Is Targeted Therapy Better Than Chemotherapy for HER2 Lung Cancer?

If you've been diagnosed with HER2-mutant lung cancer, one of the first questions you may ask is:

If my cancer has a specific genetic mutation, shouldn't we treat that precise mutation first?

As a thoracic medical oncologist, my answer is often yes.

For decades, chemotherapy was the standard first treatment for people with advanced HER2-mutant lung cancer. It remains an important and effective therapy that continues to play a critical role in treatment. But over the past few years, we've witnessed remarkable advances in HER2-directed therapies that are fundamentally changing how we think about treating this disease.

How chemotherapy works against HER2-mutant lung cancer

In general, chemotherapy works by non-selectively attacking rapidly dividing cells throughout the body. While it can shrink HER2-mutant lung cancers, it isn't designed to specifically target the genetic change driving the cancer's growth. Historically, first-line chemotherapy has produced tumor shrinkage in approximately 40 percent of patients, with the cancer remaining controlled for a median of about 6 months.¹

How targeted therapy takes aim at HER2 directly

Targeted therapy takes a different approach.

Rather than broadly attacking rapidly dividing cells, these medications are specifically designed to block the abnormal HER2 signaling pathway that is "fueling" the cancer. In other words, instead of treating lung cancer broadly, we're treating the specific biology causing the cancer to grow.

And the results have been exciting.

Response rates for newer HER2-targeted therapies

Newer oral HER2-targeted therapies such as zongertinib and sevabertinib have shown encouraging efficacy in clinical trials, with zongertinib achieving a response rate of 76 percent.² In addition to shrinking tumors in many more patients than we historically achieved with chemotherapy alone, these treatments have also demonstrated encouraging durability of response, allowing many patients to remain on therapy with good disease control for extended periods.

To me, these results represent much more than an incremental improvement. They represent a shift toward precision medicine.

That doesn't mean chemotherapy has become obsolete.

Why treatment sequencing matters more than picking one drug

In fact, I often tell my patients that cancer treatment isn't about choosing one therapy. Rather, it's about choosing the right sequence of therapies.

In general, if a highly effective targeted therapy is available upfront, my philosophy is to use the treatment that has the greatest likelihood of controlling the cancer while preserving other options for later.

Why biomarker testing guides the right treatment choice

Of course, every patient is different. The best treatment depends on several factors, including the exact type of HER2 alteration, whether the cancer has spread to the brain, a person's overall health, potential side effects, and the latest clinical evidence. This is also why comprehensive biomarker testing, typically through next-generation sequencing (NGS), is so important. Not every HER2 alteration behaves the same way, and identifying the specific genetic change helps guide the most appropriate treatment approach.

Weighing the side effects of targeted therapy

It's also important to remember that targeted therapies have their own side effects. While oral HER2 inhibitors are generally different from chemotherapy, they can still cause diarrhea, skin changes, or liver abnormalities. Other HER2-directed therapies, such as the antibody-drug conjugate trastuzumab deruxtecan, have their own unique benefits and risks. Every treatment requires thoughtful discussion between patients and their healthcare team.

Personalizing treatment is the real breakthrough

The most exciting part of this story isn't simply that we have new drugs. Rather, it's that we now have better ways to personalize treatment. Just a few years ago, patients with HER2-mutant lung cancer had few therapies developed specifically for their disease. Today, multiple HER2-directed therapies are available, more are being studied in clinical trials, and our understanding of how best to sequence these treatments continues to evolve in real time.

Dr. Singhi is widely recognized for translating complex oncology topics into clear, practical education through his social media platform, @lungoncdoc