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Key takeaways from HNSCC, NSCLC, and Pancreatic cancer trials from ASCO 2019 for Indian Oncologists: Dr. Amarendra Amar

M3 India Newsdesk Jun 11, 2019

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

TPEx versus Extreme regimen in 1st line recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC)

This large randomised trial confirmed the encouraging survival results of the TPEx regimen observed in the first phase II. OS in both arms was higher than observed in previous randomised CT or immunotherapy combination trials. Despite lack of significant OS increase, taxane based TPEx regimen appears to be a new option in 1st line R/M HNSCC, with a shorter time on CT and significantly lower toxicity than the EXTREME regimen.

The above trial is quite pertinent to India which has head and neck cancer as one of the major causes of morbidity and mortality. If we look at the number of cycles, the type of toxicities and the overall survival data (although not significantly better as required by the primary endpoint of this study, yet showing better survival in comparison to EXTREME regimen), it sounds reasonable to replace EXTREME regimen with TPEx Regimen. It can be considered as a practice-changing update.


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.


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.


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.

KEYNOTE-048 trial

Protocol-specified final analysis of the phase 3 KEYNOTE-048 trial of pembrolizumab (pembro) as first-line therapy for recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC)

Overall, KEYNOTE-048 showed that compared with EXTREME (E), Pembrolizumab (P) + Chemo (C) had superior OS in the PD-L1 CPS ≥20, CPS ≥1, and total populations with comparable safety and P had superior OS in the CPS ≥20 and ≥1 populations, non-inferior OS in the total population, and favorable safety. These results support pembrolizumab and pembrolizumab + platinum + 5-FU as new 1L standards of care for R/M HNSCC.

If we look at the results from above two studies, there’s not much difference between TPEx regimen and Pembrolizumab + chemotherapy regimen in terms of overall survival between the abovesaid arms. However, toxicity patterns and treatment cost may be different. The above said regimen however can both be considered standard regimen in treatment of metastatic or recurrent head and neck cancer.


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.


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).


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.

Non-Small Cell Lung Cancer

gef vs gef+C study

Phase III randomised trial comparing gefitinib to gefitinib with pemetrexed-carboplatin chemotherapy in patients with advanced untreated EGFR mutant non-small cell lung cancer (gef vs gef+C)

Adding pemetrexed-carboplatin chemotherapy to gefitinib significantly prolonged progression free and overall survival but also increased toxicity. Pemetrexed-carboplatin-gefitinib represents a new standard first-line therapy for EGFR mutant NSCLC.

Keypoints from this study of Gefitinib with chemotherapy versus Gefitinib underline the benefit of this regimen with respect to similar PFS advantage in comparison to Osimertinib, the current standard of Choice in EGFR sensitive Non-small cell adenocarcinoma of lung.

However, this study is different from the FLAURA trial of osimertinib in terms of inclusion of patients with performance score 2 which constituted 20 percent of patients in the Indian study of Gefitinib with chemotherapy. Moreover, this study also showed overall survival advantage of Gefitinib and chemotherapy which was not mentioned in NEJ-009 trial of the same treatment regimen.


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.


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.


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.

Pancreatic cancer

POLO trial

Olaparib as maintenance treatment following first-line platinum-based chemotherapy (PBC) in patients (pts) with a germline BRCA mutation and metastatic pancreatic cancer (mPC): Phase III POLO trial

Maintenance olaparib provided a statistically significant and clinically meaningful improvement in PFS in mPC patients with a gBRCAm who had not progressed on PBC. Safety was consistent with the known profile for olaparib. POLO is the first phase III trial to validate a biomarker-driven treatment in PC.

PFS rates at select time points*

Time, months Olaparib (O), N = 92% Placebo (P), N = 62%
6 53.0 23.0
12 33.7 14.5
18 27.6 9.6
24 22.1 9.6

*Kaplan-Meier method

The trial of Olaparib in the treatment of germline mutated BRCA patients of metastatic pancreatic adenocarcinoma is one of the best examples of biomarker-driven trials more so, in the fatal diseases as pancreatic adenocarcinoma. This is pertinent to all countries including India because metastatic pancreatic adenocarcinoma continues to be a menace to the patients.


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.


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).


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.

Disclaimer- The views and opinions expressed in this article are those of the author's and do not necessarily reflect the official policy or position of M3 India.

The author, Dr. Amarendra Amar is an Attending Consultant in Medical Oncology from Delhi.

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