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The patient died of high PD-L1 expressing after 13 days of immunotherapy.
The patient died of high PD-L1 expressing after 13 days of immunotherapy. This article are two cases of lung cancer patients with high PD-L1 expressing rapid super-progress using immunotherapy.
The high expression of PDL1 is the gold standard that patients are more suitable for immunotherapy. The NCCN guidelines for lung cancer also pointed out that for EGFR and ALK-negative NSCLC patients, PD-L1 ≥ 50%, it is recommended that patients receive K-drug monotherapy.
However, recent studies have suggested that high expression of PDL1 is not a “master key”. Some patients with high expression of PDL1 do not respond to PD1/PDL1 immunotherapy, and some may even experience “super progress”! Surprisingly!
The cases shown below are two cases of lung cancer patients with high PD-L1 expressing rapid progress in immunotherapy! Why is PD-L1 highly expressed, and the use of immunotherapy will be super progress? Perhaps the so-called routine is used for breakthroughs or thinking.
PD-L1 is highly expressed: After 13 days of using atilizumab, he died of immune hyperprogress!
The patient was a 66-year-old male with no history of smoking. He had undergone bronchoscopy and imaging examinations and was diagnosed with pleomorphic carcinoma of the right lower lobe lung, which had metastasized to the brain, lung, pleura and mediastinal lymph nodes.
The NGS detection of the primary tumor obtained by bronchoscopy revealed that the EGFR exon 21 L858R mutation and the TP53 R175H mutation were found. Immunohistochemistry (IHC) showed that the expression of PD-L1 was 90%.
1. EGFR-TKI resistance: due to consideration of EGFRL858R mutations, first-line and second-line treatments with afatinib and osimertinib were selected, but patients did not respond to EGFR-TKI.
2. Chemotherapy is short-lived and effective: Carboplatin+pemetrexed was used as a third-line treatment for 4 courses. The curative effect was evaluated as PR. However, because of multiple brain metastases, the disease progressed with whole brain radiotherapy (30 Gy/10 Fr).
3. He was admitted to the hospital for four-line PD-L1 monoclonal antibody Atezolizumab and died of HPD due to immune hyperprogress for 13 days.
Before atelizumab treatment, the patient’s vital signs were as follows: body temperature 36.7°C; blood pressure: 127/81 mmHg; heart rate 96/min; respiratory rate, 12/min; oxygen saturation 96% (indoor air); and performance status : 1. Due to the pleura fixation, the left breathing sound is slightly weakened. High levels of LDH (391 U/L; normal range 120–220) and CEA (101.9; <0.5 ng/mL) were found. The image showed that there was no pleural effusion and heart enlargement.
After 3 days of atelizumab treatment, the patient had fast heartbeat, low blood pressure, and dyspnea, requiring oxygen inhalation. X-ray examination showed mild swelling of the heart, echocardiogram showed obvious accumulation of pericardial effusion (2.7 cm), and immediate pericardial drainage was performed.
A large number of adenocarcinoma lymphoma cells and lymphocytes were seen in the cytology of pericardial effusion. After pericardial drainage, the chest X-ray showed an enlarged heart.
Repeated chest CT examination revealed that the old lesions were enlarged, bilateral ground-glass opacity and left pleural effusion (Figure 1D). The patient’s respiratory condition deteriorated rapidly and his LDH level increased (706 U/L).
Because drug-induced pneumonia related to immune-related adverse events (irAE) was suspected, methylprednisolone (1 mg/kg) was taken on day 8. Unfortunately, the patient died of respiratory failure on the 13th day after taking atelizumab.
Autopsy revealed extensive metastases in all lobes of both lungs, and new metastases in the liver and diaphragm. Due to cardiac tamponade caused by cancerous pericarditis, bilateral pleural effusion and pericardial effusion appear. The infiltration of lymphocytes into the pericardium and lung fields is mild, and there is no strong evidence for immune-related adverse reactions irAE. Therefore, the death of a patient is defined as hyperprogressive HPD after the use of immunotherapy.
PD-L1 is 100% expressed, and super progress also appears after 2 courses of treatment with K drug!
The patient was a 66-year-old African-American female with a 25-year smoking history and IIIB lung adenocarcinoma. There was no mutation or fusion of EGFR, ALK, and ROS1. Past history: history of papillary thyroid carcinoma, type 2 diabetes, and primary thrombocytosis.
Simultaneous radiotherapy and chemotherapy to achieve a safe remission, maintain 13 months without recurrence!
After the diagnosis, due to the limitation of the lesion, the patient received concurrent chemotherapy and radiotherapy for the chest and right neck masses, and received two cycles of adjuvant chemotherapy with carboplatin and paclitaxel. The treatment was well tolerated and the tumor disappeared. This state has been maintained for 13 months without recurrence.
Recurrence with brain metastasis, received 1 local brain radiotherapy + 2 courses of PD-1 treatment, and then stopped due to HPD!
After 13 months, a CT scan of the chest, abdomen, and pelvis revealed enlarged subcarinal and hilar lymphadenopathy. Bronchoscopic biopsy confirmed recurrent lung adenocarcinoma and was diagnosed as stage IVB TxN3M1c. The NGS report suggested that the patient had the following mutations: ERBB3 H292Y mutation, STK11 A218Lfs* 69 mutation, TP53 R283P mutation, amplification of AKT1, MYC, NTRK1, and 5 unknown variants ATM P604S, ATM R832C, BRCA2 S2835P, CDKN2B D86N And MLH1 R487Q. In addition, PD-L1 is 100% and the intensity is 3+.
The patient underwent a stereotactic radiosurgery (SRS) with a total radiation dose of 20 Gy. After brain SRS, the patient started systemic therapy with a single dose of pembrolizumab (Keytruda pembrolizumab) at a standard dose (200 mg) every 3 weeks.
After the first cycle of K drug treatment, minor side effects such as mild diarrhea and joint stiffness occurred. Nausea and fatigue occurred after using the K drug in the second cycle, but the patient was admitted to the hospital due to shortness of breath 2 weeks after the drug. Chest CT and echocardiogram showed a large amount of pericardial effusion and a large amount of right pleural effusion.
Emergency pericardiocentesis and thoracentesis drainage were performed to drain the effusion. Cytological examination of the pleural fluid showed that it was a malignant tumor, which was consistent with poorly differentiated cancer. Pericardial fluid was sent to basic medicine, and PD-L1 was 0%. Therefore, K drugs should be discontinued due to HPD (super-progressive) reasons.
After changing to chemotherapy, the condition was controlled and maintained long-term stability!
The patient changed treatment to carboplatin (AUC 5) and pemetrexed (500mg/m2) every 3 weeks. After 2 cycles of treatment, the patient developed severe diverticulitis and received antibiotic treatment of ciprofloxacin and metronidazole. The third cycle of chemotherapy was delayed by 2 weeks. After the third cycle of chemotherapy, the patient stopped treatment and rechecked regularly; the patient remained disease-free for up to 20 months. The picture below shows the patient’s entire treatment history.
These 2 cases of super-progress using immunization are not the only cases of immunotherapy. As early as 2016, a clinical trial found that about 10% of patients had hyperprogress while receiving immunotherapy.
1 Patients with high PD-L1 expression and EGFR mutation should use immunotherapy with caution
Although there have been reports of hyperprogressive HPD caused by atelizumab in the treatment of non-small cell lung cancer, this is the first case of atelizumab in the treatment of EGFR-mutant pleomorphic lung cancer with HPD.
Previous studies have shown that atelizumab has a higher efficacy in tumor cells with higher PD-L1 expression. However, this patient developed HPD despite the high PD-L1 expression.
The article did not give the exact cause of HPD, but through this case, we found that immune hyperprogression may occur earlier, so when using immunotherapy in patients with EGFR mutations in lung pleomorphic cancer, pay attention to the occurrence of HPD Possibility, in addition, relevant genetic testing can be carried out before immunotherapy to rule out genetic mutations that cause immune hyper-progression.
2 Loss of PDL1 expression is the cause of immunotherapy resistance or HPD
The most significant feature of the second patient is the expression change of PDL1 before and after immunotherapy. From the initial expression of 100% to 0% of PDL1 expression after super-progression.
There was a completely reversed loss of PDL1 expression. This loss of PDL1 expression during immunotherapy is not uncommon.
In a post-mortem analysis of 3 patients, 3 patients with non-small cell lung cancer showed a decrease or even loss of PD-L1 expression after receiving immunotherapy.
The expression of PD-L1 decreased from 75.6% to 13.2% in one case, and decreased from 100% to 58.8% in one case. The expression of PD-L1 in the third patient dropped from 98% to <1%.
The loss of PD-L1 expression may be one of the mechanisms by which immunosuppressive treatment of non-small cell lung cancer and other cancers develop resistance to immunotherapy.
Perhaps even the speed at which PD-L1 disappears can be used as an indicator of HPD. In cases where HPD and immunotherapy have failed, the mechanism of PD-L1 loss needs to be further studied.
3 STK11 may be related to immune hyperprogress!
Previous studies have demonstrated the link between STK11 and hyperprogressive in non-small cell lung cancer, in which (3/16) HPD patients have STK11 mutations, while those without STK11 mutations (0/28) have no HPD. STK11 mutations in lung cancer patients generally have a worse prognosis.
In a larger cohort study, 377 patients with metastatic non-small cell lung cancer received K drug, platinum-containing dual chemotherapy (carboplatin or cisplatin) and pemetrexed treatment, 102 patients with STK11 gene alterations Lower ORR (32.6% vs. 44.7%), significantly shorter mPFS (4.8 vs. 7.2 months) and mOS (10.6 vs. 16.7 months).
The co-mutation of STK11 and KEAP1 occurs in about 13% of lung cancers, and the median tumor mutation burden is higher than the overall average level (9.4 vs. 6.1), but PFS and OS are reduced when receiving PD1/PDL1 immunotherapy.
Both NGS and liquid tumor biopsy of this patient showed STK11 and TP53 mutations. It can be said that STK11 mutation patients represent a subtype of patients with advanced lung cancer that urgently need new treatment strategies. Persistent STK11 mutations are also very correlated with hyperprogression in patients.
Although these two cases are only individual cases, they also give some enlightenment. Many so-called experiences need to be questioned or broken. The patient’s treatment mistakes, and the long-term accumulation of steps, defend the life of every patient!
(source:internet, reference only)