Background: Head and neck cancer is a huge burden in South East Asia with frequent relapse after curative therapy while the rest presenting in advanced unresectable stages. Financial constraints for targeted and immunotherapy make it inaccessible for the bulk of population. Thus, low-cost but efficacious regimen is highly implicated. We assessed if readily available triplet therapy of EMF, is superior in terms of extending life and maintaining quality of life along with evaluation of CTCs as a predictive biomarker in such patients. Methods: This was a single arm, phase II, investigator initiated interventional study, wherein 35 patients were enrolled. Platinum resistant/refractory patients of HNSCC were treated with combination of erlotinib 150mg daily, methotrexate 40 mg/m² and 5-fluourouracil 500 mg/m² (d1, d8) q28 days till progression or unacceptable toxicities. The primary endpoint was overall response rate(ORR) at 3 months; additional endpoints were disease control rate(DCR) at 3 months, overall survival (OS), progression free survival (PFS) safety and patient reported quality of life(QOL). The role of CTCs in gauging the responders and non-responders was monitored using anti Epithelial Cell Adhesion Molecule antibody based enrichment - OncoDiscover Drug Controller General of India (DCGI) approved platform. Results: The ORR and DCR at 3 months was 45.7% and 68.5%, respectively. The median PFS was 5 months (95%CI: 3.9-6 months) and median OS was 9 months (95%CI:7.4 -10.5 months). The 3 and 6 months PFS rates was 86 + 6% and 45 + 9%, respectively, while OS rates at 3 and 6 months were 91+ 5% and 68+ 8%, respectively. Rash, mucositis and fatigue were common adverse events occurring in 23 (65%), 14 (40%) and 9 (25.7%) respectively. The grade 3 events seen were rash in 5 (14.2%) and diarrhea in 2 (5.7%). Clinically significant improvement was seen in domains of role functioning, social functioning, fatigue, pain and global health status, swallowing, dryness of mouth and feeling ill. The mean CTC count at baseline was 0.90 + 1.1 /1.5ml of blood. Responders showed decline in levels from 1.19 + 0.25 to 0.33 + 0.48, while non-responders had increasing trend: 0.29 + 0.48 to 1+ 0.10 at 3 months (p = 0.010); with concordance rates with response being 52.9%. Additionally, CTC clearance at 3 months had numerically better PFS ̃ 6 months (95% CI: 4.72-7.72) and OS of 10 months (95% CI: 2.3-5.65) vs 4 months (95% CI: 2.3-5.65), p = 0.258 and 8 months (95% CI: 4.3-11.6), p = 0.203 in those with persistence of CTCs. Conclusions: The triplet regimen of EMF is a feasible, safe therapeutic option with favourable response rates and improved QOL in patients with platinum resistant/refractory HNSCC. CTCs have a promising futuristic role as a predictive biomarker and can be extrapolated in clinical upfront setting too. Clinical trial information: CTRI/2020/02/023378.