squibb.

Disclosure

F. Pietrantonio: Financial Interests, Invited Speaker: Merck Serono; Sanofi; Servier; Lilly; Amgen; Bayer HealthCare Pharmaceuticals; Financial Interests, Research Grant: Bristol-Myers Squibb; AstraZeneca. F. Morano: Financial Interests, Invited Speaker: Servier; Financial Interests, Other, Travel accomodations: Sanofi; Servier. S. Lonardi: Financial Interests, Invited Speaker: Merck Serono; Roche; Servier; Bristol Myers Squibb Foundation; Incyte; Daiichi Sankyo; Pierre Fabre; AstraZeneca; Amgen; Bayer HealthCare Pharmaceuticals; Financial Interests, Research Grant: AstraZeneca; Bristol Myers Squibb Foundation; Lilly; Merck Serono; Roche; Amgen. L. Salvatore: Financial Interests, Advisory Board: Merck Serono; Servier; Bayer; Roche; Amgen; AstraZeneca; Sanofi; Pierre Fabre; Financial Interests, Other, travel accomodations/expenses: Sanofi; Merck Serono; Bayer; Roche; Servier; Celgene; Financial Interests, Invited Speaker: Roche; Merck Serono; Servier; Bayer; Amgen; Sanofi; AstraZeneca; Pierre Fabre. A. Zaniboni: Financial Interests, Invited Speaker: Sanofi; Merck Serono; Roche; Amgen; Bayer HealthCare Pharmaceuticals. M. Di Bartolomeo: Financial Interests, Advisory Board: Lilly; MSD Oncology; Financial Interests, Other, Travel accomodations: Roche; Sanofi; Financial Interests, Invited Speaker: Lilly; MSD Oncology; Servier; Financial Interests, Research Grant: Lilly. F. de Braud: Financial Interests, Advisory Board: Roche; Incyte; Teofarma; EMD Serono; Bristol-Myers Squibb; Nerviano Medical Sciences; Sanofi; Novartis Italia; Financial Interests, Invited Speaker: Roche; Bristol-Myers Squibb; Merck; MSD; Servier; Sanofi; Financial Interests, Research Grant: Novartis; Roche; Merck Serono; Pfizer; Servier; Philogen; Loxo; Tesaro; Nerviano Medical Sciences; Kymab. All other authors have declared no conflicts of interest.