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Immunotherapy Regimen Proves Successful For A Patient With Advanced Lung Cancer

Lung cancer remains a severe malignancy, expected to account for over 125,000 deaths in 2024.  With high rates of mortality in both males and females, lung cancer accounts for more cancer-related deaths than any other malignancy. 

Advanced cases of lung cancer can metastasize to the brain, and about 20% of patients have brain metastases when diagnosed.  Non-small cell lung cancer (NSCLC) represents a highly aggressive subtype of lung cancer, accounting for over 80% of lung cancer cases.  As NSCLC skews towards late-stage diagnoses, five-year survival rates remain around 20%. 

Approximately 30 – 50% of NSCLC patients experience brain metastasis.  Due to the complexity of finding feasible therapies to reach cancer cells in the brain, NSCLC with brain metastasis presents significant clinical challenges.  In addition, brain metastasis can hinder quality of life and negatively impact survivorship. 

Immune checkpoint inhibitors (ICIs), a breakthrough in cancer treatment, have provided novel treatment options for stage IV NSCLC patients over the past several years.  Despite the promise of these therapies, scientists and oncologists have not yet fully optimized ICI therapeutic regimens. 

A new case study published in Oncosciene details a patient who experienced a notable response to ICI therapy.  The patient, a 51-year-old man with stage IV NSCLC with brain metastasis, received whole-brain radiation followed by chemotherapy.  Initially, the treatment regimen induced a partial response characterized by a lung tumor size reduction.  Additional lesions appeared on the liver, and although these areas could not undergo biopsy, doctors suspected that additional metastatic lesions arose in the liver.  The lesions in the brain experienced a complete response, which the patient maintained despite progression in the liver. 

As a second-line treatment, the patient received pembrolizumab, an ICI that targets programmed death-1 (PD-1), a checkpoint located on immune cells.  After three treatment cycles, the patient experienced a partial response in the liver and stable disease in the lung.  By the sixth cycle of treatment, the patient had a complete response in the liver and a partial response in the lung.  In addition, a complete response occurred on the brain lesions.  The lesion in the lung continued to shrink, leading to a complete response in all three regions (liver, lung, brain). 

Through 53 cycles of ICI, the patient maintained a complete response with only one minor adverse event, a grade 1 skin rash.  The patient recently had a follow-up appointment 26 months after his last treatment.  At this appointment, doctors noted the patient had no symptoms, no evidence of disease, and an excellent quality of life.  Since diagnosis, the patient has reached 87 months of overall survival (OS) and 73 months of progression-free survival (PFS). 

While the study presents just a single case of NSCLC, the results are promising.  The researchers suggest that sequencing the regimen with radiation followed by ICI could present an optimal strategy for administering treatment.  While more work is needed, the study provides new insight into ways to optimize the benefits of ICI therapy for a vulnerable cohort of patients. 

Sources: CA Caner J Cln, Annals Oncol, Oncosci

14 Little Known And Surprising Symptoms Of Lung Cancer You Need To Get Checked Out Immediately

Cancer is complicated and can cause a range of symptoms (

Image: Getty Images/Science Photo Library RF)

There are a number of signs people can look out for if they are worried about lung cancer.

Most symptoms are a sign of something far less severe or nothing at all, but it is always best to talk to your GP if you are worried or even just unsure. Cancer Research UK said that close to 65 percent of people who are diagnosed with stage one lung cancer will live for five years or more following diagnosis, this drops to around 40 percent for people diagnosed with stage two lung cancer.

A medically reviewed guide on WebMD shares some excellent insight into the range of symptoms that can signify lung cancer. So here they are.

Eye problems could be a sign of something else (

Image:

Getty Images)

Pain in the shoulder and back

Pain in the shoulder and back could be a sign of what is known as a Pancoast tumour. Cancer Research UK explained: "A Pancoast tumour can spread into one or more structures in the top part of the chest, which include: the first ribs in the chest (thoracic ribs); upper part of the back; the bundle of nerves that sends signals from the spinal cord to the shoulder, arm and hand (the brachial plexus); blood vessels that supply blood to the arms."

The charity and cancer experts said Pancoast tumours are "rare" and only occur in around five percent of every 100 lung cancer cases.

Eye problems

WebMD said that Pancoast tumours can also affect "the nerves to your eyes and part of your face" due to Horner's syndrome. Manchester Royal Eye Hospital explained: "Horner's syndrome is a rare condition that results from an interruption of the sympathetic nerve supply to your eye. The nerve that dilates your pupil (black part of your eye) in the dark is called the oculosympathetic nerve. This also controls a muscle that helps to keep your eyelid open. When this nerve is not working, the pupil on that side is abnormally small and the upper eyelid droops slightly."

The hospital said serious conditions of Horner's can be caused by a tumour in the lung.

Fatter fingertips

It may seem strange, but fatter fingertips could be a sign of lung cancer. This is because lung tumours can make chemicals that are like hormones, which push more blood and fluid to the fingertips, leading to fatter fingertips. Further signs may be that a person's skin near the nails is shiny or that the nails curve more than usual.

Watch out for fatter fingertips (

Image:

Getty Images)

Feeling tired

Lung cancer can affect your red blood cell count. Low levels of red blood cells are known as anaemia and can leave you feeling fatigued due to parts of your body not getting enough oxygen. Anaemia is a common side effect of lung cancer.

Aches and pains

Feeling weak and suffering from aches and pains could occur when lung cancer spreads and gets into your bones. This can cause new tumours that damage your bones.

Hypercalcemia can also weaken you and lead to aches all over your body, while the cancer could also impact your nervous system.

Blood clots

People with lung cancer are more likely to get a blood clot. This can happen in their legs and arms. Web MD said: "We don't know exactly why. The cancer could cause inflammation that triggers the clotting process, or chemicals from the tumour itself might cause clots."

Stomach pain

Stomach pain is usually a sign of something else far less severe. The common ailment is still something you should speak to your GP about if you are concerned, however.

High calcium levels, a condition known as hypercalcemia, is known to affect many cancer patients, so belly aches, and feeling constipated or sick could be signs of cancer, including lung cancer. This is because cancer can mess around with your kidneys.

Mental health

A downturn in your mental health could be a sign of cancer. Again, this really is something you should talk with your doctor about and the research around this is currently limited. Hypercalcemia can affect your mental health by impacting clarity of thought and depression.

Bad balance

Bad balance could be a sign of lung cancer. WebMD explained: "Small-cell lung cancers may tell your immune system to attack your nervous system, which can in turn affect how your muscles work. It may be hard to stand up when you're sitting, or you might feel unsteady."

Tumours can also make you dizzy if they are affecting the vein that moves blood from your brain to your head.

Weight gain

You may gain weight with small-cell lung cancer due to cancer making your body make ACTH, a hormone that raises the level of cortisol in your body. This makes it easier to retain fluid and you can gain weight which could be a sign of Cushing's syndrome - when the body has too much cortisol.

The NHS said: "Cushing's syndrome is uncommon. It mostly affects people who have been taking steroid medicine..." Most tumours causing Cushing's are benign, the health service said.

Headaches

Your superior vena cava carries blood away from the neck, arms, head and upper chest and into the heart. A tumour in the lung can lean on the vein and cause headaches.

Puffy features

Similarly, a puffy face, neck or arms can be caused by a tumour choking part of the superior vena cava.

Swollen breasts in men

This is rare, but swollen breasts in men could be a sign of lung cancer due to a hormone imbalance. This can cause swelling or tenderness in male breast tissue.

Heart problems

Hypercalcemia and anaemia can give you an irregular heartbeat. WebMD said: "If your heart issues are from hypercalcemia, chances are it's severe, and you could have a heart attack or go into a coma. Severe anaemia can also cause chest pains and shortness of breath."

Pembrolizumab/Chemo Continues To Impress In NSCLC With 5-Year Updates

During a Case-Based Roundtable® event, Ticiana Leal, MD, discusses phase 3 trials of combinations in the non–small cell lung cancer setting in the second article of a 2-part series.

Ticiana Leal, MD

Associate Professor

Department of Hematology and Medical Oncology

Director

Thoracic Medical Oncology Program

Emory University School of Medicine

Winship Cancer Institute

Atlanta, GA

Targeted Oncology: Please discuss the long-term data from the KEYNOTE-407 trial (NCT02775435) evaluating chemotherapy plus pembrolizumab.

Ticiana Leal, MD: Data from the KEYNOTE-407 study led to FDA approval of the combination of chemotherapy plus pembrolizumab [Keytruda] for patients who were treatment naive with non–small cell lung cancer [NSCLC] and squamous histology.1 In this trial, patients who had stage IV disease and had no symptomatic brain metastases were included.

Patients were a randomly assigned 1:1 to receive pembrolizumab plus chemotherapy with the backbone of carboplatin plus paclitaxel followed by pembrolizumab maintenance for up to 31 cycles vs placebo plus chemotherapy and followed by placebo maintenance. In this study, they did allow optional crossover of pembrolizumab for up to 35 cycles. The primary end points were progression-free survival [PFS] and overall survival [OS].

The 5-year OS and PFS data from the KEYNOTE-407 trial showed sustained benefit in the squamous cell population with an OS of 18.4% with pembrolizumab vs 9.7% with placebo and an HR of 0.71.2 The PFS was also improved in the treatment arm at 10.8% months vs 3.5%, respectively.

How does PD-L1 expression affect the efficacy for patients with NSCLC?

When evaluating the breakdown by PD-L1 expression, what has been demonstrated across the KEYNOTE trials is that the higher the PD-L1 expression, the greater the magnitude of benefit from the combination.

In the population with a PD-L1 expression of 50% or greater, the 5-year updated OS rate is 23% [in the experimental arm] vs 8.3%. In the population with a PD-L1 of 1% to 49%, the OS update is 20.6% vs 7.5%. In the population with a PD-L1 negative expression, the OS rates are 10.7% vs 13%, and the median was 15 months of follow-up. For the PD-L1 negative subgroup, especially in frontline, monotherapy is not recommended.

Regarding the PFS, the greater the PD-L1 expression, the greater the magnitude in terms of PFS benefit. For patients with a PD-L1 expression of greater than 50%, the PFS is 15% vs not reached [NR]. For those with a PD-L1 expression of 1% to 49%, the PFS was 11.8% [vs NR], and then for the patients with a negative PD-L1 expression the PFS was 7.1% [vs 6.7%]. For patients with a PD-L1 less than 1% the median is 7.1 months vs 6.7 months.

What were the adverse events (AEs) seen on KEYNOTE-407?

In terms of AEs, we have all been accustomed to using this regimen. The majority of the AEs are from the chemotherapy backbone [occurring in 20% of patients in the experimental vs control arms]. These AEs include anemia [53.2% vs 51.8%], alopecia [46.0% vs 36.4%], neutropenia [38.7% vs 32.9%], nausea [35.6% vs 32.1%], and thrombocytopenia [30.6% vs 23.2%; in each arm respectively].1

For the immune mediated AEs, the grade 3 to 5 AEs were lower [than the grade 1 and 2 AEs]. Pneumonitis was 2.1% with chemotherapy alone and 6.5% with pembrolizumab plus chemotherapy. [Other most common immune-mediated AEs included hypothyroidism (1.8% vs 7.9%, respectively) and hyperthyroidism (0.7% vs 7.2%)].

What were the long-term data from the phase 3 POSEIDON trial (NCT03164616) evaluating durvalumab with or without tremelimumab plus chemotherapy?

The phase 3 POSEIDON trial is an open-label, global, randomized study evaluating patients with metastatic NSCLC in the front line.3 Patients were also stratified by PD-L1 expression, disease stage, and histology.

In this trial, the study design is a little bit different, because patients were randomly assigned 1:1:1. In the first arm, patients received tremelimumab [Imjudo], the CTLA-4 inhibitor, plus durvalumab [Imfinzi], the PD-L1 inhibitor, plus chemotherapy for 4 cycles. This was followed with tremelimumab for only 1 additional dose on cycle 5, and then continued with durvalumab monotherapy maintenance. In the second arm, patients received durvalumab plus chemotherapy for 4 cycles, followed by durvalumab maintenance. In the control arm, patients received platinum-based chemotherapy for up to 5 or 6 cycles. The end points for the durvalumab/chemotherapy vs chemotherapy arm were PFS and OS as well as for the quadruplet, tremelimumab/durvalumab/chemotherapy vs chemotherapy.

In terms of PFS and OS, the durvalumab/tremelimumab plus or minus chemotherapy 4-year update showed durable benefit for PFS and OS for the quadruplet. For the triplet, which was durvalumab/chemotherapy vs chemotherapy, the PFS rate was improved but did not meet OS. Thus, we do not have approval for this combination, but we do have approval for the quadruplet.

At the 4-year update, the HR was 0.77 and the 24-month OS was 32.9 months in the quadruplet vs 22.1 in the triplet.

What did the 5-year update of POSEIDON show?

For the updated OS rate at 5 years, at the 60-month landmark analysis, the probability of OS with tremelimumab/durvalumab/chemotherapy vs chemotherapy was 15.7 months vs 6.8 in all comers.4

Although numerically improved, the durvalumab/chemotherapy vs chemotherapy did not meet statistical significance in terms of OS by histology. At the 60-month update for the non–squamous population, the OS rate was 20.5% in the quadruplet vs 9.1% chemotherapy alone. In the squamous population at the 60-month analysis, the OS rate was 7.6% vs 2.9%, respectively. The OS was 10.4 months for the squamous population with the quadruplet vs 10.5 months with chemotherapy alone. It is important to note that the greater benefit was in the non–squamous population here, with an OS rate of 20% vs 9%.

In terms of the 5-year OS for the PD-L1 negative population receiving tremelimumab/durvalumab/chemotherapy the OS rate was 6.1% vs 4% in the chemotherapy-alone arm.

In terms of subsequent anti-cancer therapy, data showed that for the patients receiving the tremelimumab/durvalumab/chemotherapy vs chemotherapy alone, approximately 19 patients were still receiving chemotherapy in the tremelimumab/durvalumab/chemotherapy arm at the data cutoff vs 0 patients in the chemotherapy-alone arm. There were approximately 10 patients who were still ongoing with maintenance pemetrexed, and approximately 35% of patients received subsequent therapies, including a small number of patients that received subsequent immunotherapy.

There were higher rates of patients receiving immunotherapy in the chemotherapy arm, which are quite low. This was a global study, and even though you might expect more patients would have received immune therapy, this was not the case.

In terms of safety, overall, when adding the CTLA-4 inhibitor and comparing with chemotherapy, the treatment-related AEs leading to death were comparable to the chemotherapy-alone arm. In the longer-term follow-up, there was no additional signal of increased toxicity with this combination strategy.

REFERENCES: 1. Paz-Ares L, Luft A, Vicente D, et al. Pembrolizumab plus chemotherapy for squamous non-small-cell lung cancer. N Engl J Med. 2018;379(21):2040-2051. Doi:10.1056/NEJMoa1810865 2. Novello S, Kowalski DM, Luft A, et al. Pembrolizumab plus chemotherapy in squamous non-small-cell lung cancer: 5-year update of the phase III KEYNOTE-407 study. J Clin Oncol. 2023;41(11):1999-2006. Doi:10.1200/JCO.22.01990 3. Johnson ML, Cho BC, Luft A, et al. Durvalumab with or without tremelimumab in combination with chemotherapy as first-line therapy for metastatic non-small-cell lung cancer: the phase III POSEIDON study. J Clin Oncol. 2023;41(6):1213-1227. Doi:10.1200/JCO.22.00975 4. Peters S, Cho BC, Luft AV, et al. Durvalumab with or without tremelimumab in combination with chemotherapy in first-line metastatic NSCLC: five-year overall survival outcomes from the phase 3 POSEIDON trial. J Thorac Oncol. Published online September 5, 2024. Doi:10.1016/j.Jtho.2024.09.1381

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