On the surface, the relationship between non-small cell lung cancer (NSCLC) and chronic hepatitis B virus (HBV) infection may seem unclear. However, it is understandable these conditions overlap in millions of people, as approximately 296 million worldwide are infected with HBV,

Centers for Disease Control & Prevention. Fast Facts on Global Hepatitis B. Updated July 27, 2022.

and NSCLC is the most common type of cancer. The issue of HBV infection is especially important in Asian countries, as these populations shoulder the burden of high HBV rates. For instance, up to 15% of Taiwanese citizens are infected with HBV, as reported in the European Journal of Cancer.

Yao ZH, Liao WY, Ho CC, et al. Incidence of hepatitis B reactivation during epidermal growth factor receptor tyrosine kinase inhibitor treatment in non-small-cell lung cancer patients. Eur J Cancer. 2019;117:107–115.

 

The interaction between these two comorbidities is likely rooted in immune status. The progression of HBV infection to acute, chronic, or occult disease, as well as spontaneous remission, depends on immune status. Immunity plays an important role in prognosis as well.

Alandag C, Konak E, Fidan S, et al. Effects of hepatitis B virus infection prognosis to non-small cell lung cancer survival. Euras J Med Investig. 2022;6(3):332–334.

An emerging body of research—much from Asian countries—elucidates the link among immune-oncology agents and HBV.

 

 

HBV reactivation

 

Hematologic cancers treated with cytotoxic and targeted therapy can set the stage for HBV reactivation. The highest-risk group is patients with lymphoma who are administered an anti-CD20 antibody-containing regimen. In these specific patients—including those with resolved HBV infection or undetectable HBV viral loads—up to 41.5% experience HBV reactivation, as reported in the European Journal of Cancer.

Some studies have specifically focused on tyrosine kinase inhibitors (TKIs).

A study published in the European Journal of Cancer analyzed the incidence of HBV reactivation in 171 Taiwanese patients with NSCLC who were positive for HBV surface antigen (HBsAg+). All of these patients received EGFR TKI treatment (median duration; 10.5 months).

Reactivation of HBV referred to either 1) an increase in HBV DNA by 10-fold or greater vs baseline, or 2) an absolute increase to >105 IU/mL, along with abnormal liver function.

The results confirmed a clinically meaningful risk of HBV reactivation during the treatment period.

Overall, 9.36% of patients had a reactivation during EGFR TKI treatment; the annual incidence of HBV reactivation was 7.86%. The number of patients affected, by treatment type, was erlotinib, 6 patients; gefitinib, 5 patients; osimertinib, 3 patients; and afatinib, 2 patients. The investigators found no independent risk factor for HBV reactivation.

Given this risk of HBV reactivation in NSCLC patients with positive HBsAg who are undergoing EGFR TKI therapy, the authors recommended monitoring for liver function and also HBV viral load and serology of HBV (ie, HBeAg and anti-HBc).

 

HBV antiviral prophylaxis

 

A case report published in Thoracic Oncology spotlighted why antiviral prophylaxis is important for patients with chronic HBV disease comorbid with NSCLC.

Kang YK, Meng FC. Acute fulminant hepatitis associated with osimertinib administration in a lung cancer patient with chronic hepatitis B: The first mortality case report. Thorac Cancer. 2022;13(7):1091-1094.

 

The case involved a 68‐year‐old Taiwanese woman with chronic HBV and aggressive NSCLC. She received osimertinib for 4.5 months without antiviral prophylaxis, and then she died. This is the first published case study of death secondary to osimertinib‐related acute fulminant hepatitis.

“Considering the fewer adverse events of EGFR‐TKI therapy, recommendations to prevent and treat HBV reactivation are frequently neglected,” the authors noted.

It may persuade clinicians to consider routine HBV screening, and antiviral prophylaxis should be prescribed for patients with chronic HBV before osimertinib therapy.

Although the mechanisms underlying TKI-induced HBV reactivation are unknown, chimpanzee models have demonstrated that TKIs could suppress CD8+ T-cells needed to fight HBV infection.

Practice guidelines, such as those from the American Society of Clinical Oncology (ASCO), stipulate the use of antiviral prophylaxis. As the case report authors summarized, ASCO guidelines recommend that all patients about to receive systemic anticancer therapy be tested for HBsAg, anti‐HBc, and anti‐HBs before treatment. Patients with chronic HBV infection should be given antiviral prophylaxis during treatment and at least 12 months after treatment ceases. HBV DNA viral loads should also be checked every 6 months during antiviral therapy.

“Coordination of care with a clinician experienced in HBV management is recommended for patients with chronic HBV to determine HBV monitoring and long-term antiviral therapy after completion of anticancer therapy,” states ASCO in a provisional clinical opinion.

Hwang JP, Feld JJ, Hammond SP, et al. Hepatitis B virus screening and management for patients with cancer prior to therapy: ASCO Provisional Clinical Opinion Update. J Clin Oncol. 2020;38(31):3698-3715. 

 

On a related note, hormonal therapy was exempt from this guidance. “Hormonal therapy alone should not pose a substantial risk of HBV reactivation in patients with chronic HBV receiving hormonal therapy alone; these patients may follow noncancer HBV monitoring and treatment guidance,” ASCO advised.

 

What about PD-(L)1 inhibitors and NSCLC?

 

However, data on patients with advanced NSCLC and chronic or previous HBV has been limited to case reports or small case series.

One study involving 62 Asian patients with NSCLC evaluated safety and survival outcomes among those with varying states of HBV infection.

Zhang X, Tian D, Chen Y, et al. Association of hepatitis B virus infection status with outcomes of non-small cell lung cancer patients undergoing anti-PD-1/PD-L1 therapy. Transl Lung Cancer Res. 2021;10(7):3191-3202.

Of these patients, 10 patients had chronic hepatitis (HBsAg+), and 52 patients had resolved hepatitis (HBsAg– and HBcAb+).

 

The investigators found the patients with chronic HBV who were treated with anti–PD-(L)1 monotherapy fared better than those with resolved HBV who received this therapy, showing a durable clinical benefit rate of 60.0% vs 23.1%, respectively. Survival outcomes were longer in the chronic HBV group as well—overall survival was 8.3 months vs 2.0 months, and progression-free survival was 35.0 months vs 18.2 months.

“Our study indicates that anti-PD-(L)1 immunotherapy could be safe and effective in HBV-infected patients,” the authors concluded.

Patients with positive HBsAg (chronic HBV infection) were more likely to have durable benefit than those with resolved HBV infection.

With respect to HBV reactivation, the authors noted that “HBV reactivation may occur upon treatment with PD-(L)1 inhibitors, and this should be monitored attentively throughout the therapeutic process.” Nevertheless, their findings “support the use of anti-PD-(L)1 immunotherapy in these patients, along with regular monitoring of HBV serological markers and properly administrated antiviral prophylaxis to prevent HBV reactivation.”