Papillon Trial: New Treatment for a Specific Lung Cancer

The PAPILLON trial established amivantamab plus chemotherapy as the first targeted treatment to significantly extend survival for people with a rare and historically stubborn form of lung cancer driven by EGFR exon 20 insertion mutations. In this phase 3 trial, adding the bispecific antibody amivantamab to standard chemotherapy nearly doubled the time before the cancer progressed, pushing median progression-free survival from about seven months to more than eleven months. Those results led to FDA approval in early 2024 and a preferred first-line recommendation from the National Comprehensive Cancer Network, giving patients with this mutation a treatment option that, until recently, simply did not exist.

Why EGFR Exon 20 Insertions Have Been So Hard to Treat

Lung cancers driven by mutations in the EGFR gene have generally responded well to targeted therapies called tyrosine kinase inhibitors, or TKIs. But not all EGFR mutations are created equal. The most common ones, like exon 19 deletions and the L858R point mutation, are “sensitizing” mutations that make the cancer vulnerable to widely available oral drugs. Exon 20 insertions are a different beast. These mutations change the shape of the EGFR protein in a way that makes the cancer largely resistant to the same drugs that work so well against the common EGFR mutations.

Exon 20 insertions account for roughly 1 to 10 percent of all EGFR mutations in non-small cell lung cancer, depending on the population studied and the testing method used.¹ A systematic review found they represent anywhere from 0.1 to 4 percent of all NSCLC cases, with the highest rates reported in Asia-Pacific populations and the United States.² That makes them rare enough to be underappreciated but common enough that thousands of patients each year face a diagnosis with few good targeted options.

Before PAPILLON, those patients were typically treated with standard platinum-based chemotherapy, the same regimen used for lung cancers without any actionable mutation at all. That approach offered modest response rates and limited durability. Patients with exon 20 insertions consistently had poorer outcomes compared to those with the more common sensitizing EGFR mutations across a wide range of therapies and treatment lines.² The mutation made their tumors resistant to targeted therapy but no more responsive to chemotherapy, leaving a genuine treatment gap.

The Diagnostic Hurdle That Comes Before Treatment

Even identifying exon 20 insertions reliably has been a challenge. Unlike the common EGFR mutations, which are easily detected by standard PCR-based testing, exon 20 insertions are a diverse family of variants. Dozens of distinct insertion types exist, each with a slightly different stretch of extra genetic material wedged into the same region of the gene. Older PCR-based tests were designed to detect only a handful of known variants and could miss half or more of actual exon 20 insertions.³ One study estimated that the proportion of exon 20 insertions detectable by any PCR test alone ranged from roughly 12 to 59 percent, depending on the specific data source.⁴

Next-generation sequencing, or NGS, does a far better job. Because NGS reads the full sequence of the gene rather than looking for a short list of known changes, it can catch the rarer and novel variants that PCR tests miss. In a Chinese cohort, NGS identified 34 unique exon 20 insertion variants, eight of them reported for the first time, while an older PCR-based platform detected only a fraction of the mutations NGS found.⁵ The broader adoption of NGS over the past decade likely explains why reported rates of exon 20 insertions have climbed: the mutation was always there, but it was being missed.³

This matters practically for anyone recently diagnosed with non-small cell lung cancer. If your tumor is tested only with a PCR panel, an exon 20 insertion could be missed entirely, which would mean you would never be considered for amivantamab. The takeaway is straightforward: NGS-based testing gives you the best chance of learning whether this mutation is driving your cancer and whether the PAPILLON regimen applies to you.

How Amivantamab Works

Amivantamab is a bispecific antibody, meaning it is engineered to grab onto two different targets at once. One arm binds to the EGFR protein on the surface of the cancer cell, while the other binds to a second receptor called MET. The logic behind this dual targeting is rooted in what makes exon 20 insertion-driven cancers tricky: these tumors can rely on both EGFR signaling and MET signaling to grow and survive, and blocking only one often is not enough.

On the EGFR side, amivantamab latches onto a specific region of the receptor and drives it off the cell surface, effectively reducing the number of growth signals the cancer cell receives. On the MET side, it blocks a growth factor called HGF from activating the receptor, shutting down a parallel survival pathway.⁶ The combined effect is that the cancer cell loses access to two of its key growth programs simultaneously.

Beyond starving the tumor of growth signals, amivantamab has an immune component. Preclinical work showed that it triggers immune-directed antitumor activity, increasing certain markers of immune engagement and encouraging the body’s own defenses to go after the cancer.⁷ This three-pronged approach, blocking EGFR, blocking MET, and enlisting the immune system, helps explain why amivantamab succeeds where conventional TKIs failed against exon 20 insertions.

What the PAPILLON Trial Actually Found

PAPILLON was an international, randomized, open-label phase 3 trial that enrolled 308 patients with previously untreated, advanced non-small cell lung cancer harboring EGFR exon 20 insertions. Half were assigned to receive amivantamab plus carboplatin-pemetrexed chemotherapy, and half received the same chemotherapy alone. Amivantamab was given intravenously every three weeks, while carboplatin was administered for four cycles and pemetrexed continued until the disease progressed.⁸

The primary result was striking. Median progression-free survival, the time before the cancer started growing again, was 11.4 months in the amivantamab-chemotherapy group compared to 6.7 months with chemotherapy alone. At 18 months, about 31 percent of patients in the combination arm had not yet progressed, compared to just 3 percent in the chemotherapy-only arm.⁹ The overall response rate, the proportion of patients whose tumors shrank meaningfully, was 73 percent with the combination versus 47 percent with chemotherapy alone.⁹

A subgroup analysis of Asian patients enrolled in the trial showed broadly consistent results, with an overall response rate of about 70 percent versus 51 percent for chemotherapy and a duration of response of roughly 10 months compared to about five and a half months.¹⁰ The consistency across geographic subgroups was important for establishing that the benefit was not limited to one population.

Side Effects to Expect

Adding amivantamab to chemotherapy does add side effects, and they are distinct from what patients typically experience with chemotherapy alone. The most common ones fall into predictable categories based on the drug’s targets.

Because amivantamab blocks EGFR, it causes skin-related reactions in many patients: rash, nail-bed inflammation (paronychia), itching, and mouth sores. Because it blocks MET, peripheral edema (swelling in the hands and feet) and low albumin levels are common. And because it is an infusion-based antibody, infusion-related reactions are expected, particularly during the first dose. These reactions are predominantly mild to moderate and tend to lessen with subsequent infusions.¹¹ Diarrhea and, more rarely, blood clots and pneumonitis have also been reported.¹¹

None of these side effects are trivial, but oncologists have developed management strategies for most of them. Prophylactic approaches such as pre-medications before the first infusion, moisturizers and topical treatments for skin reactions, and diuretics for edema can keep many patients on treatment comfortably enough to continue receiving the benefit.¹² When compared indirectly to another exon 20 insertion-targeted agent, mobocertinib, amivantamab had a more favorable safety profile: 15 of 23 reported treatment-related side effects were significantly less common with amivantamab.¹³ (Mobocertinib was voluntarily withdrawn from the market in 2023 after a confirmatory trial failed, making the comparison largely historical.)

What Patients Report About Quality of Life

Raw survival numbers matter, but so does how patients feel while on treatment. PAPILLON collected patient-reported outcomes on physical functioning, symptom burden, and overall well-being. At 12 months, 77 percent of patients on amivantamab-chemotherapy remained free of symptomatic progression, meaning their cancer-related symptoms had not worsened, compared to 60 percent on chemotherapy alone.¹⁴

Physical functioning and global health scores were maintained in both arms, but a higher proportion of patients receiving the combination reported stable or improved quality of life at both six and twelve months.¹⁴ In plain terms, although amivantamab added its own side effects, the delay in cancer progression appeared to offset them for most patients. When a tumor is kept from growing, the symptoms it causes, things like pain, breathlessness, and fatigue, tend to stay at bay longer, and that effect showed up clearly in the patient reports.

When Treatment Stops Working

Like nearly all cancer therapies, amivantamab does not work forever. Eventually, tumors develop resistance and begin growing again. Understanding how resistance happens is critical for figuring out what treatments might work next.

An early circulating tumor DNA study of 25 patients treated with amivantamab found that among 12 patients with matched blood samples at baseline and at the time of progression, about 58 percent showed at least one new genetic alteration that was not present before treatment. The most frequently observed change was a deletion in a gene called EP300, found in a quarter of those patients. Other resistance mechanisms involved bypass signaling through familiar cancer pathways.¹⁵ Some patients acquired multiple resistance mechanisms simultaneously, underscoring that the cancer does not always find a single escape route.

This diversity of resistance patterns means there will not be a one-size-fits-all second-line approach after amivantamab fails. Researchers are still working out which combinations or next-generation agents might overcome specific resistance pathways. Clinical trials are ongoing. For patients currently benefiting from the PAPILLON regimen, the practical point is that repeat genetic testing of the tumor or through liquid biopsy at the time of progression can reveal the specific resistance mechanism and potentially guide the next treatment choice.

The Cost Problem

The clinical benefit of amivantamab-chemotherapy is clear, but its price is significant. A cost-effectiveness analysis from a U.S. perspective found that the combination yielded roughly one additional quality-adjusted life year compared to chemotherapy alone, while increasing costs by about $484,000. That translates to an incremental cost-effectiveness ratio of approximately $432,000 per quality-adjusted life year, well above the commonly used willingness-to-pay threshold of $150,000 per quality-adjusted life year.¹⁶

Cost-effectiveness thresholds are policy tools, not decisions about individual patients. A drug can be genuinely life-extending and still be priced in a way that strains healthcare budgets. For patients and families, this can mean navigating insurance coverage, manufacturer assistance programs, and difficult conversations about affordability. It is one of the most frustrating aspects of modern oncology: a breakthrough for a rare cancer subtype often comes with a price tag that reflects both its research costs and its small eligible population.

The Shift Toward Subcutaneous Delivery

One practical barrier with intravenous amivantamab is the infusion time. The first dose can take several hours to administer, requiring patients to spend a full day at an infusion center. A subcutaneous formulation of amivantamab has been developed to address this. In the PALOMA-3 trial, which tested subcutaneous versus intravenous amivantamab in a different EGFR-mutated lung cancer setting, the median time for administering the subcutaneous version was under five minutes, compared to about five hours for the first intravenous infusion.¹⁷ The subcutaneous injection also came with lower rates of infusion-related reactions.¹⁸

PALOMA-3 studied a different patient population than PAPILLON, so the subcutaneous formulation is not identical to the PAPILLON regimen. But the delivery innovation is relevant because it could meaningfully reduce the treatment burden for future patients receiving amivantamab-based combinations. Spending minutes rather than hours in a chair makes a real difference when you are coming in for treatment every three weeks for months or years. As the subcutaneous formulation moves through regulatory pathways, it has the potential to make the PAPILLON-style regimen considerably easier to live with.

How PAPILLON Changed the Treatment Standard

Before PAPILLON, there was no preferred first-line targeted therapy for EGFR exon 20 insertion-mutated lung cancer. The National Comprehensive Cancer Network now lists amivantamab plus chemotherapy as a preferred first-line treatment for these patients.¹⁹ The FDA granted approval for this indication in March 2024.²⁰ For a mutation subtype that had been essentially invisible to targeted therapy, that represents a genuine shift.

The trial name itself is a nod to transformation. “Papillon” is French for “butterfly,” and amivantamab was internally known during development by a code name that also referenced the butterfly motif, reflecting the bispecific antibody’s two-armed structure. Whether the metaphor feels apt or heavy-handed probably depends on your tolerance for pharmaceutical branding, but the underlying clinical advance is real. Patients with a mutation that once guaranteed they would receive only generic chemotherapy now have a targeted option that roughly doubles the time before their cancer progresses and meaningfully improves the odds that their tumor will shrink. The treatment landscape for this rare EGFR mutation looks quite different than it did just a few years ago, and ongoing research into resistance mechanisms, subcutaneous delivery, and combination strategies suggests it will continue evolving.