Dr. Amarendra Amar, a Consultant Medical Oncologist who attended this year's ASCO (American Society of Clinical Oncology) Annual Meeting provides key takeaways and commentaries on India-relevant studies in head and neck, non-small cell lung, and pancreatic cancer, presented at the event.

Head and Neck Cancer

TPExtreme randomised trial

Background

GORTEC TPEx phase II trial showed the benefit of triplet of docetaxel,cisplatin and cetuximab in recurrent/metastatic head nad neck squamous cell carcinoma. However, the role of taxane instead of 5FU in 1st-line R/M HNSCC chemotherapy (CT) remained to be confirmed by comparing TPEx to the reference EXTREME regimen.

Method

It was randomised (1:1), open-label trial. Main inclusion criteria were R/M HNSCC not suitable for locoregional treatment, age 18-70 years, PS <2, creatinine clearance >60ml/min, prior cisplatin <300 mg/m². Reference EXTREME regimen (arm A: 6 cycles every 3 weeks (Q3W) of 5FU–cisplatin-cetuximab (cetux) followed by weekly cetux maintenance) was compared to TPEx regimen (arm B: 4 cycles Q3W of docetaxel 75mg/m²–cisplatin 75mg/m²- cetux 250mg/m² with mandatory G-CSF support followed by every 2W cetux 500mg/m² maintenance).

The primary endpoint was Overall Survival (OS). To detect a hazard ratio (HR) of 0.72 (median OS increase from 10.1 to 14.0 months (mo) with 88% power, 2-sided significance level of 0.05, 374 deaths were required. 540 patients (pts) were planned to enroll.

Findings

539 patients were enrolled in 37 months. Median age was 60 years, 93% were smokers, 40% had oropharyngeal tumor (p16 or HPV DNA was done in 85%, positive in 28%). In arm A, 44% of patients received all CT cycles vs 72% in arm B.

1. Delays in administration were more frequent in arm A (27% vs 10%). Cisplatin was more frequently switched to carboplatin in arm A (34% vs 9%).
2. Toxicity was lower in arm B: 34% patients had grade ≥4 adverse events during CT in arm B vs 50% in arm A (p<0.001).
3. Less patients in arm A started maintenance than in arm B (53% vs 73%).

At time of analysis, the median follow-up duration was 30 months and 406 patients had died. OS was not significantly different between arms: HR=0.87 (95%CI: 0.71-1.05), p=0.15. Median OS was 13.4 months in arm A vs 14.5 in arm B. 2-year OS rate was 21.0% in arm A vs 28.6% in arm B.

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KEYNOTE-048 trial

Background

KEYNOTE-048 is a phase 3 study of Pembrolizumab (P) or P + chemo (C) vs EXTREME (E) as 1st line therapy for Recurrent/Metastatic HNSCC (NCT02358031). At the second interim analysis (IA2), P significantly improved OS in the PD-L1 combined positive score (CPS) ≥20 and ≥1 populations and had noninferior OS in the total population with favorable safety; P+C significantly improved OS in the total population with comparable safety. The protocol-specified final results.

Methods

882 patients with locally incurable R/M HNSCC and no prior systemic therapy in the R/M setting who provided a tumour sample for PD-L1 testing were randomised to P 200 mg Q3W for 24 months (n = 301), P for 24 months + 6 cycles of C (cisplatin 100 mg/m² or carboplatin AUC 5 Q3W + 5-FU 1000 mg/m²/d for 4 d Q3W) (n = 281), or E (cetuximab 400 mg/m² loading/250 mg/m² QW + 6 cycles of chemo) (n = 300).

OS superiority was tested sequentially for P+C vs E in the CPS ≥20 population, then the CPS ≥1 population, and for P vs E in the total population (superiority thresholds: one-sided P = .0023, .0026, and .0059, respectively). Data cutoff was 25 Feb 2019 (~25 months after last patient randomised).

Findings

P+C significantly improved OS vs E in the CPS ≥20 (HR 0.60, 95% CI 0.45-0.82, P = .0004; median 14.7 vs 11.0 months) and CPS ≥1 (HR 0.65, 95% CI 0.53-0.80, P< .0001; median 13.6 vs 10.4 months) populations. HR (95% CI) for PFS was 0.76 (0.58-1.01) for CPS ≥20 and 0.84 (0.69-1.02) for CPS ≥1. ORR (P+C vs E) was 42.9% vs 38.2% for CPS ≥20 and 36.4% vs 35.7% for CPS ≥1; median DOR was 7.1 vs 4.2 months and 6.7 vs 4.3 months, respectively.

P did not significantly improve OS vs E in the total population (HR 0.83, 95% CI 0.70-0.99, P = .0199; median 11.5 vs 10.7 months). HR (95% CI) for PFS was 1.29 (1.09-1.53). ORR (P vs E) was 16.9% vs 36.0%; median DOR was 22.6 vs 4.5 months. All-cause gr 3-5 AE rates were 54.7% for P, 85.1% for P+C, and 83.3% for E.

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Non-Small Cell Lung Cancer

gef vs gef+C study

Background

Standard first-line therapy for EGFR mutant advanced non-small cell lung cancer (NSCLC) is an EGFR-directed oral TKI. This study evaluated whether adding pemetrexed-carboplatin to oral TKI would improve outcomes.

Methods

Phase III randomised trial in advanced chemotherapy-naïve NSCLC harboring EGFR sensitising mutation (exon 19, 21 or 18) with performance status (PS) 0 to 2 planned for palliative therapy. Patients were stratified for PS and EGFR mutation and randomly assigned (computer-generated randomisation by independent biostatistician) 1:1 to gefitinib 250 mg orally daily (gef) or gefitinib 250 mg orally daily with pemetrexed 500 mg/m² IV and carboplatin AUC 5 IV every 3 weeks for 4 cycles, followed by maintenance pemetrexed 500 mg/m² IV every 3 weeks (gef+C).

Restaging was every 2 to 3 months; therapy continued until progression or intolerable toxicity. Primary end point was progression-free survival (PFS); secondary end points included overall survival (OS), toxicity and response rate. Survival endpoints were assessed in the intention-to-treat population.

Findings

Between August 2016 and August 2018, 350 patients were randomly assigned to gef (n = 177) and gef+C (n = 173). Median age was 54 yrs, 48% were females, 84% never-smokers, 21% were PS 2 and 18% had brain metastases. Median follow-up in surviving patients was 17 months (range, 7 to 30). Radiologic response rates were 81% and 69% in gef+C and gef respectively, P = 0.012. 234 patients (67%) have had events for PFS, 98 in gef+C and 136 in gef.

1. Estimated median PFS was significantly longer with gef+C than gef (16 months, [95% CI, 13.7 to 18.3] vs. 8 months [95% CI, 7.1 to 8.9]; hazard ratio for disease progression or death, 0.5; 95% CI, 0.39 to 0.65; P < 0.001). 120 patients (34%) died, 42 in gef+C and 78 in gef.
2. Estimated median OS was significantly longer with gef+C than gef (not reached vs. 18 months [95% CI, 14.28 to 21.72]; hazard ratio for death, 0.45; 95% CI, 0.31 to 0.66; P < 0.001).
3. Clinically relevant ≥grade 3 toxicities occurred in 51% and 25% of patients in gef+C and gef arms respectively, P < 0.001.

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Pancreatic cancer

POLO trial

Background

Pancreatic cancer (PC) patients with a germline BRCA1 and/or BRCA2 mutation (gBRCAm) have shown response to the PARP inhibitor olaparib (Kaufman 2015). POLO is the first phase III trial to evaluate efficacy of maintenance treatment with a PARP inhibitor in PC.

Methods

POLO is an international, randomised, double-blind, placebo-controlled trial of patients with a gBRCAm and pancreatic adenocarcinoma who had received ≥16 weeks of first-line PBC for metastatic disease without progression. Patients were randomised 3:2 to maintenance olaparib (O) tablets (300 mg bid) or placebo (P). Treatment began 4 to 8 weeks after last PBC dose, continuing until investigator-assessed progression or unacceptable toxicity. The primary endpoint was progression-free survival (PFS) by blinded independent central review (modified RECIST 1.1).

Findings

A total of 3315 patients, identified 247 with a gBRCAm, randomised 154 (O 92, P 62), and treated 151 (O 90, P 61). Patient characteristics (O/P): age, median (range) 57 (37–84)/57 (36–75); male, 58%/50%; ECOG performance status 0, 71%/61%.

1. With 104 events, PFS was significantly improved with O vs. P (hazard ratio [HR] 0.53; 95% CI 0.35, 0.82; p = 0.0038; median PFS was 7.4 vs. 3.8 months [mo], respectively) and consistent irrespective of response to prior PBC (complete/partial HR 0.62; stable disease HR 0.50).
2. From 6 months, the % of patients progression-free in the O arm was more than twice that in the P arm (Table).
3. At the interim overall survival analysis (46% maturity), HR was 0.91 (95% CI 0.56, 1.46; p = 0.68).
4. Grade ≥3 adverse events (AE) occurred in 40% of O- and 23% of P-treated patients; 5.5% and 1.7% of patients, respectively, discontinued treatment due to an AE.