Incredible Progress For ‘Big Bang Theory’ Star Kate Micucci and Millions of Others Affected by Lung Cancer — Promising New Advancements

Hope for Lung Cancer Survivors

• The Big Bang Theory actress Kate Micucci, 44, is fortunate to have caught her lung cancer early, announcing her diagnosis — and immense gratitude for her remission status — in December after undergoing surgery.
• Thankfully, the musical comedian, who never smoked a cigarette in her life, explained that she does not need further treatment, though the reality is that many others, especially in advanced stages of the disease, have not been so lucky. However, recent advancements in science are showing more promise for the disease, in part, due to molecular testing and profiling, along with newer treatments.
• Bottom line, lung cancer is easier to treat when caught early, so if you are experiencing any lingering symptoms, be sure to consult your doctor. If you are recently diagnosed, just know that there is more and more hope with this disease.
• Check out SurvivorNet’s overview on lung cancer HERE .

The Big Bang Theory actress Kate Micucci , 44, is "very very lucky" to have caught her lung cancer early, announcing her diagnosis — and immense gratitude for her remission status — in December after undergoing surgery. Thankfully, the musical comedian, who never smoked a cigarette in her life, explained that she does not need further treatment, though the reality is that many others, especially in advanced stages of the disease, have not been so fortunate. However, recent advancements in science are showing more promise for the disease, in part, due to molecular testing and profiling. Additionally, research presented at this year’s American Society of Clinical Oncology (ASCO) annual meeting, a massive conference where professionals present the latest in cancer research, showed lorlatinib, a type of drug known as a tyrosine kinase inhibitor, has shown real promise treating a specific type of non-small cell lung cancer (NCSLC).

What Did the Study Find?

Research presented at ASCO reported the highly-anticipated 5-year follow-up of the phase 3 CROWN study . In this trial, patients with a specific type of advanced NSCLC, ALK-positive, were randomized to receive either lorlatinib (i.e. Lorbrena, Pfizer) or crizotinib (Xalkori, Pfizer). ALK is a signaling protein which is inappropriately present on the tumors of about 5% of patients with NCSLC. Lorlatinib and crizotinib are both drugs in a class called tyrosine kinase inhibitors, which target ALK. In approximately 90% of patients with ALK-positive NSCLC, the cancer has already metastasized, or spread to other parts of the body, at the time of diagnosis. RELATED : Progress Treating Lung Cancer With ALK-Positive Mutations — The Drug Lorlatinib Shows Major Benefit For Progression Free Survival The control arm treatment in the study, crizotinib, is a Food and Drug Administration (FDA)-approved treatment for adults with ALK-positive metastatic NSCLC. Earlier studies showed that crizotinib was superior to chemotherapy in such patients. The new research aimed to compare lorlatinib — and experts are excited about the results. “It is encouraging that the upfront benefits of lorlatinib over crizotinib continue for several years in more than half the patients. It also is encouraging that patients receiving lorlatinib had much fewer incidences of brain metastasis, which can be devastating,” Dr. Leslie Busby , oncologist at Rocky Mountain Cancer Centers, told SurvivorNet. Lorlatinib was originally approved by the FDA in November 2018 as a second- and third-line drug, meaning that it could be given after a patient’s tumor had already stopped responding to the one or more previous treatment regimens. The CROWN study examined whether lorlatinib was superior in the first-line setting, meaning it was given as the first treatment course after patients were diagnosed. Previous reports of the CROWN study with shorter follow-up time had already shown improved progression-free survival (PFS) and intracranial activity for patients receiving lorlatinib compared to criztonib. PFS refers to time where patients are living and their disease has not progressed or worsened. Five-year PFS, or the percentage of patients who lived five years without any evidence of cancer growth or death, was 60% among patients who received lorlatinib as compared to only 8% among patients who received crizotinib — an absolute difference greater than 50%. The study authors commented that this was the longest PFS that has ever been reported in advanced NSCLC. As a result of these promising earlier reports of the CROWN study, lorlatinib received FDA-approval as a first-line treatment in March 2021. The new, five-year study provides that much more evidence of its effectiveness.

How Molecular Testing Helps Lung Cancer Patients

Molecular testing is crucial to understanding specific genetic alterations and mutations that drive the growth, development, and progression of cancer cells. “It’s always a good idea for the patient to ask about molecular testing,” Dr. Mohamed Mohamed , a thoracic medical oncologist at Cone Health Cancer Center, tells SurvivorNet. How Does Molecular Testing Help Determine the Best Lung Cancer Treatment Option? Some of these molecular characteristics can be targeted using precise and effective new therapies to improve patient outcomes. Essentially, understanding the molecular profile of each person’s cancer allows oncologists to use customized and personalized treatments. “In today’s day and age, it’s hard to treat without having the full knowledge of [genetic] sequencing and profiling of the tumor,” Dr. Ankit Madan, MD , a medical oncologist and hematologist at MedStar Health, previously told SurvivorNet. In general, treatment options for lung cancer depend on its type, its location, and its staging. In general, treatment methods include surgery, chemotherapy, radiation therapy, targeted therapy, or a combination of any of these treatments.

What Molecules Are Tested For in Lung Cancer Molecular Profiling?

As investigations into the molecular characteristics and their effectiveness of lung cancer treatments evolve, the array of molecules being tested continuously expands. A thorough molecular profiling of lung cancer, usually through testing called next-generation sequencing (NGS), and using other methods such as immunohistochemistry currently may consist of:

PD-L1:

Discovered almost 20 years ago, Programmed Death Ligand 1 (PD-L1) is an integral part of lung cancer workup these days. “Nowadays, we do PDL one testing for [all new] lung cancer [diagnoses]," Dr. Madan said. PD-L1 is a protein expressed on the surface of cancer cells that interacts with a complementary protein, programmed cell death-1 (PD-1), present on the surface of a patient’s native immune system cells. This interaction effectively blinds the immune system to cancer cells, helping them evade detection and continue proliferation. RELATED : What Is PD-L1 Testing In Lung Cancer And Why Does It Matter? Increased levels of PD-L1 expression can predict improved response to PD-1/PD-L1 inhibitor class of immunotherapy medications, such as pembrolizumab (Keytruda), nivolumab (Opdivo), and atezolizumab (Tecentriq). These inhibitors block the interaction between PD-1/PD-L1, preventing the cancer cells from turning off the immune system, which attacks and destroys them. Whatever the PD-L1 expression level, these immunotherapies are used for treatment regardless because of their immense benefit, even in those patients with low levels of PD-L1 expression.

EGFR:

EGFR testing is now done as a routine part of lung cancer workups. The epidermal growth factor receptor (EGFR) gene produces the EGFR protein, which plays a role in the growth and division of normal cells. Mutant EGFR genes can produce unchecked cell growth and lead to the formation of several types of cancers, including lung cancers, especially non-small cell lung cancers (NSCLC). “In [patients with EGFR mutations], you can use medications such as osimertinib, erlotinib, gefitinib,” Dr. Madan noted. The discovery of EGFR lead to targeted therapies and the search for other gene mutations When present, EGFR mutations can be targeted by drugs called tyrosine kinase inhibitors (TKIs), such as osimertinib (brand name: Tagrisso). This medication has shown great promise in patients with advanced-stage lung cancers. It has also recently been demonstrated to improve outcomes for early-stage lung cancer patients. “For stage four lung cancer, even in stage one-B onwards, we [check] EGFR mutations. [Having this ]knowledge beforehand [is] in the patient’s best interest,” Dr. Madan continued. RELATED : Decreasing the Lung Cancer Death Rate by Half and the Ambition for Genuine Cures– Why One Drugmaker Continues to Invest in Targeted Therapies TKIs bind to the mutated EGFR protein on the surface of cancer cells. This prevents the protein from being activated. The molecular signals that lead to uncontrolled proliferation are blocked, ultimately inhibiting cancer growth and survival.

ALK and ROS1 Rearrangement:

Anaplastic lymphoma kinase (ALK), named so because it was first discovered in blood cancers called lymphomas, is a mutation routinely found in NSCLCs. ALK is an essential gene that shepherds the proper development of the gut and the nervous system in embryos. However, it gets turned off before birth. Sometimes, the gene gets erroneously turned on by fusing with other genes. This errant process, called ALK rearrangement, can lead to unchecked cell growth and cancer development. Knowing the status of ALK rearrangements is essential, especially for metastatic or stage four patients, because they can be targeted with ALK inhibitors, such as crizotinib (Xalkori), ceritinib (Zykadia), alectinib (Alecensa), and brigatinib (Alunbrig). The ROS1 gene is involved in cell growth and differentiation. Like ALK rearrangement, ROS1 can be erroneously turned on by fusing with many other genes, leading to cancer development. Stage four lung cancers with such fusions can be targeted by either ceritinib (Zykadia), or entrectinib (Rozlytrek).

KRAS:

KRAS is a ubiquitous protein involved in normal cell function and growth. KRAS mutations, however, can ramp up this signaling and lead to abnormal cell growth, resulting in cancers. RELATED : How is Lung Cancer With a KRAS Mutation Treated? While mutations in KRAS are routinely tested for new lung cancer diagnoses, they do not generally change the initial management of the disease. However, some lung cancers may stop responding to the standard chemotherapies and immunotherapies. Such patients with a specific KRAS mutation (KRAS G12C) can be treated with the targeted KRAS agent sotorasib (brand name: Lumakras).

BRAF:

Another protein that helps regular cellular growth, BRAF, can be mutated in lung cancers. A specific form of this mutation, BRAF-V600, “can be treated with [a combination of] dabrafenib [brand name Tafinlar] and trametinib [brand name: Mekinist],” notes Dr. Madan.

HER2:

Although more well-known in the breast cancer realm, HER2 mutations can also be present in lung cancers. These patients “can be treated with trastuzumab [Herceptin],” per Dr. Madan.

Other Mutations:

An ever-increasing number of mutations can be tested through NGS in lung cancer. These include but are not limited to:

• IDH 1/2
• MYC
• MET
• RET
• PTEN
• AKT1

While many of these mutations do not have specific targeted agents yet, new research is continuously uncovering targeted ways of exploiting them.

NGS Testing

There are several next-generation sequencing (NGS) tests you may encounter, depending on where you are getting treatment and what you are getting treatment for. Here are some of the common ones currently on the market:

• FoundationOne®CDx looks at 324 genes in solid tumors and says results can take up to 12 days. Test results include microsatellite instability (MSI) and tumor mutational burden (TMB) to help inform immunotherapy decisions.
• OmniSeq Insight provides comprehensive genomic and immune profiling for all solid tumors. It looks for 523 different genes. Test results include microsatellite instability (MSI) and tumor mutational burden (TMB), as well as PD-L1 by immunohistochemistry (IHC).
• Cobas EGFR Mutation Test v2 identifies 42 mutations in exons 18, 19, 20, and 21 of the epidermal growth factor receptor (EGFR) gene. It is designed to test tissue and plasma specimens with a single kit, allowing labs to run tissue and plasma simultaneously on the same plate.

Lung Cancer: The Basics

Lung cancer is the second most common cancer in men and women in the United States. The American Cancer Society says there will be around 234,580 new cases of lung cancer in 2024 and an estimated 125,070 deaths. Lung cancer can be particularly tricky to treat because often, symptoms don't show up until the cancer has spread to other organs. There are two main types of lung cancer, which doctors group together based on how they act and how they're treated:

• Non-small cell lung cancer (NSCLC) is the most common type and makes up about 85% of cases
• Small cell lung cancer (SCLC) is less common, but it tends to grow faster than NSCLC and is treated very differently

Though non-smokers like Micucci do get lung cancer, cases are declining because smoking rates are on the decline.  Also, there have been improvements in surgical techniques and radiation delivery that have improved outcomes and decreased side effects. Finally, newer treatments — like immunotherapy and targeted agents — are dramatically improving the length and quality of life for people who are diagnosed with lung cancer.

What Are the Symptoms of Lung Cancer?

Lung cancer often doesn't cause symptoms until it has already spread outside the lungs. Your doctor may suspect lung cancer after seeing a shadow on a routine chest X-ray that requires further evaluation. Diagnosing Lung Cancer and Determining Treatment Some people with lung cancer can experience the following symptoms:

• A cough that doesn't go away, that gets worse, or that brings up bloody phlegm
• Shortness of breath
• Fatigue
• Chest pain
• Hoarse voice
• Appetite loss
• Weight loss

Mention any of these lingering symptoms to your doctor, who will ask questions to get a better picture of what is happening inside your body. If your symptoms suggest lung cancer, you'll likely need to have more tests. Contributing by SurvivorNet staff