There have been major developments in terms of treatments for advanced lung cancer. For many years, the only thing patients could rely on was conventional chemotherapy, which helped eliminate cancer cells but induced numerous side effects throughout the body.

The breakthrough of precision medicine allowed the situation to be drastically changed. It was found that there were many genetic mutations responsible for the development of lung cancers, and patients had to get targeted treatment rather than one-size-fits-all therapy in the form of pills.

Tagrisso (generic name: osimertinib) from AstraZeneca has become a key element of this revolution. This third-generation pill became a new benchmark treatment for all patients suffering from EGFR-mutated advanced NSCLC.

But the progress of medicine never stops there. Despite the fact that the sole use of Tagrisso has already helped thousands of people, cancer cells are smart enough and will find a way to bypass this treatment in time.

In order to fight such resistance to the drug, scientists started to investigate a revolutionary approach to treatment: what if we start combining the targeted treatment of Tagrisso with chemotherapy from the very first days of the treatment?

The recent results of two landmark clinical trials, namely the Phase III FLAURA2 trial and the Phase III TOP trial, have confirmed the assumption about the effectiveness of this treatment. These results are discussed in detail in the following guide.

The Scientific Rationale: Why Combine a Targeted Pill with Chemo?

To understand why this combination works so well, it helps to understand how cancer cells behave inside the body.

The Power and Limitation of Monotherapy

If the drug is administered alone without any combination, the drug mechanism entails its use as an EGFR tyrosine kinase inhibitor (TKI).

The drug blocks the mutated Epidermal Growth Factor Receptor located on the cancerous cells and stops the internal signaling process of instructing the tumor to divide.

This treatment has worked perfectly for a lot of people. The tumors shrink quickly, and the symptoms are improved.

However, cancerous tumors are usually not homogeneous masses, rather heterogeneous collections of different clonal cell populations.

As time passes by, even though the drug has killed off the main cancerous cells with the mutation in the EGFR, some cancer cells have developed alternative means of surviving and growing.

These cells start multiplying and become resistant to the drug making it ineffective.

The Double-Whammy Effect

A platinum-based chemotherapy doublet, which usually entails using pemetrexed in tandem with cisplatin or carboplatin, is used in conjunction with your daily dose of Tagrisso medication to launch a two-pronged assault against the cancer.

The Targeted Attack: Tagrisso continuously blocks the primary EGFR growth signals, keeping the majority of the tumor suppressed.
The Broad-Spectrum Attack: The chemotherapy steps in to actively destroy rapidly dividing cells, sweeping away the hidden, aggressive, or mutated cell clones before they have a chance to adapt and resist the TKI pill.

This powerful combination prevents the tumor from establishing a clear resistance pathway, delaying cancer progression far longer than the pill could achieve on its own.

The Landmark Data: FLAURA2 Sets a New Survival Benchmark

The initial wave of extensive data that backed up this treatment was found through the international Phase III FLAURA2 trial. The study involved the comparison of the efficacy of Tagrisso combined with chemotherapy to that of using only Tagrisso in its entirety as a first-line treatment option.

The results of the FLAURA2 trial were considered a breakthrough in lung cancer research as they offered an unparalleled life expectancy improvement.

Shifting the Survival Timeline

It became apparent from the study that the combined therapy produced a median overall survival of nearly four years (47.5 months, to be exact).

On the other hand, patients on Tagrisso alone had a median overall survival of 37.6 months.

Adding another 10 months of median survival time is a huge step ahead for modern oncology.

Moreover, according to the results of the clinical trial, patients who got the combined treatment from the very start of their therapy had a 23% lower risk of death (hazard ratio – 0.77).

The TOP Trial: A Lifeline for High-Risk TP53 Mutations

While the FLAURA2 trial looked at advanced lung cancer patients generally, a second study called the Phase III TOP trial focused heavily on a specific, incredibly vulnerable group of patients.

The "Double Mutation" Problem

In testing a sample of lung cancer, a doctor tests for the first mutation. Nevertheless, up to 60% of these patients have a second mutation referred to as the TP53 mutation.

TP53 gene codes for the protein that works as a tumor suppression system and also helps repair cellular DNA damage.

In the case where the TP53 gene becomes defective or inactive, a person’s natural protective mechanism is lost. Those patients with concomitant mutations have a high-risk biological group.

Such patients' tumors historically tend to be more aggressive, less susceptible to conventional treatment, and also grow back rapidly when treated with a TKI tablet alone.

The TOP Trial Breakthrough

TOP trial focused on how effective the combination of Tagrisso and chemotherapy was in treating such aggressive double mutations.

It was found that the inclusion of chemotherapy in the treatment increased the progression-free survival rate twofold in the case of these high-risk patients. Progression-free survival means the exact time when a person survives without growth or development of cancer.

Patients with TP53 co-mutations receiving Tagrisso treatment had a median PFS of 15.6 months.
Patients with TP53 co-mutations receiving Tagrisso and chemotherapy had a median PFS of 34.0 months.

By extending the time before the cancer progressed to nearly three years, the combination regimen proved it could effectively neutralize the aggressive nature of the TP53 mutation, offering a vital lifeline to patients who previously faced a more difficult prognosis.

Strategic Comparison Matrix

To help visualize the difference between these two treatment approaches, this table compares the clinical trial data across both options:

Clinical Feature	Tagrisso Monotherapy (Pill Alone)	Tagrisso + Chemotherapy Combination
Primary Treatment Goal	Long-term targeted control	Upfront intensification to prevent drug resistance
Median Overall Survival (FLAURA2)	37.6 Months	Nearly four years (47.5 Months)
Median PFS for TP53 Co-Mutations (TOP Trial)	15.6 Months	34.0 months (Doubled timeline)
How Treatment is Given	One daily oral tablet taken at home	Daily oral tablet + 4 cycles of IV chemotherapy, followed by maintenance chemo infusions
Primary Side Effect Profile	Generally mild (skin rash, diarrhea, dry skin)	Moderate to severe (fatigue, nausea, lowered blood counts)

FDA Approval: Who Benefits Most from This Combination?

In light of the success of this clinical trial, steps were rapidly taken. The FDA granted definitive approval for osimertinib with chemotherapy as the first-line treatment for locally advanced or metastatic NSCLC with mutations in EGFR.

Although this treatment has been widely approved, it has also undergone extensive subgroup analysis to show that some patients can reap the greatest benefits from such a treatment regimen.

Patients with Central Nervous System (CNS) Metastases

Brain metastases are common in cases of advanced lung cancer. Treating brain metastases has always been quite challenging due to the fact that many drugs are unable to pass through the blood-brain barrier. Although Tagrisso passes through the blood-brain barrier effectively, its combination with chemotherapy was even more effective at inhibiting brain tumors.

Patients With L858R Exon 21 Substitution Mutations

EGFR mutations can be classified into two major groups: exon 19 deletions and exon 21 L858R mutations. In general, it is true that in the past, tumors that had the exon 21 mutation were less responsive to treatment with the TKI pills alone than those that had exon 19 mutation. This is confirmed by the FLAURA2 study, where it was shown that the addition of chemotherapy helped overcome this deficiency.

Side Effect Profiles: Balancing Efficacy and Quality of Life

Comparison of Safety Profiles

Tagrisso Monotherapy: The pill alone is highly tolerated by most patients. The most common adverse effects include a minor skin rash, brittle fingernails, mild diarrhea, and fatigue. All these conditions have very little impact on patients' everyday activities.
Chemotherapy Combined with Tagrisso: This treatment adds cytostatic adverse effects associated with chemotherapy. These effects include increased fatigue, nausea, alopecia (hair thinning), and temporary hematologic toxicity. Chemotherapy temporarily disrupts your bone marrow, resulting in anemia (tiredness caused by low levels of red blood cells) and neutropenia (low levels of white blood cells, thus increasing your susceptibility to infections).

Managing the Journey with Supportive Care

It is crucial to understand that the administration of chemotherapy in the treatment process is temporary. Normally, the patient receives the aggressive regimen of chemotherapy only for 4 courses (approximately 3 weeks apart). After completing this phase of the treatment, patients enter into maintenance mode, where they experience significantly less toxicity.

Your oncologists use proactive measures of supportive care in order to minimize the side effects. It involves taking very potent anti-nausea drugs prior to your chemotherapy, as well as growth factor injections, such as pegfilgrastim.

Conclusion: Shared Decision-Making

The outcomes of the FLAURA2 and TOP trials have dramatically changed the way the medical community deals with advanced lung cancer.

We now know for certain that the combination of Tagrisso with chemotherapy leads to an increase in survival by up to nearly four years, resulting in the median overall survival of 34.0 months and double the progression-free survival rate.

Deciding whether to go with the stand-alone medication or the combination therapy should be discussed openly with your oncologist.

If you are in good physical condition and are concerned with prolonged tumor suppression, then the combination therapy from the very start is a good solution.

If you are frail or prefer a gentler daily routine, starting off with Tagrisso is a good choice.

Frequently Asked Questions

1. If I start with Tagrisso alone, can I just add chemotherapy later if the tumor grows?

Though you can always go for the chemotherapy treatment when it comes to your second choice, it seems that the results of the FLAURA2 trials are giving a very clear indication that it would be far more beneficial for you to have this combination right from the start.

2. How do I find out if I have the high-risk TP53 mutation mentioned in the TOP trial?

This will be obtained from your Next-Generation Sequencing (NGS) comprehensive biomarker profile.

This is the genomic testing done on your blood or tissue sample at the time of your initial diagnosis. You may freely request from your physician a discussion on the co-mutations detected in your case.

3. Will I lose all my hair during the combination treatment?

Anti-cancer medications such as pemetrexed and carboplatin may lead to hair thinning and hair loss, but do not result in the complete loss of hair that is typical of aggressive treatments of breast and ovarian cancer. Hair growth will be full again after the first four cycles of chemotherapy.

References

AstraZeneca Media Centre: Tagrisso Plus Chemotherapy Demonstrates Near Four-Year Median Overall Survival Milestone
The New England Journal of Medicine (NEJM): Osimertinib with or without Chemotherapy in EGFR-Mutated Advanced NSCLC (FLAURA2)
US Food and Drug Administration (FDA): FDA Approves Osimertinib with Chemotherapy for EGFR-Mutated Non-Small Cell Lung Cancer
Oncology News Central / OncLive: TOP Trial Analysis: Osimertinib Plus Chemotherapy Doubles PFS in High-Risk EGFR/TP53 Mutant Subgroups
National Center for Biotechnology Information (NCBI) Bookshelf: Osimertinib Profile and Applications in Precision Oncology

Tagrisso (Osimertinib) TOP Trial Results: Why Combination with Chemo is Better.