Research 3184675760

Hana Maor

Case #3184675760 | 18.09.22

סיכום

1.הטיפולים הקיימים בשוק

1.1. כימותרפיה ואימונותרפיה

1. כימותרפיה מבוססת פלטינום (קרבופלטין/ציספלטין) + פמטרקסד (“אלימטה”) + אימונותרפיה הוא ככל הנראה הטיפול המומלץ כקו ראשון. שרידות כללית של כ-12.6 חודשים. נמצא בסל התרופות.[6][1]
2. פמברוליזומאב (“קיטרודה”) בשילוב עם כימותרפיה מראה שיפור בשרידות. נמצא בסל התרופות.[8]
3. אטזוליזומאב + בווקיזומאב (“אבסטין”) היא אלטרנטיבה אפשרית לפמברוליזומאב אשר הוכחו כמשפרי שרידות יחד עם כימותרפיה. שרידות כללית יחד עם כימותרפיה של כ18 חודשים. נמצא בסל התרופות.[10]
4. ניבולומאב+איפילימומאב + כימותרפיה הוא ככל הנראה השילוב המומלץ מבחינת שרידות כללית ושרידות ללא התקדמות מחלה. שיפור ל14.1 חודשים אל מול 10.7 חודשים עם כימותרפיה בלבד. נמצא בסל התרופות.[12]
5. אימונותרפיה כטיפול בודד אינה מומלצת.[14]

1.2. מעכבי אוסטאוקלסטים מורידים משמעותית ומעכבים את זמן ההופעה של אירועים קשורים לשלד במטופלים עם גרורות בעצמות. נמצא בסל התרופות.[16]

1.3. רדיותרפיה חוזרת יכולה להיות מועילה בהפחתת הכאבים במידה והטיפול הראשוני נכשל.[17][19]

2.מחקרים קליניים

על פי ממצאינו, האופציות הקיימות להשתתפות במחקרים קליניים עבור מטופלים עם NSCLC מתקדם מסוג אדנוקרצינומה עם ביטוי PD-L1<1% אשר עוד לא החלו בטיפול כימותרפיה קו ראשון הינו מועט. נמצאו 2 מחקרים קליניים רלוונטיים אשר מפורטים בדוח. נוספו לדוח 2 מחקרים קליניים נוספים אפשריים במידה ותתרחש התקדמות במחלה לאחר תחילת טיפול כימותרפי.

1. תרופה נסיונית + פמברוליזומאב /פמברוליזומאב +כימותרפיה. NCT04165798 פנינו לעורכי המחקר לפירוט אודות התרופה הנסיונית, טרם נתקבלה תשובה.
2. השתלת צואה + ניבולומאב. NCT04521075
3. סאקיטוזומאב /דוקטקסל לאחר התקדמות במחלה תוך טיפול כימותרפי. NCT05089734
4. נוגדנים מונוקלונאליים לאחר התקדמות במחלה תוך טיפול כימותרפי. NCT03893955

3.טיפולים אינטגרטיביים

לפני יישום או נטילת התרופות המוצעות בחלק זה יש להיוועץ ברופא המטפל וביחידות לרפואה משלימה ואינטגרטיבית במחלקות האונקולוגיות בבתי חולים מובילים.

1. תזונה נכונה ותוספי תזונה כגון ויטמינים, מינרלים, שמן דגים ומלטונין, יכולים להעלות את רמות האנרגיה, הרכב הגוף, הפחתת עייפות והפחתת איבוד תיאבון ושיפור איכות חיים. [20][21] [9] [22]
2. מטפורמין יכול להועיל בשיפור שרידות ללא התקדמות מחלה והורדת בחילות במהלך טיפול כימותרפי. [4]
3. דיקור יכול להועיל בהפחתת תופעות לוואי של הטיפולים והמחלה, הורדת מתח ושיפור באיכות החיים. (מומלץ להיעזר במטפלים ביחידות לרפואה משלימה ואינטגרטיבית במערכים האונקולוגיים של מרבית בתי החולים) [10] [11][12][13][15]
4. עשבי מרפא סיניים כגון אסטרגלוס, יכולים לשפר שרידות כללית ולהפחית תופעות לוואי מטיפולי כימותרפיה. טיפולים אחרים, כמו זריקת “Kushen”, יכולים לסייע בהפחתת כאבים.[16][17][23]
5. הומואפתיה יכולה לסייע בהפחתת סימפטומים ושיפור איכות חיים.[20][26]
6. רפלקסולוגיה יכולה להועיל בהפחתת תופעות לוואי של הטיפולים והמחלה, הורדת מתח ושיפור באיכות החיים. (מומלץ להיעזר במטפלים ביחידות לרפואה משלימה ואינטגרטיבית במערכים האונקולוגיים של מרבית בתי החולים)[19][24]
7. קנאביס רפואי יכול לשמש כטיפול תומך להפחתת בחילות וכאבים.[2]

 

Research Inquiries

Research Inquiry #1

• Platinum based chemotherapy + Pemetrexed + Immunotherapy is probably the best first line treatment for advanced NSCLC Adenocarcinoma with low PD-L1 expression.
• Pembrolizumab is a good first line immunotherapy combined with platinum based chemotherapy.
• According to several studies, combination of Nivolumab, Ipilimumab and chemotherapy is most likely the best regimen in terms of Overall Survival (OS). Also, combination of Nivolumab, chemotherapy, and Bevacizumab is most likely the best regimen in terms of Progression Free Survival (PFS).
• Immunotherapy alone is not recommended for patients with low PD-L1 expression.
• Osteoclast inhibitors significantly reduce the frequency of and delay the time to onset of skeletal-related events in patients with bone metastases.
• If the initial radiotherapy fails to relieve bone pain, reirradiation (second radiotherapy) may be a useful option and can be considered.

Research Inquiry #2

• Based on our findings, the options for relevant clinical trials for Advanced NSCLC patient with PD-L1<1% who hasn’t started first line therapy are limited. Two relevant clinical trials were found and described below. Therefore, we added two possible clinical trials in case of disease progression after initial therapy.

Research Inquiry #3

• Metformin can be beneficial in terms of PFS and reduce occurrence of chemotherapy induced-nausea.
• Nutrition and nutritional supplements such as vitamins, minerals, fish oil and melatonin can improve energy and protein intake, body composition, decreased fatigue and loss of appetite and quality of life.
• Acupuncture can be effective for chemotherapy-induced nausea and vomiting, helpful in managing cancer-related pain and improving chemotherapy-related fatigue.
• Chinese herbal medicine can be considered for improving pain relief in patients with bone cancer pain. Astragalus, a Chinese herbal medicine, can improve overall survival and decrease side effects.
• Reflexology can be considered as a treatment for reducing pains.
• Medical cannabinoids can be considered as supportive care for anti nausea and pain relief.

 

Patient Medical Background

Age	79
Gender	Female
Diagnosis	Non-Small Cell Lung Cancer (NSCLC) adenocarcinoma in Right Lower Lobe (RLL) with 2 spine metastasis (L2,L4)
Diagnosed at	14.08.2022
Genetic Mutations	FGFR3 mutation (p.Phe384Leu), NF1 (splice site 7739-1G>A)
Pathology	PD-L1<1% , TTF positive
Symptoms	Severe Back pain, Constipation, Lack of appetite.
Organs	Lungs (RLL), Spine (L2, L4)
Current Treatment	September 2022 – 3 cycles of radiation therapy to L2,L4 vertebrae.Pain relievers – Dexamethasone – 2mg PO – twice a day for a month.Fentanyl – 37 mcg – every 3 days.Syrup Oxycod – 6mgFamotidine Gastro – 40mg PO – once a day for 2 weeks.Plavix – 75mg – once a day.Supplements: Vitamin B12, Folic acid, Vitamin D.
History of Procedures	June 2022-CT scan exhibits space occupying lesion in RLL.August 2022 -PET CT exhibits absorbance in RLL with progression in tumor size compared to previous CT. Absorbance in the right part of sacrum and L2,L4 vertebrae. No involvement of lymph nodes.Brain MRI – Exhibits no signs of parenchymal dispersal. Cyst causing a mass effect on optic chiasm. Space occupying lesion in right Parotid.

 

Meta Medical Findings

Research Inquiry #1

What are the treatment options as first line therapy for patients with advanced NSCLC Adenocarcinoma with metastasis with low PD-L1 (<1%).

Answer

According to the National Cancer institute (NCI), Chemotherapy is one of the main standard treatment options for patients with advanced NSCLC and has produced short-term improvement in disease-related symptoms. Studies suggest that tumor-related symptoms may be controlled by chemotherapy without adversely affecting overall quality of life.[1][2]

Terms that will be used in this section:

Overall survival (OS) – The percentage of people in a study or treatment group who are still alive for a certain period of time after they were diagnosed with or started treatment for a disease.

Progression free survival (PFS) – The length of time during and after the treatment of a disease, such as cancer, that a patient lives with the disease but it does not get worse.

 

1.Combination Chemotherapy – Carboplatin/Cisplatin + Pemetrexed (“Alimta”)

1.1. Carboplatin/Cisplatin

What is it? Carboplatin or Cisplatin injections, are used alone or in combination with other medications to treat types of cancer. The two drugs are in a class of medications known as platinum-containing compounds. It works by stopping or slowing the growth of cancer cells. [3][4]

Efficacy evidence: Cisplatin and carboplatin yield similar improvements in outcome. A retrospective study assessed the effect of carboplatin combined with other chemotherapies as a treatment for 15,318 patients with stage 3 or 4 NSCLC. The study found that the median survival for patients treated with Carboplatin + chemotherapy is around 8 months.[20] Some trials suggest that outcomes with Cisplatin may be superior, although with a higher risk of certain toxicities such as nausea and vomiting.

Side effects: The most common side effects are: nausea, vomiting, diarrhea, constipation, sores in the mouth and throat, hair loss, pain, weakness, loss in ability to taste food.  Platinum-based therapy increases the risk of adverse side effects such as anemia, neutropenia, thrombocytopenia and neurotoxicity. In a meta analysis examining the different side effects between the 2 drugs, Carboplatin-based doublet regimen included a higher risk of anemia and thrombocytopenia, but no increased nausea and/or vomiting, contrarily to cisplatin.[21][22]

How to get it? The two drugs are included in the Israeli basket and can be prescribed by your physician, according to his medical judgment.

• Pemetrexed (“Alimta”)

What is it? Pemetrexed injection is used in combination with other chemotherapy medications as a first treatment for NSCLC. It works by blocking the action of a certain substance in the body that may help cancer cells multiply. [5]

Efficacy evidence: Although other chemotherapies can be used with platinum based chemotherapy to treat NSCLC, a phase 3 clinical trail suggest that patients with adenocarcinoma may benefit more from pemtrexed. A large, noninferiority, phase III randomized study compared the OS in 1,725 chemotherapy-naive patients with stage IIIB/IV NSCLC. In patients with adenocarcinoma (n = 847), OS was statistically superior for cisplatin and pemetrexed (12.6 months) versus cisplatin and gemcitabine (10.9 months).[6]

Side effects: In clinical trials, the most common adverse reactions (incidence ≥20%) of pemetrexed, when administered as a single agent, are fatigue, nausea, and anorexia. When administered in combination with cisplatin are vomiting, neutropenia, anemia, stomatitis/pharyngitis, thrombocytopenia, and constipation. When administered in combination with pembrolizumab and platinum chemotherapy, are fatigue/asthenia, nausea, constipation, diarrhea, decreased appetite, rash, vomiting, cough, dyspnea, and higher body temperature. In a study including 607 patients with advanced NSCLC, 23% of patients stopped taking pemetrexed due to adverse side effects that included: acute kidney injury (3%) and pneumonitis (2%). The most common adverse reactions or laboratory abnormalities leading to interruption of pemetrexed in this arm (≥2%) were neutropenia (12%), anemia (7%), asthenia (4%), pneumonia (4%), thrombocytopenia (4%), increased blood creatinine (3%), diarrhea (3%), and fatigue (3%).[23]

How to get it? The drug is included in the Israeli basket and can be prescribed by your physician, according to his medical judgment.

 

2.Chemotherapy + Immunotherapy

Adding immunotherapy drugs to chemotherapy has improved outcomes relative to chemotherapy alone as discussed below.

2.1. Pembrolizumab (“Keytruda”)

What is it? Cancer cells may use the PD-1 coinhibitory immune checkpoint to hide from T cells. This stops T cells from attacking cancer cells and allows cancer cells to grow and spread. Pembrolizumab blocks the PD-1 pathway to help prevent cancer cells from hiding.[7]

Efficacy evidence: In a phase III clinical trial published in The New England journal of medicine in 2018, examined the effect of pembrolizumab on 616 patients with metastatic, nonsquamous NSCLC. Adding Pembrolizumab to platinum-based chemotherapy showed an improved outcomes relative to chemotherapy Pembrolizumab improved 12-month overall survival (OS) rates. 49% of patients treated with chemotherapy alone has reached 12 month overall survival compared to 69% of patients treated with pembrolizumab + chemotherapy and showed improvement in all PD-L1 categories.[8]

Side effects: nausea, skin changes, anemia, hypothyroidism, Loss of appetite, Diarrhea or constipation, Fatigue.[9]  in a multicenter, open-label, randomized, active-controlled trial, in patients with advanced NSCLC, the most common reason for permanent discontinuation of KEYTRUDA was pneumonitis (1.8%). Adverse reactions leading to interruption of KEYTRUDA occurred in 23% of patients; the most common (≥1%) were diarrhea (1%), fatigue (1.3%), pneumonia (1%), liver enzyme elevation (1.2%), decreased appetite (1.3%), and pneumonitis (1%).[24]

How to get it? The drug is included in the Israeli basket and can be prescribed by your physician, according to his medical judgment.

 

2.2. Atezolizumab + Bevacizumab

What is it? Atezolizumab is an Anti-PD-L1 monoclonal antibody. Bevacizumab is an antiangiogenic agent. It works by stopping the formation of blood vessels that bring oxygen and nutrients to tumors. This may slow the growth and spread of tumors.

Efficacy evidence:  Bevacizumab and Atezolizumab are potential alternatives to Pembrolizumab. In IMpower130 trial, 723 patients with stage IV non-squamous NSCLC, who received no previous chemotherapy, were randomaly assigned to receive Atezolizumab + chemotherapy + nab paclitaxel or chemotherapy alone. The trial shows that adding Atezolizumab to chemotherapy improved median PFS (7.6 months versus 5.2 months) and improved OS (18.1 versus 13.5 months) relative to chemotherapy alone. [10] A IMpower150 trial, evaluated the effect of atezolizumab + bevacizumab + chemotherapy in 356 patients with metastatic nonsquamous NSCLC who had not previously received chemotherapy compared to bevacizumab + chemotherapy alone. The results showed that adding Atezolizumab to Bevacizumab improved PFS (8.3 versus 6.8 months) and OS (19.2 versus 14.7 months) relative to those receiving Bevacizumab alone.[29]

Side effects:

Atezolizumab :

In IMpower trial, among 2421 patients with NSCLC and SCLC who received Atezolizumab in combination with other antineoplastic drugs, the most common adverse reactions in ≥20% of patients were fatigue/asthenia (49%), nausea (38%), alopecia (35%), constipation (29%), diarrhea (28%) and decreased appetite (27%).

In a multicenter study with 549 patients, fatal adverse reactions occurred in 3.8% of patients. these included death (reported as unexplained death and death of unknown cause), aspiration, chronic obstructive pulmonary disease, pulmonary embolism, acute myocardial infarction, cardiac arrest, mechanical ileus, sepsis, cerebral infarction, and device occlusion (1 patient each). Serious adverse reactions occurred in 28% of patients. The most frequent serious adverse reactions (>2%) were pneumonia (2.8%), chronic obstructive pulmonary disease (2.1%) and pneumonitis (2.1%).[11]

Bevacizumab:

In a phase IV trial, performed on 2,212 patients, evaluating the safety of bevacizumab in first-line treatment in combination with standard chemotherapy, significant adverse events were rare: bleeding was observed in 80 cases (4%), pulmonary hemorrhages in 15 cases (1%), hypertension in 125 cases (6%), proteinuria in 67 cases (3%) and venous thromboembolism in 172 cases (8%).[25]

How to get it? The two drugs are included in the Israeli basket and can be prescribed by your physician, according to his medical judgment.

 

2.3. Nivolumab + Ipilimumab

What is it? Nivolumab is a human monoclonal antibody that block PD-1. Ipilimumab is an anti CTLA-4 monoclonal antibody that turns off an inhibitory mechanism and boosts the body’s immune response against cancer cells.

Efficacy evidence: In a phase 3 clinical trial published in Lancet Oncology journal in 2021, First-line Nivolumab plus Ipilimumab combined with two cycles of chemotherapy in 719 patients with stage 4 NSCLC, provided a significant improvement in overall survival (14.1 vs 10.7 months) versus chemotherapy alone and had a favorable risk-benefit profile.[12]

Side effects: In a multi center study, the safety of Nivolumab + Ipilimumab was evaluated on 1146 patients with previously untreated metastatic or recurrent NSCLC with no mutations. The most frequent (≥2%) serious adverse reactions were pneumonia, diarrhea/colitis, pneumonitis, hepatitis, pulmonary embolism, adrenal insufficiency, and inflammation of the pituitary gland (hypophysitis). Fatal adverse reactions occurred in 1.7% of patients; these included events of pneumonitis (4 patients), myocarditis, acute kidney injury, shock, hyperglycemia, multi-system organ failure, and renal failure. The most common (≥20%) adverse reactions were fatigue, rash, decreased appetite, musculoskeletal pain, diarrhea/colitis, dyspnea, cough, hepatitis, nausea, and pruritus.[26].

How to get it? The two drugs are included in the Israeli basket and can be prescribed by your physician, according to his medical judgment.

Additional information: A literature review, published in Frontiers in 2021, examined 14 trials for first line treatment for PD-L1 negative NSCLC. Combinations of the drugs discussed above were compared. In terms of Overall Survival, none of the treatments performing significantly better than other. Combination of Nivolumab and Ipilimumab and chemotherapy was the most possible therapy to be ranked as first for OS.

In terms of progression free survival, combination of Nivolumab, chemotherapy, and Bevacizumab was most likely to be the best regimen. Combinations were statistically superior to chemotherapy alone.[13]

 

3.Immunotherapy as monotherapy

Based on our findings, immunotherapy treatment without chemotherapy is not recommended in patients with low PD-L1 expression. Drugs such as Atezolizumab or Pembrolizumab are approved by the FDA for first-line treatment only in patients with high PD-L1 expression.[1] A systematic review article published in Frontiers in 2021, examined the efficacy and safety of using PD-1/PD-L1 Inhibitors without chemotherapy in 3,204 patients with advanced NSCLC. In patients with low PD-L1 expression levels (1%–49%), PD-1/PD-L1 inhibitors plus chemotherapy significantly improved OS and PFS compared with PD-1/PD-L1 inhibitors as monotherapy.[14]

 

4.Osteoclast inhibitors

What is it? An Osteoclast is a type of bone cell that breaks down bone tissue. Osteoclast inhibitors (also called antiresorptive agents), such as Bisphosphonates and Denosumab, significantly reduce the frequency of and delay the time to onset of skeletal-related events (bone fractures, spinal cord compression, orthopedic surgical intervention) in patients with bone metastases.

Efficacy evidence:

• A meta-analysis of randomized trials in advanced breast cancer, compared with placebo, bisphosphonates significantly reduced the absolute risk of skeletal-related events by 14 percent Treatment was also associated with a significant delay in median time to skeletal-related events and improvements in bone pain. However, there was no difference in overall survival.[30[
• A meta analysis of three phase III trials comparing zoledronic acid (Bisphosphonates) with Denosumab for metastatic bone disease concluded that Denosumab was superior to zoledronic acid in reducing the risk of a first on-study skeletal-related events and in delaying the time to a first skeletal-related event or hypercalcemia of malignancy (median 26.6 versus 19.4 months). Overall survival and disease progression rates were similar with both treatments. [16]

Side effects: Osteonecrosis of the jaw (ONJ) can happen in <2% percent in patients receiving either drug in the first year of therapy and rises with prolonged therapy. In integrated analysis of 3 trials, hypocalcemia occurred in 12.4 percent of patients treated with denosumab versus 5.3 percent of those treated with zoledronic acid.[15]

Bisphosphonates: In 1/3 of patients who receive IV bisphosphonate therapy, a transient acute phase reaction may occur; it usually lasts 24 to 72 hours and is characterized by fever, myalgias, and arthralgias. Bishphosphonates can increase the risk of Atrial fibrillation, as described in HORIZON Pivotal Fracture Trial. In this study, a statistically significant increase (1.3% vs 0.5%) in the incidence of serious atrial fibrillation was noted in patients receiving yearly IV zoledronic acid vs placebo.[27]

Denosumab: The most common adverse reactions leading to discontinuation of Prolia in patients with postmenopausal osteoporosis are back pain and constipation(>10%). In a trial including 7808 patients, Denosumab increased the risk (10.8% vs 8.2% in placebo group) to develope epidermal and dermal adverse events (such as dermatitis, eczema, and rashes), Most of these events were not specific to the injection site.[28]

How to get it? The two drugs are included in the Israeli basket and can be prescribed by your physician, according to his medical judgment.

 

5.Radiotherapy

Bone metastases are a common manifestation of distant relapse from many types of solid cancers and external beam radiation therapy (EBRT) to the painful sites can provide pain relief in approximately 60 to 85 percent of cases. The patient had already been treated with 3 cycles of radiation therapy and therefore the treatment itself will not be described.

Pain relief: Pain relief after EBRT is often rapid. An analysis of data from the NCIC, examined the benefit of dexamethasone to prevent pain flare in patients receiving EBRT. A total of 122 out of 298 patients with painful bone metastases had a beneficial response by day 10, while an additional 116 patients responded by day 42. [17] A transient worsening of pain (“pain flare”) occurs in approximately 30 to 40 percent of patients undergoing radiotherapy for a painful bone metastasis. This typically occurs in the first few days after radiotherapy, and the flare in pain generally lasts one to two days. [18]

If the initial radiotherapy fails to relieve bone pain, reirradiation (second radiotherapy) may be a useful option and can be considered. A meta-analysis of seven studies found that reirradiation produced some benefit in terms of pain relief in 58% of patients.[19]

 

Research Inquiry #2

Relevant clinical trials for for patients with advanced NSCLC Adenocarcinoma with metastasis with low PD-L1 (<1%).

Answer

 

Trial 1 – NCT0 4165798

Therapy tested

Investigational Agents With Either Pembrolizumab Alone or With Pembrolizumab + Chemotherapy.

Trial description

Phase 2 umbrella study that includes 3 pembrolizumab substudies. The study aims to evaluate the efficacy of different investigational agents in combination with pembrolizumab given in sequence or in combination with pembrolizumab + chemotherapy.

Therapy description

Substudy 1 is for Treatment-Naive Patients with advanced NSCLC and includes: Carboplatin + Pemetrexed + Pembrolizumab + investigational agent.

Phase – 2

Location and contact details

• Rabin Medical Center, Petah Tikva, Israel, 4941492.

Contact: Gal Medalia – Email: Galmed@clalit.org.il , danaav2@clalit.org.il Phone number: 03-9378074/76/77/86.

Study Coordinator  +97239378101.

• Meir Medical Center, Kfar-Saba, Israel, 4428164. Contact: Study Coordinator  +97297472414.

Trial 2 – NCT04521075

Therapy tested

Fecal Microbial Transplantation (FMT) in combination with Nivolumab

Trial description

A Phase Ib trial to evaluate the safety and efficacy of Fecal Microbial Transplantation (FMT) in combination with Nivolumab in several types of cancer, including metastatic NSCLC.

Therapy description

Several studies indicate that fecal microbiota transplantation can enhance the efficacy of immune checkpoint inhibitors therapy against cancer. [1][2] in this study, FMT will be conducted with fecal capsules, originating from patients that have achieved a durable complete response with immune checkpoint inhibitors. Patients will receive the capsules orally + Nivolumab.

Phase 1b

Location and contact details

• Sheba Medical Center, Ramat Gan, Israel.

Contact: Bar Meital – Email: Meital.Bar@sheba.health.gov.il , Nili Golan – Email: Nili.Golan@sheba.health.gov.il

 

Trial 3 – NCT05089734

Therapy tested

Sacituzumab Govitecan-hziy (SG) Versus Docetaxel.

Trial description

This study compare overall survival (OS) of Sacituzumab govitecan-hziy (“Trodelvy”) versus Docetaxel in participants with advanced or metastatic (NSCLC) with progression on or after platinum-based chemotherapy and anti PD-1/PD-L1 immunotherapy received either in combination or sequentially.

Therapy description

Sacituzumab govitecan (“Trodelvy”) is an antibody-drug conjugate that specifically targets Trop-2 (glycoprotein that is upregulated in types of cancer) expressing cells to enable local delivery of a cytotoxic payload that selectively kills the targeted cells. The use of Trodelvy for the treatment of NSCLC is investigational.

Docetaxel is commonly used chemotherapy as a first-line or second-line treatment for NSCLC. In this trial, participants will be randomly assigned in a 1:1 ratio to receive either Trodelvy or docetaxel.

Relevant if there will be progression under standard therapy.

Phase 3

Location and contact details

• Soroka Medical Center, Beer Seva, Israel.

Contact: Dr. Yulia Dudnik. Email: galavi1@clalit.org.il

• Hadassah University Hospital Ein Kerem, Jerusalem, Israel.

Contact: Prof. Nechushtan Hovav. Email: gilada@hadassah.org.il

• Kaplan Medical Center, Rehovot, Israel.

Contact: Yaelsha@clalit.org.il

• Shamir Medical Center (Assaf Harofeh), Tzrifin, Israel.

Contact: daphnas@shamir.gov.il

 

Trial 4 – NCT03893955

Therapy tested

ABBV-927 + ABBV-368 + ABBV-181

Trial description

A study evaluating the safety and efficacy of ABBV-927 with ABBV-368, Budigalimab (ABBV-181) and/or chemotherapy in participants with selected solid tumors.

Therapy description

Budigalimab (ABBV-181), ABBV-927 is and ABBV-368 are monoclonal antibodies that are being investigated for solid tumors. In another phase 1 trial, Budigalimab showed safety and efficacy similar to other PD-1 inhibitors.[3]

Relevant if there will be progression under standard therapy.

Phase 1

Location and contact details

The Chaim Sheba Medical Center. Ramat Gan, Tel-Aviv, Israel.

Contact: Dr. Talia Golan. Phone: 03-5305338. Email: Talia.Golan@sheba.health.gov.il

 

Research Inquiry #3

Complementary and Integrative treatments that can be beneficial for patients with advanced NSCLC Adenocarcinoma with metastasis with low PD-L1 (<1%).

Answer

We focused our research on treatments with medical evidence that can help slowing disease progression and relieve the patient’s current symptoms and pain.

Before applying or taking the medications suggested in this section, the attending physician and complementary and integrative medicine units in the oncology departments of leading hospitals should be consulted.

 

1.Nutrition and nutritional supplements

Nutrition is a main issue regarding patient’s overall health. The 2007 World Cancer Research Fund/American Institute for Cancer Research (WCRF/AICR) Report, ‘‘Food, Nutrition, Physical Activity and the Prevention of Cancer: a Global Perspective,”, provides a comprehensive review of the relationship between certain food groups and lung cancer. The main possible beneficial foods are listed below:[20]

What is it? nutritional supplements are products such as herbal remedies, minerals, vitamins certain other substances. These are generally available as liquid preparations so that they are easy to consume. nutritional supplements are indicated for malnourished patients who have malignancy, chronic disease and/or anorexia.[7]

Efficacy evidence: Preliminary studies suggest that the use of antioxidant vitamins and minerals following a diagnosis of cancer reduces chemotoxicity and radiotoxicity during treatment but may reduce the therapeutic effects of free radical-generating radiotherapy or chemotherapeutic agents.

For lung cancer specifically, two preliminary Mayo Clinic cohort studies showed improved survival in patients with small-cell lung cancer and NSCLC who used vitamin or mineral supplements, along with improved quality of life. A randomized controlled trial of 136 patients with advanced NSCLC showed improved survival with supplementation, although this was not statistically significant.[20][21]

Fish oil – fish oil contains fatty acids, that may have activity against lung cancer cell. Eicosapentaenoic acid is one of several omega-3 fatty acids and has been proposed to have anti-inflammatory, anticachectic and antitumoural effects. Clinical trial published in ScienceDirect journal, examined the effect of ONS+EPA on patients with advanced NSCLC. Patients were randomized to receive diet plus oral nutritional supplement containing EPA or only isocaloric diet. All patients received chemotherapy treatment. Patients with NSCLC receiving ONS-EPA significantly improved energy and protein intake, body composition, decreased fatigue, loss of appetite and neuropathy.[9]

Melatonin – Melatonin is a hormone produced within the pineal gland. A 2014 randomized controlled trial of

151 patients with NSCLC showed improved quality of life with treatment with melatonin but no significant difference in median survival.[22]

Side effects: increased body weight slightly ,nausea, vomiting and feeling of fullness.[8]

How to get it: Can be found in various nature shops and online supplements shops.

 

2.Metformin

What is it? Metformin is used to treat high blood sugar levels that are caused by a type of diabetes mellitus or sugar diabetes called type 2 diabetes.

Efficacy evidence: Several observational studies reported beneficial effects of metformin use on survival in non-small cell lung cancer in diabetic patients. Clinical trials were also conducted in non-diabetic patients with advanced NSCLC. A phase II study enrolled patients with chemotherapy-naive advanced or metastatic NSCLC and randomized them to receive chemotherapy with or without concurrent metformin. The study showed show a minor benefit in PFS with the use of metformin (15.9 months vs 13.9 months). However, number of patients participated in this trial was small (n=25) and further research is needed.[4] Another study showed that Metformin administration reduced occurrence of chemotherapy induced-nausea in non diabetic patients.[5]

Side effects: Gastrointestinal events such as nausea, vomiting, diarrhea, abdominal pain, and loss of appetite have been frequently reported during therapy initiation and resolve spontaneously in most cases[6].

How to get it: is in the Israeli health basket, but for other indications (Diabetes). Special requests can be approved following the treating oncologist recommendation.

 

3.Acupuncture

What is it? Acupuncture is the practice of penetrating the skin with thin, solid, metallic needles which are then activated through gentle and specific movements of the practitioner’s hands or with electrical stimulation. 

Efficacy evidence: Recent advances in acupuncture clinical research suggest that acupuncture may provide clinical benefit for cancer patients with treatment-related side effects.[10] Randomized clinical trials have demonstrated that acupuncture is effective for chemotherapy-induced nausea and vomiting.[11] Another study suggests that acupuncture may be helpful in managing cancer-related pain.[12]. A study conducted in Memorial Sloan-Kettering Cancer Center suggested that acupuncture may improve chemotherapy-related fatigue.[13]

A case report of a 79 year old female with Stage IV NSCLC treated with Korean Medicine Therapy (KMT) Alone, showed that the size of the tumor mass was markedly decreased. KMT consists of intravenous pharmacopunctures (wild ginseng, Cordyceps sinensis, Trichosanthes kirilowii) and oral herbals (soramdan).[15]

Side effects: Rarely, some people experience mild, short-term side effects such as: pain where the needles puncture the skin, bleeding or bruising where the needles puncture the skin, drowsiness, feeling dizzy or faint, worsening of pre-existing symptoms.[14]

How to get it? Acupuncture can be done through various health maintenance organizations and private centers. The attending physician and complementary and integrative medicine units in the oncology departments of leading hospitals should be consulted.

 

4.Chinese herbal medicine

What is it?

Chinese herbal medicine is part of a larger healing system called traditional Chinese medicine (TCM), which also includes acupuncture, massage dietary advice and exercise.

Efficacy evidence: A systematic literature search was conducted to examine Compound kushen injection (CKI), a traditional Chinese medicine, versus current western therapies for bone cancer pain such as radiotherapy and bisphosphonates. seven trials with 521 patients showed significant effects of CKI for improving pain relief in patients with bone cancer pain.[16] Another Meta-analysis of oral Chinese herbal medicine (CHM), found that CHM plus conventional treatment (bisphosphonates, radio therapy and analgesics) increased the pain-relief rate compared with the conventional treatment alone.[17]

Astragalus is a herbal remedy that has been used in traditional Chinese Medicine. It is thought to play a role in

protecting the body against various stressors, including physical, mental, or emotional stress. The Astragalus root has antioxidant effects and also affects the immune system. A 2016 meta-analysis of Astragalus use in patients with advanced NSCLC showed improved overall survival, improved performance status, and tumor overall response rate, and fewer side effects compared with platinum-based chemotherapy alone.[23]

Side effects: In the meta-analysis described above, the adverse events included nausea, vomiting, dizziness, fever, and constipation. No serious adverse events were reported in any of the included studies. However, Chinese herbal medicine is diverse, and is not risk-free and should be consulted with a physician before using.

How to get it: Astragalus can be found in various nature shops and online supplements shops.

 

5.Homeopathy

What is it? Homeopathy is an alternative medicine. A central principle of the treatment is that a substance that causes certain symptoms can also help to remove those symptoms. Homeopathic products come from plants (such as red onion, arnica, poison ivy, belladonna and stinging nettle), minerals (such as white arsenic), or animals (such as crushed whole bees).[25]

Efficacy evidence: In a recent study of an integrative oncology service in a large comprehensive cancer center in Israel, homeopathy was found to be successfully incorporated as a supportive care modality. Review of 124 files of cancer patients who received homeopathy for symptom relief revealed that nearly three-quarters of these patients reported a beneficial effect when they used homeopathic treatment for symptom relief.[20] In another multicenter, phase III study, the possible effects of additive homeopathic treatment compared with placebo in patients with stage IV NSCLC, showed improved quality of life in the homeopathy group compared with placebo. In addition, survival was significantly longer in the homeopathy group versus placebo and control.[26]

Side effects: Homeopathy products are diverse and some products sold or labeled as homeopathic may not be safe. they can contain substantial amounts of active ingredients, which may cause side effects or drug interactions. Homeopathy products should be consulted with a physician before using it.[27]

How to get it? Homeopathy can be done through various health maintenance organizations and private centers.

 

6.Reflexology

What is it? Reflexology is a type of massage that involves applying different amounts of pressure to the feet, hands, and ears. It’s based on a theory that these body parts are connected to certain organs and body systems.

Efficacy evidence: An article published in ScienceDirect in 2018, examined the effect of reflexology on cancer. There are many studies on the symptomatic effects of reflexology in cancer, especially its effect on pain, nausea, depression, anxiety, and dyspnea in cancer patients are emphasized. Some studies gave favorable results but are methodologically incomplete. Only possible inference about the favorable effects of reflexology can be that it reduces stress by providing a general relaxation, and is useful in reducing pains.[19] A clinical trial including 23 patients with breast and lung cancer showed that following foot reflexology intervention, patients experienced a significant decrease in anxiety.[24] 

Side effects: Generally, reflexology appears to be safe and doesn’t cause many side effects.[18]

How to get it: Reflexology can be done through various health maintenance organizations and private centers and in complementary and integrative medicine units in oncology departments in leading hospitals.

 

7.Medical cannabinoid – Supportive care

What is it? Cannabinoid are ingredients found in the plant Cannabis Sativa. There are 85 known cannabinoids in the plant, Tetrahydrocannabinol (THC), and Cannabidiol (CBD) are the most common types. THC has psychoactive properties, creating a “high” sensation, whereas CBD has antipsychotic properties. Both THC and CBD exhibit anti nausea, pain relief, anxiolytic, anti-inflammatory and decreased seizures.[1]

Efficacy evidence: LABORATORY Studies show that the use of cannabinoid are efficienty inhibiting cancer growth via immunomodulation. Recent study published in Nature in 2021, show that NSCLC cells growth is decreased in vitro due to the use of cannabinoid.[2]

Side effects: Rapid heart beat, dizziness, headache, depression, hallucination, low blood pressure, paranoia and panic attacks.[3]

How to get it? Medical cannabis can be obtained through license, your oncologist or supportive care team can be consulted for more information.

 

References

Research Inquiry #1

1. National Cancer Institute, Non-Small Cell Lung Cancer Treatment – Health Professional Version, Janet Dancey, MD, FRCPC (Ontario Institute for Cancer Research & NCIC Clinical Trials Group), Arun Rajan, MD (National Cancer Institute), Eva Szabo, MD (National Cancer Institute).
2. S G Spiro, R M Rudd, R L Souhami, J Brown, D J Fairlamb, N H Gower, L Maslove, R Milroy, V Napp, M K B Parmar, M D Peake, R J Stephens, H Thorpe, D A Waller, P West, Big Lung Trial participants.
3. medlineplus.gov
4. medlineplus.gov
5. medlineplus.gov
6. Giorgio Vittorio Scagliotti, Purvish Parikh, Clinical Trial , J Clin Oncol,  2008 Jul 20;26(21):3543-51. doi: 10.1200/JCO.2007.15.0375. Epub 2008 May 27.
7. keytruda.com
8. https://pubmed.ncbi.nlm.nih.gov/29658856/
9. cancerresearchuk.org
10. https://pubmed.ncbi.nlm.nih.gov/31122901/
11. https://www.rxlist.com/tecentriq-side-effects-drug-center.htm#consumer
12. Clinical Trial, Lancet Oncol, 2021 Feb;22(2):198-211. Epub 2021 Jan 18. First-line nivolumab plus ipilimumab combined with two cycles of chemotherapy in patients with non-small-cell lung cancer (CheckMate 9LA): an international, randomised, open-label, phase 3 trial. Luis Paz-Ares, Tudor-Eliade Ciuleanu.
13. Front. Oncol., 23 June 2021, Sec. Thoracic Oncology, First-Line Treatment Options for PD-L1–Negative Non-Small Cell Lung Cancer: A Bayesian Network Meta-Analysis, Ling Peng, Wen-Hua Liang.
14. SYSTEMATIC REVIEW article. Front. Oncol., 11 January 2021. Sec. Thoracic Oncology. Efficacy and Safety of PD-1/PD-L1 Inhibitors Plus Chemotherapy Versus PD-1/PD-L1 Inhibitors in Advanced Non-Small Cell Lung Cancer: A Network Analysis of Randomized Controlled Trials. Xiang Li, Shi Yan
15. uptodate.com
16. https://www.uptodate.com/contents/osteoclast-inhibitors-for-patients-with-bone-metastases-from-breast-prostate-and-other-solid-tumors
17. JAMA Oncol, 2017 Jul 1;3(7):953-959.Effect of Radiotherapy on Painful Bone Metastases: A Secondary Analysis of the NCIC Clinical Trials Group Symptom Control Trial SC.23. Rachel McDonald.
18. Multicenter Study, Int J Radiat Oncol Biol Phys. 2009 Sep 1;75(1):193-7. Epub 2009 Jan 23. Determining the incidence of pain flare following palliative radiotherapy for symptomatic bone metastases: results from three canadian cancer centers. Amanda Hird.
19. Review, Int J Radiat Oncol Biol Phys. 2012 Sep 1;84(1):8-14.. Epub 2012 Jan 31. Effectiveness of reirradiation for painful bone metastases: a systematic review and meta-analysis. Merel Huisman.
20. https://pubmed.ncbi.nlm.nih.gov/23564469/
21. https://pubmed.ncbi.nlm.nih.gov/17720276/
22. https://www.ncbi.nlm.nih.gov/books/NBK75595/
23. https://www.rxlist.com/alimta-side-effects-drug-center.htm#consumer
24. https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/125514s012lbl.pdf
25. https://ar.iiarjournals.org/content/34/4/1537
26. https://www.rxlist.com/opdivo-side-effects-drug-center.htm#consumer
27. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2704135/
28. https://www.rxlist.com/prolia-side-effects-drug-center.htm#consumer
29. https://www.nejm.org/doi/full/10.1056/NEJMoa1716948
30. https://pubmed.ncbi.nlm.nih.gov/29082518/

 

Research Inquiry #2

1. World J Gastroenterol. 2021 Aug 28; 27(32): 5362–5375. Published online 2021 Aug 28. Faecal microbiota transplantation enhances efficacy of immune checkpoint inhibitors therapy against cancer. Yong-Bo Kang and Yue Cai.
2. NCI Press Release. Fecal microbiota transplants help patients with advanced melanoma respond to immunotherapy. February 4, 2021.
3. Clinical Trial ,Cancer Immunol Immunother, 2022 Feb;71(2):417-431. 2021 Jul 3. First-in-human phase 1 study of budigalimab, an anti-PD-1 inhibitor, in patients with non-small cell lung cancer and head and neck squamous cell carcinoma. Antoine Italiano, Philippe A Cassier.

Research Inquiry #3

1. Dialogues Clin Neurosci. 2017 Sep; 19(3): 309–316. doi: 10.31887/DCNS.2017.19.3/glafaye. Cannabis, cannabinoids, and health. Genevieve Lafaye, MD.
2. Article, Open Access, Published: 11 January 2021. ACPA decreases non-small cell lung cancer line growth through Akt/PI3K and JNK pathways in vitro. Özge Boyacıoğlu, Elif Bilgiç.
3. rehabspot.com
4. A Randomized Phase II Study of Metformin plus Paclitaxel/Carboplatin/Bevacizumab in Patients with Chemotherapy-Naïve Advanced or Metastatic Nonsquamous Non-Small Cell Lung Cancer. Kristen A Marrone.
5. Metformin Addition to Chemotherapy in Stage IV Non-Small Cell Lung Cancer: an Open Label Randomized Controlled Study. Rana Sayed.
6. Drugs.com
7. Drugs.com
8. cambridge.org
9. Clinical Nutrition, Volume 33, Issue 6, December 2014, Pages 1017-1023. Effects of an oral nutritional supplement containing eicosapentaenoic acid on nutritional and clinical outcomes in patients with advanced non-small cell lung cancer: Randomised trial. KarlaSánchez-Lara.
10. The Value of Acupuncture in Cancer Care. Weidong Lu, MB, MPH, Elizabeth Dean-Clower, MD, MPH, Anne Doherty-Gilman, MPH, and David S. Rosenthal, MD.
11. Acupuncture prophylaxis of cancer chemotherapy-induced sickness. J W Dundee.
12. Journal of clinical oncology, Analgesic Effect of Auricular Acupuncture for Cancer Pain: A Randomized, Blinded, Controlled Trial. David Alimi
13. Journal of clinical oncology, Acupuncture for Postchemotherapy Fatigue: A Phase II Study. Andrew J. Vickers
14. nhs.uk
15. Case Rep Oncol. 2013 Sep-Dec; 6(3): 574–578. Published online 2013 Nov 15. A Case of Stage IV Non-Small Cell Lung Cancer Treated with Korean Medicine Therapy Alone. Dong-hyun Lee.
16. A systematic review and meta-analysis on the use of traditional Chinese medicine compound kushen injection for bone cancer pain. Bao Yanju.
17. Meta-analysis of oral Chinese herbal medicine as an adjuvant treatment in relieving pain secondary to bone metastases. Shi-Jun Wang.
18. cancerresearchuk.org
19. ScienceDirect, Reflexology and cancer. AhmetUnlu.
20. https://www.researchgate.net/publication/327853505_Complementary_and_Integrative_Medicine_in_Lung_Cancer_Questions_and_Challenges
21. https://pubmed.ncbi.nlm.nih.gov/15670980/
22. https://pubmed.ncbi.nlm.nih.gov/25503168/
23. https://pubmed.ncbi.nlm.nih.gov/27330356/
24. https://pubmed.ncbi.nlm.nih.gov/10660924/
25. https://www.nccih.nih.gov/health/homeopathy
26. https://pubmed.ncbi.nlm.nih.gov/33010094/
27. https://www.nccih.nih.gov/health/homeopathy