- OUTBACK
[Adjuvant chemotherapy following chemoradiation as primary treatment for locally advanced cervical cancer compared to chemoradiation alone: The randomized phase III OUTBACK Trial (ANZGOG 0902, RTOG 1174, NRG 0274)]
OUTBACK was a randomised, phase III, GCIG trial comparing concurrent chemoradiation followed by adjuvant chemotherapy (4 cycles of carboplatin and paclitaxel) (n=463) versus concurrent chemoradiation alone (n=456) in women with locally advanced cervical cancer (FIGO 2008 stage IB1 and node positive, IB2, II, IIIB or IVA). Primary endpoint of overall survival (OS) at 5 years was similar in both groups (HR 0·91, 95% CI 0.70 to 1.18). Grade 3-5 AE’s were higher in adjuvant chemotherapy group than control (81% v 62%). No difference in pattern of cancer recurrence.
OUTBACK is my top pick of ASCO abstracts for 2021 as an Australian-lead, negative trial selected as a plenary abstract and for being the clear standout plenary presentation. OUTBACK was a well-designed trial addressing an important clinical question with OS as the primary endpoint in a cancer with global relevance. Its successful completion highlights the essential role of investigator-initiated research and international collaboration of research co-operative groups. A wise PhD supervisor said much research success is about timing, and here the negative practice-changing results espouse the oncology community’s current theme of less is more. Congratulations to Prof Mileshkin on an excellent presentation and to all involved on getting this trial done. Also, best name ever for an Aussie trial.
2. KEYNOTE-564
(Pembrolizumab versus placebo as post-nephrectomy adjuvant therapy for patients with renal cell carcinoma: Randomized, double-blind, phase III KEYNOTE-564 study)
KEYNOTE-564 was a phase III, double-blind trial of 1 year of pembrolizumab (n= 496) or placebo (n=498) after nephrectomy for clear cell renal cell carcinoma (RCC) with intermediate-high risk or high-risk disease or M1 NED. The primary endpoint of DFS was met at 1st pre-specified analysis: HR 0.68, 95% CI 0.53−0.87; P=0.0010 [one-sided] and 2-year DFS rate 77.3% with pembrolizumab v 68.1% with placebo. OS data was immature [HR 0.54, 95% CI 0.30−0.96; P=0.0164 (one-sided)]. Grade 3-5 all cause AE’s 32.4% for pembrolizumab arm and 17.7% for placebo arm.
Selecting this trial means bravely entering the debate on the value of DFS as a clinically meaningful endpoint and the early adoption of adjuvant therapy prior to the availability of mature OS results. The OlympiA trial (abstract #LBA1) and IMpower010 trial (abstract #8500) also highlight these issues.
KEYNOTE-564 was endorsed as a ‘quantum leap’ and ‘paradigm shift’ by the plenary discussant as the first phase III trial of adjuvant immunotherapy in RCC. This was not my take; I think the general response could be more critical and considered given the many unanswered questions (eg post-trial access to immunotherapy) in addition to immature OS data. I fall on the traditional side of adjuvant therapies needing to improve OS to be a standard of care (or DFS where it is correlated with OS), especially given the detrimental effect on quality of life. Some patients will no doubt value living longer without cancer at the cost of side effects of treatment. The adjuvant setting, however, involves treating all patients for a minority to benefit, and hence the value of adjuvant treatment needs to be considered in the treatment population in its entirety. Regardless, the role of (neo)adjuvant immunotherapy across cancer types is an exciting space I look forward to seeing more mature results from this trial.
3. VISION
Phase III study of lutetium-177-PSMA-617 in patients with metastatic castration-resistant prostate cancer (VISION).
VISION was a randomised, open-label of 177Lu-PSMA-617 + standard of care (SOC) (n=551) versus SOC alone (n=280) in men with previously treated PMSA-positive mCRPC with ≥1 androgen receptor pathway inhibitor and 1-2 taxanes and for whom further chemotherapy was ‘inappropriate’. rPFS and OS (both primary endpoints) were significantly improved in the 177Lu-PSMA-617 + SOC arm: rPFS (median rPFS, 8.7 vs 3.4 months; HR, 0.40 [99.2% CI: 0.29, 0.57]; p < 0.001, one-sided) and OS (median OS, 15.3 vs 11.3 months; HR, 0.62 [95% CI: 0.52, 0.74]; p < 0.001, one-sided). Treatment-emergent adverse events were higher in 177Lu-PSMA-617 + SOC arm v SOC arm for all-grade (85.3% v 28.8%), grade 3-5 (28.4% v 3.9%) and deaths (5/0.9% v 0/0%).
VISION has helped establish 177Lu-PSMA-617 + SOC as a potential targeted radioligand treatment option for men with mCRPC. It complements the ANZUP TheraP randomised phase II trial of [177Lu]Lu-PSMA-617 v cabazitaxel (MS Hofman et al, Lancet, 2021). Key questions about VISION include the control arm and optimal imaging for treatment selection. Eligible participants had to have 1-2 taxane chemotherapy agents and be ‘inappropriate’ for further chemotherapy. Routine clinical practice (ie off trial) involves 2 taxanes hence making for a potentially inferior control arm in VISION and biasing of the results in favour of the 177Lu-PSMA-617 + SOC arm. PMSA positivity was assessed by 68Ga-PSMA-11 PET-CT scans and required 1 PMSA-positive lesion and no PMSA-negative lesions with a high imaging positive screening rate of 87%. Hence the question of the need for imaging to select patients for treatment; no imaging requirement would remove one barrier to treatment, opening access and creating more equitable care in line with the ASCO Annual Meeting’s 2021 theme of ‘Equity: Every Patient. Every Day. Everywhere.’
