Dr. Vishwanath Sathyanarayanan reviews 7 noteworthy trials in NSCLC, CRC, prostate, hepatocellular and esophageal squamous cell carcinomas, providing his expert take on each.

FLAURA: Non-small cell lung cancer (NSCLC)

Dr. Vishwanath S: With this impressive data, the sequencing of agents may change with several clinicians opting for Osimertinib in the first line.

There is also data from Tata Memorial Hospital, Mumbai which has shown that adding Pemetrexed and Carboplatin chemotherapy to Gefitinib significantly prolonged progression free survival (PFS) and overall survival (OS), but increased toxicity in patients with epidermal growth factor receptor (EGFR) mutated advanced non-small cell lung cancer (NSCLC) which may also be a practical option in the Indian scenario where cost is a consideration.

The final overall survival results of the phase III FLAURA trial was presented at ESMO 2019. First-line treatment with Osimertinib extended overall survival compared with the older tyrosine kinase inhibitors Gefitinib and Erlotinib in patients with EGFR-mutated treatment naïve advanced non-small cell lung cancer (NSCLC).

Median overall survival was 38.6 months with Osimertinib vs 31.8 months with first-generation EGFR tyrosine kinase inhibitors. It is important to note that around one-third of patients in the control group crossed over to Osimertinib at disease progression. Though not powered to assess differences between Asians and Non- Asians, the benefit was more pronounced in non-Asian patients. Osimertinib was previously used only in the second line setting in those who have progressed on first generation EGFR inhibitors with a T790M mutation positivity.

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IMpower110 trial: Non–small cell lung cancer (NSCLC)

Dr. Vishwanath S: Atezolizumab represents a promising first-line treatment option in patients with PD-L1 high wild type NSCLC. However, longer follow up is required to substantiate these findings.

In an interim survival analysis of the phase III Impower 110 study, Atezolizumab monotherapy improved overall survival (OS) compared with platinum-based chemotherapy as a first-line treatment of patients with wild-type non–small cell lung cancer (NSCLC) who had ≥50% expression of PD-L1 on tumour cells (TC3) or ≥10% expression on tumour-infiltrating immune cells (IC3).

At a median follow-up of 15.7 months, median OS was 20.2 months (95% CI, 16.5-not evaluable) in the Atezolizumab arm compared with 13.1 months (95% CI, 7.4-16.5) in the chemotherapy (HR, 0.59; 95% CI, 0.40-0.89; P = .0106) arm. Median PFS was 8.1 months (95% CI, 6.8-11.0) in the Atezolizumab arm and 5.0 months (95% CI, 4.2-5.7) in the chemotherapy arm (HR, 0.63; 95% CI, 0.45-0.88; P = .007) in the TC3 or IC3 wild-type population; the confirmed overall response rate (ORR) was 38.3% vs 28.6%, respectively; and the median duration of response (DOR) was not reached versus 6.7 months, respectively.

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IDEA (pooled analysis): Colorectal Cancer (CRC)

Dr. Vishwanath S: Treatment of stage 2, high risk disease is a highly controversial area and the IDEA trial results are definitely practice-changing with shorter duration of CAPOX being non-inferior and less toxic as compared to 6 months in stage II high risk colon cancer. However, CAPOX cannot be substituted with a shorter FOLFOX regimen.

The pooled analysis of the four IDEA studies in patients with stage II disease were presented at the 2019 ASCO Annual Meeting. In patients with high-risk (T4 tumours, inadequate nodal harvest, poorly differentiated tumours, obstruction, perforation, or vascular/perineural/lymphatic invasion) stage II colorectal cancer, 3 months of adjuvant Capecitabine plus Oxaliplatin (CAPOX) was non-inferior to 6 months and well tolerated with lesser incidence of neuropathy. However, 6 months of Fluorouracil, Leucovorin, and Oxaliplatin (FOLFOX) yielded better efficacy than 3 months of FOLFOX, with added toxicity than the shorter duration of treatment.

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Atezolizumab in combination with Bevacizumab provides superior outcome compared with Sorafenib in Unresectable Hepatocellular Carcinoma (HCC)

Dr. Vishwanath: Sorafenib has been the standard therapeutic option for patients with advanced HCC. Recently, Lenvatinib has emerged as an alternative to Sorafenib and Nivolumab in the second-line setting. The use of an immunotherapy in combination with Bevacizumab in the first-line based on these results will prompt clinicians to use this regimen and offer some hope to patients with advanced HCC.

The primary analysis of data from the phase III IMbrave150 trial of Atezolizumab plus Bevacizumab versus Sorafenib in patients with unresectable HCC was presented at the ESMO Asia conference held recently. With median follow-up of 8.6 months, median OS with the Atezolizumab combination was not estimable (NE) compared to 13.2 months (95% confidence interval [CI], 10.4, NE) with Sorafenib (hazard ratio [HR] 0.58; 95% CI, 0.42-0.79;p = 0.0006).

Median PFS with the combination was 6.8 months (95% CI, 5.7-8.3) versus 4.5 (95% CI, 4.0-5.6) with Sorafenib (HR 0.59 (95% CI, 0.47-0.76; p < 0.0001). The response rates were also better with Atezolizumab plus Bevacizumab over Sorafenib. The adverse effects grade 3/4 was not different in the two arms.

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ATTRACTION-3: Esophageal squamous cell carcinoma (ESCC)

Dr. Vishwanath S: In patients with advanced ESCC, where treatment options are restricted to taxanes, fluoropyrimidine and platinum agents; Nivolumab may be a new standard second-line treatment option.

This was a phase III ATTRACTION-3 study of Nivolumab versus chemotherapy in patients with unresectable advanced or recurrent esophageal squamous cell carcinoma (ESCC) refractory or intolerant to 1 prior fluoropyrimidine/platinum-based CT. In this final analysis, second-line treatment with Nivolumab demonstrated significant improvement in OS vs Paclitaxel or Docetaxel in patients with unresectable ESCC.

Median OS with Nivolumab, 10.9 months; chemo, 8.4 months; HR: 0.77 (95% CI: 0.62-0.96; P = .019). Most subgroups trended towards OS benefit with Nivolumab, including those with variable PD-L1 levels. Nivolumab showed a tolerable safety profile with numerically fewer grade 3/4 serious treatment-related adverse events (TRAEs) vs chemo.

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ARCHES trial: Prostate Cancer

Dr. Vishwanath S: Based on this study, patients with hormone sensitive metastatic carcinoma prostate can be offered Enzalutamide with ADT as an alternative to Abiraterone of Docetaxel. However, the OS data is still immature.

This was a randomised, Phase III Study of Androgen Deprivation Therapy with Enzalutamide or placebo in men with metastatic hormone-sensitive prostate cancer. The primary endpoint was radiographic progression-free survival (rPFS) or death within 24 weeks of treatment discontinuation. Secondary endpoints included time to prostate-specific antigen (PSA) progression, PSA and radiographic responses and overall survival (OS).

Median follow-up was 14.4 months. ENZA + ADT significantly improved rPFS (NR vs 19.4 months, HR 0.39) and similar significant improvements in rPFS were reported in prespecified subgroups of disease volume, the pattern of spread, region and prior Docetaxel (HRs 0.24–0.53). Enzalutamide was well tolerated.

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CARD trial: Prostate Cancer

Dr. Vishwanath S: The authors showed that regardless of which anti-androgen is administered first, the second anti-androgen has minimal efficacy, especially relative to Cabazitaxel. Though there is impressive data with only 3.2% incidence of febrile neutropenia in the current study, previous studies have shown a higher incidence of febrile neutropenia with 25mg/m² dose of Cabazitaxel. Hence, a word of caution for the clinicians.

This was a randomised, open-label study of Cabazitaxel vs Abiraterone or Enzalutamide in metastatic castration-resistant prostate cancer (mCRPC). Sequencing of agents- chemotherapy or androgen inhibitors is always a challenge in mCRPC. This trial hopes to answer some questions. Men with mCRPC who progressed within 12 months on either Abiraterone or Enzalutamide were then randomised to either Cabazitaxel or the other anti-androgen therapy.

Docetaxel and abiraterone were allowed in the HSPC setting. A dose of 25 mg/m2 of Cabazitaxel with granocyte-colony stimulating factor (G-CSF) prophylaxis was given. The primary endpoint was radiographic progression-free survival (PFS). Secondary endpoints were overall survival, PFS and tumour response. Cabazitaxel treatment offered statistically significant radiographic progression free survival and overall survival benefit over alternative anti-androgen therapy (HR 0.54, P <0.001).

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 writer, Dr. Vishwanath Sathyanarayan is a Medical Oncologist from Apollo Hospitals, Bangalore with a fellowship from MD Anderson Cancer Center.