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With the evolving understanding of the interaction between tumor and the immune system, novel therapies with sophisticated mechanisms of action are establishing themselves as the standards of care. In human cancer, the immune system plays a double edged sword with both protecting against tumor development as well as promoting tumor growth. In recent times, innumerable practice-changing clinical studies have being reported on immunotherapy. In this review article, we highlight the recently approved immunotherapy and chemotherapy combination in adjuvant and 1^st line metastatic setting in various solid tumors except renal cell carcinoma and melanoma.

Immunotherapy in metastatic/unrespectable head and neck cancer (excluding Nasophaynx)

In Keynote 048 trial Pembrolizumab alone improved overall survival versus Cetuximab with chemotherapy in the CPS of 20 or more population (median 14.9 months vs. 10.7 months, Hazard Ratio (HR) 0.61 (95% CI 0.45–0.83), p=0.0007) and CPS of 1 or more population (12.3 vs. 10.3,0.78 (0.64–0.96), p=0.0086) and was noninferior in the total population (11.6 vs. 10.7,0.85 (0.71−1.03)). Pembrolizumab with chemotherapy had better overall survival compared with Cetuximab and chemotherapy in the total population (13.0 months vs. 10.7 months, HR 0.77 (95% CI 0.63–0.93), p=0.0034) at the second interim analysis and in the CPS of 20 or more population (14.7 vs. 11.0,0.60 (0.45–0.82), p=0.0004) and CPS of 1 or more population (13.6 vs. 10.4,0.65 (0.53-0.80), p<0.0001) at final analysis. However neither pembrolizumab alone nor pembrolizumab with chemotherapy improved progression free survival at the second interim analysis. Based on result of Keynote 048 trial Pembrolizumab with chemotherapy is first line treatment in recurrent, unrespectable or metastatic head and neck tumor. Pembrolizumab also improved overall survival compared to chemotherapy in patients having CPS>1 [5]. NCCN recommends Single agent pembrolizumab (category 1) for CPS>20. Consolidation Immunotherapy in Stage III Non-small cell carcinoma lung

Regardless of PDL-1 expression, consolidation Durvalumab after concurrent chemo radiotherapy (the ‘PACIFIC regimen’) is the standard of care in patients with unrespectable Stage III NSCLC whose disease had not progressed after platinum based cCRT. Updated Median OS and PFS in Durvalumab vs. placebo arm was 47.5 vs. 29.1 months (stratified HR 0.72, 95% CI 0.59–0.89) and 16.9 vs. 5.6 months (stratified HR 0.55, 95% CI 0.45–0.68) respectively. The 60- month OS rates were 42.9% and 33.4% and 60 months PFS rates were 33.1% and 19.0% with Durvalumab and placebo, respectively. These updated survival analyses, showed continue sustained OS and PFS benefit with the PACIFIC regimen [6].

Non driver mutation advanced NSCLC

By phase III KEYNOTE-024 study, Pembrolizumab alone significantly improved progression-free survival and Overall Survival (OS) compared with platinum-based chemotherapy in patients with previously untreated advanced non–small-cell carcinoma PDL 1>50%. Median OS was 30.0 months (95% CI, 18.3 months to not reached) with Pembrolizumab and 14.2 months (95% CI, 9.8 to 19.0 months) with chemotherapy (hazard ratio, 0.63; 95% CI, 0.47 to 0.86). Pembrolizumab had less Grade 3 to 5 adverse events compared with chemotherapy (31.2% vs. 53.3%, respectively) [7]. After keynote 189 and keynote 407 trial Pembrolizumab with chemotherapy combination became standard of treatment in non-driver mutation NSCLC regardless of PDL 1 expression.

Extensive stage small lung cancer

Immunotherapy has also demonstrated clinical activity in Extensive-Stage SCLC (ES-SCLC) wherein most patients with Small- Cell Lung Cancer (SCLC) fall at presentation, and for whom the prognosis remains poor.

In IMpower 133 trial, Atezolizumab was combined with chemotherapy. At a median follow-up of 13.9 months, the median overall survival was 12.3 months in the atezolizumab group and 10.3 months in the placebo group (hazard ratio for death, 0.70; 95% Confidence Interval (CI), 0.54 to 0.91; P=0.007). The median progression-free survival was 5.2 months and 4.3 months, respectively (hazard ratio for disease progression or death, 0.77; 95% CI, 0.62 to 0.96; P=0.02). The addition of atezolizumab to chemotherapy in the first-line treatment of extensive stage small cell lung cancer led to significantly longer overall survival and progression free survival than chemotherapy alone [8].

The CASPIAN trial assessed Durvalumab, with or without Tremelimumab, in combination with platinum topside in treatment naive patients with ES-SCLC. Durvalumab plus platinum topside was associated with a significant improvement in overall survival, with a hazard ratio of 0.73 (95% CI 0.59–0.91; p=0.0047); median overall survival of 13.0 months (95% CI 11.5–14.8) in the Durvalumab plus platinum topside group versus 10.3 months (9.3–11.2) in the platinum topside group.

First-line Durvalumab plus platinum topside significantly improved overall survival in patients with ES-SCLC [9].

Triple negative early carcinoma breast

At the first interim analysis of keynote 522 trial, the percentage of patients with a pathological complete response was 64.8% (95% Confidence Interval (CI), 59.9 to 69.5) in the Pembrolizumab chemotherapy group and 51.2% (95% CI, 44.1 to 58.3) in the placebochemotherapy group (estimated treatment difference, 13.6 percentage points; 95% CI, 5.4 to 21.8; P<0.001). After a median follow-up of 15.5 months, disease progression that precluded definitive surgery, had local or distant recurrence or a second primary tumor, or died from any cause was observed in 58 of 784 patients (7.4%) in the Pembrolizumab chemotherapy group and 46 of 390 patients (11.8%) in the placebo chemotherapy group had (hazard ratio, 0.63; 95% CI, 0.43 to 0.93). Among patients with early triple-negative breast cancer, Pembrolizumab plus neoadjuvant chemotherapy receiving patients had significantly higher percentage with a pathological complete response than those who received placebo plus neo-adjuvant chemotherapy [10].

Metastatic triple negative carcinoma breast

Atezolizumab received approval in March 2019 based on data from the phase 3 IM passion130 trial which demonstrated a statistically significant benefit to progression-free survival with the exploratory regimen vs. placebo/chemotherapy (HR, 0.60; 95% CI, 0.48-0.77; P<. 0001), however, results published in 2021 indicated that the trial failed to meet the primary end point of PFS superiority in the frontline treatment of patients with PD-L1 positivity (HR, 0.82; 95% CI, 0.60-1.12; P=.20). Also, there was observed no difference in survival advantage in the PD-L1–positive (HR 1.11, 95% CI 0.76-1.64) nor the intention to treat population [11]. After this the indication for Atezolizumab in combination with nab-paclitaxel chemotherapy as treatment for patients with Triple-Negative Breast Cancer (TNBC) with tumors expressing PD-L1 was withdrawn by FDA in 2021. Role of immunotherapy is limited to recurrent, unrespectable or metastatic in carcinoma breast patients having MSI high or tumor mutation burden >10 mutt/mob [12].

Hepatocellular carcinoma

IMbrave150 trial included patients with unrespectable hepatocellular carcinoma who had not previously received systemic treatment. The hazard ratio for death with Atezolizumab–Bevacizumab as compared with Sorafenib was 0.58 (95% Confidence Interval (CI), 0.42 to 0.79; P<0.001). Overall survival at 12 months was 67.2% (95% CI, 61.3 to 73.1) with Atezolizumab–Bevacizumab and 54.6% (95% CI, 45.2 to 64.0) with Sorafenib. Median progression free survival was 6.8 months (95% CI, 5.7 to 8.3) and 4.3 months (95% CI, 4.0 to 5.6) in the respective groups (hazard ratio for disease progression or death, 0.59; 95% CI, 0.47 to 0.76; P<0.001). In patients with unresectable hepatocellular carcinoma, Atezolizumab combined with Bevacizumab resulted in better overall and progression free survival outcomes than Sorafenib (Table 1).

Table 1 : Justify about clinical trial and its outcomes.

Immunotherapies have revolutionized the treatment standards in solid tumours. They have provided meaningful survival improvements in patients with poor-prognosis cancers and for certain cancer types in which therapeutic options were limited. Many aspects of their use, including optimal combinations, sequencing, duration, and clinical setting, remain to be clarified. Ongoing clinical trials will serve to further increase their role, but careful consideration must be given to finding the safest, most individualized, and most cost-effective way to integrate them into the core of cancer care.

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