Immunotherapy May Increase Cancer Growth Among Certain Patients

Patients with certain characteristics observed to experience hyper-progression of cancer growth on immunotherapy.

Immunotherapy has become a popular and promising treatment in the oncology world, with many patients receiving the drugs instead of chemotherapy. Since these drugs work with the immune system and are less toxic than traditional treatments, patients may experience less side effects and have better outcomes.

Some patients, called hyper-responders, experience long-term remission, while most patients experience a response rate of 20% to 40%, according to a study published by Clinical Cancer Research. Approximately 9% of patients treated with immunotherapies are considered hyper-progressors, which involves accelerated disease progression on the drugs.

In the study, the authors describe 6 case reports of hyper-progressive patients with stage 4 cancers to determine which characteristics may lead to hyper-progression on immunotherapy.

The first patient described was a 73-year-old man with metastatic bladder cancer with an MDM2 amplification. This patient was treated with atezolizumab, a PD-L1 inhibitor. After nearly 2 months on the drug, the patients’ liver tumors increased 258% compared with pre-immunotherapy sizes, according to the study. Imaging also showed the development of new metastases.

The authors said that the patient lost weight, developed tumor fevers, and had progressive syndrome of inappropriate antidiuretic hormone (SIADH). The patient died soon after progression was confirmed.

The second patient had triple negative breast cancer with metastases in the brain and lungs, and had an MDM2 amplification. Only 1.5 months after beginning treatment with pembrolizumab, the patient’s left lung tumor increased 55%. The patient also developed new tumors and lymphadenopathy, according to the study.

The third patient described had endometrial stromal sarcoma that progressed to the liver over a period of 6 months on targeted therapy. The patient was switched to nivolumab plus sterotactic body radiation therapy, and developed palpable masses in her abdomen. For this patient, a CT scan revealed a 242% increase in the liver metasis after only 1.5 months into treatment.

A fourth patient with lung adenocarcinoma, with an KIF5B-RET fusion and MDM2 amplification, experienced gradual progression on Abraxane, and was switched to pembrolizumab. After only 9 days, the patient experienced a 135% increase in lung metastases compared with pre-immunotherapy, according to the study.

The fifth patient described was first treated with carboplatin, paclitaxel, and bevacizumab for lung adenocarcinoma, but switched to pembrolizumab upon progression. The patient developed worsening dyspnea, fatigue, and new brain metastases after 1.5 months. This patient had MDM2 and CDK4 amplifications.

The final patient described was diagnosed with squamous cell carcinoma and was treated with an OX40 antagonist. The drug was discontinued after 1.4 months due to altered mental status, which was linked to hyponatremia from tumor-associated SIADH, according to the study. The patient died 3 months later.

The authors performed next-generation sequencing for each patient to determine detection of copy number alterations, gene rearrangements, and somatic mutations, the authors wrote.

The authors reported that patients with MDM2 family amplifications may be particularly at risk of hyper-progression. These patients were all taken off immunotherapy within 2 months of treatment initiation due to significant disease progression.

The authors reported that EGFR and DNMT3A alterations were also observed to cause treatment failure less than 2 months in 8 out of 10 patients and 4 out of 5 patients, respectively.

These findings suggest that MDM2 family amplifications and EGFR alterations may be part of why patients progress on the drugs; however, another study suggests that patients with liposarcomas, which commonly have the MDM2 amplification, may benefit from immunotherapy.

The investigators speculate that hyper-progression may be more common in certain cancers and that the response pattern may not be universal, which may explain the differing results.

These conflicting findings highlight for additional studies to determine all factors involved with hyper-progression after immunotherapy.

“Our observations suggest that patients for whom anti-PD1/PDL1 monotherapy is planned may require genomic testing to determine if their tumors harbor specific alterations associated with hyper-progression,” the authors concluded. “Individuals with these alterations, if treated with anti-PD1/PDL1 agents, should be closely monitored. Larger studies, validation cohorts, and translational research are urgently needed.”