Summit Therapeutics – Ivonescimab in Non-Squamous NSCLC Clinical Trial and Beyond

Executive Summary

Summit Therapeutics has a clinical readout from the Harmoni trial in mid-year 2025. Given the positive results of an identical trial in China, the Harmoni trial will likely have a positive readout. However, Summit is valued at $17.5B, a reflection of the fact that some investors believe ivonescimab has the potential to become the next Keytruda. So far, the data from China has been impressive in both NSCLC and colorectal cancer.

The recent decline in Summit's share price presents a buying opportunity. The interim data from Akeso on Friday did not meet statistical significance. However, the data is only 39% mature, and an HR of 0.777 is considered clinically significant. In the long term, I would expect OS data not to be as impressive as mPFS data as VEGF inhibitors seem to show a superior benefit in PFS compared to OS in most cancers. Options are expensive, so it seems prudent to own the common stock.

Background Information

Lung Cancer

There are two types of lung cancer: non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC). 85% of cases are NSCLC; the rest are SCLC. SCLC is almost always the result of smoking, whereas NSCLC can have other causes. SCLC is usually fast-growing and aggressive. Treatment options are limited, and the prognosis is poor. NSCLC, on the other hand, has many more treatment options, and the prognosis is much more positive.

NSCLC has three subtypes: adenocarcinoma, squamous cell carcinoma, and large cell carcinoma. Large cell carcinoma and adenocarcinoma are grouped into non-squamous cell NSCLC. These two are treated similarly and are less linked to smoking as compared to squamous cell carcinoma.

There are four stages of lung cancer. Stage I-II is localized in the lung and can be curable with surgery. Stage III is locally advanced and may require chemoradiation. Stage IV is metastatic and requires systemic therapy.

This is the prognosis of each disease:

Type	5-Year Survival Rate
Localized NSCLC	~63%
Regional NSCLC	~35%
Distant NSCLC	~8%
Limited-stage SCLC	~30%
Extensive-stage SCLC	~3%–7%

The Harmoni trial focuses on 2L+, EGFR mutated, non-squamous NSCLC that has failed previous EGFR-TKI treatment.

Treatments:

Treatment for this type of cancer is based on mutations. If a mutation is present, then targeted therapies are preferred.

Mutation	First-Line Targeted Therapy
EGFR	Osimertinib
ALK	Alectinib, Lorlatinib
ROS1	Entrectinib, Crizotinib
BRAF V600E	Dabrafenib + Trametinib
MET exon 14	Capmatinib, Tepotinib
RET	Selpercatinib, Pralsetinib
KRAS G12C	Sotorasib (often second-line)

If no mutations are present, then the PD-L1 score is used to drive treatment.

PD-L1 TPS	Recommended First-Line Treatment
≥50%	Keytruda (pembrolizumab) monotherapy
1–49%	Keytruda + chemotherapy (pemetrexed + platinum)
0%	Keytruda + chemotherapy (same as above)

Notably, the Harmoni trial is testing ivonescimab in patients who have already progressed on EGFR therapy, so there is no data for Keytruda in this patient population.

Development History in NSCLC with Focus on Keytruda

Keytruda Indications in NSCLC

Stage / Setting	PD-L1 / Mutation	Keytruda Use
Stage IV (metastatic)	PD-L1 ≥50%	Monotherapy (KEYNOTE-024)
	PD-L1 <50% or any	Keytruda + chemo (KEYNOTE-189, -407)
	EGFR/ALK mutations	Not first-line; may use later
Stage III unresectable	Any	Not standard (durvalumab used)
Stage II–IIIA resectable	Any	Neoadjuvant Keytruda + chemo (KEYNOTE-671)
	PD-L1 ≥1%	Adjuvant Keytruda x1 year (KEYNOTE-091)
Previously treated	PD-L1 ≥1%, no prior IO	Monotherapy (KEYNOTE-010)

The results from the varying Keynote studies in Keytruda have been impressive. For example, in previously untreated advanced NSCLC, Keytruda + chemotherapy showed a significant difference compared to chemotherapy alone.

Endpoint	Keytruda Combo	Chemo Alone	P-value / HR
Median Overall Survival (OS)	22.0 months	10.7 months	HR = 0.56, p < 0.00001
Median Progression-Free Survival (PFS)	9.0 months	4.9 months	HR = 0.49, p < 0.00001
12-month OS rate	69.2%	49.4%	—
PD-L1 Subgroup	OS benefit across all levels of PD-L1 (TPS <1%, 1–49%, ≥50%)	—	—

As ivonescimab has both PD-1 and anti-VEGF properties, it is likely to be most effective in cancers where anti-VEGF therapy is used in addition to Keytruda. These cancers are:

·         Renal cell carcinoma - Advanced

·         Endometrial Cancer – Advanced

·         Hepatocellular carcinoma

Subgroup analysis from various trials has indicated a significant benefit when liver metastasis is involved. 

Pemetrexed

The other molecule being tested with ivonescimab in the Harmoni trial is pemetrexed, an antifolate chemotherapy agent. The PARAMOUNT trial established its efficacy in late-stage NSCLC.

Compared to chemotherapy alone, pemetrexed improved PFS and OS:

Outcome	Pemetrexed Maintenance	Placebo	Hazard Ratio	P-value
Median PFS	4.1 months	2.8 months	0.62	p < 0.0001
Median OS	13.9 months (from randomization)16.9 months (from the start of therapy)	11.0 months14.0 months	0.78	p = 0.0195
1-year survival	58%	45%	—	—

Summit Therapeutics and Ivonescimab

Ivonescimab

Ivonescimab (also known as AK112 or SMT112) is a novel bispecific antibody designed to treat cancer, particularly non-small cell lung cancer (NSCLC). It is being developed through a partnership between Akeso, Inc. (China) and Summit Therapeutics (U.S.). It targets both PD-1 and VEGF-A, attempting to neutralize both.

It has already undergone a few phase 3 trials in China. The most relevant for the near-term readout is Harmoni-A, which is essentially the same study as the one being conducted by Summit in the US. It investigated ivonescimab plus chemotherapy against a placebo and chemotherapy in advanced, EGFR-mutated, non-squamous NSCLC.

Given the success of this trial in China, it is highly likely the Summit trial will meet its primary endpoint.

The Harmoni-2 trial in China compared ivonescimab against pembrolizumab (Keytruda) in advanced NSCLC with PD-L1 > 1% and no EGFR/ALK mutations. The data was impressive, with ivonescimab showing a median PFS of 11.1 vs 5.8 months with Keytruda. The interim OS was slightly less impressive, with an HR of 0.777 (clinically significant is considered to be 0.8 and below).

The Harmoni-6 trial compared ivonescimab against tislezumab (Tevimbra), another PD-1 inhibitor, in squamous NSCLC. Ivonescimab demonstrated a superior median PFS compared to Tevimbra; the benefit was observed in both PD-L1 positive and PD-L1 negative tumors.

This past Friday, April 25th, Akeos announced interim OS analysis for ivonescimab from the Harmoni-2 trial. The HR was 0.777, which, although clinically meaningful, was considered to be a disappointing result for investors. As a result, Summit’s stock crashed about 35% on the news.

Clinical Trials – Harmoni

Phase 3 Study Design

The trial design is identical to the Harmoni-A trial completed in China. Given the success of that trial, this trial is also likely to be successful.

Phase 2 Study Results

The most notable study here is a positive phase 2 study investigating ivonescimab in metastatic colorectal cancer. The ORR from this study was 82% for ivonescimab + FOLFOXIRI and 88.2% with ivonescimab + ligufalimab + FOLFOXIRI. These figures are higher than the historical ORR for the FOLFOXIRI regimen alone.

Analysis and Discussion

The near-term readout in the Harmoni trial will be positive. However, Summit is currently valued at $17.5B, even after the precipitous drop from Friday, April 25th. This valuation reflects the fact that some investors believe ivonscimab could take significant market share from Keytruda in the future. So far, the results have been positive, but it is likely the PFS numbers will be superior to the OS figures when comparing ivonescimab to Keytruda. Many of the VEGF inhibitors show robust results in mPFS but little efficacy in OS.

Conclusion

Given the recent pullback in Summit's share price, it is likely a good time to buy. A $17.5B valuation for a clinical-stage company is steep, but the results of ivonescimab so far have warranted the price of the company. I would expect a modest increase in the share price, given the results of the Harmoni trial are positive. Options are expensive, so my recommendation would be to own the common stock for now.