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Pfizer SHP2 Inhibitor Shows Early Efficacy Across Resistant Tumors in Combination Regimens


NEW YORK – Pfizer wants to further study a SHP2 inhibitor after it showed activity in combination with other targeted drugs in a range of treatment-resistant tumors in a first-in-human Phase I trial.

Although PF-07284892 didn't appear to have much efficacy as a monotherapy in the Phase I trial, when researchers gave it to patients with treatment-resistant tumors in combination with other targeted therapies, it helped resensitize those refractory cancers.

Researchers published initial results from the Phase I study of PF-07284892 in Cancer Discovery in August. The cancer types represented in the study included EML4-ALK fusion-positive non-small cell lung cancer, BRAF V600E-mutant colorectal cancer, KRAS G12D-mutant low-grade serous ovarian cancer, and GOPC-ROS1 fusion-positive pancreatic cancer. Researchers enrolled patients with advanced solid tumors that demonstrated acquired or intrinsic resistance to precision drugs that targeted these oncogenes.

In this trial, patients could remain on the study after progressing on single-agent PF-07284892 and receive the SHP2 inhibitor in combination with other agents that targeted the genetic mutations driving their tumors. This "staggered" trial design allowed the researchers to begin testing combination treatment approaches more quickly because other studies had already suggested that SHP2 inhibitors alone had minimal activity, according to S. Michael Rothenberg, senior author of the paper and head of early oncology clinical development at Pfizer.

"When we started the trial, there was an emerging body of preclinical and early clinical evidence that SHP2 inhibitors on their own have minimal anticancer activity or clinical benefit for patients," Rothenberg added. "In addition, there was laboratory evidence that combining SHP2 inhibitors with other drugs, such as some targeted therapies, immune-oncology agents, and others, could increase anticancer effects over either agent on its own."

In a commentary on the Cancer Discovery study, Alberto Hernando-Calvo and Elena Garralda from Vall d'Hebron Institute of Oncology in Spain, noted this trial is likely the first Phase I dose-escalation study to include both a monotherapy portion to determine dosage followed by a personalized combination treatment portion. They noted that that the challenge of studying biomarker-informed treatment combinations have hindered such regimens from coming to market. While n-of-1 studies, where a patient also acts as the control, have been advanced as one way to study treatment combinations in tumors characterized by low-prevalence molecular markers, this still raises regulatory issues because "fewer data on safety and pharmacokinetic analyses are expected to be gathered with this clinical trial design and questions remain on how to pool data from different single-patient trials to inform drug approval."

In contrast, the present study involving Pfizer's SHP2 inhibitor, "defines an optimized framework for accelerated testing of novel treatment combinations in Phase I dose-escalation clinical trials," Hernando-Calvo and Garralda wrote.

In designing the study, Pfizer certainly hoped it would offer greater benefit to patients than the typical Phase I study.

"The design of traditional Phase I oncology trials, which was developed decades ago in the era of cytotoxic chemotherapies, was inflexible, took a long time, required many patients, and could lead to treating many patients who did not derive any benefit," Rothenberg said. "For all these reasons, we felt it was imperative to conduct the trial in a way that maximized safety for each patient while also increasing the chances that as many patients might derive real clinical benefit, in less time, and with less patients overall."

In the study, the first four patients to progress from PF-07284892 to personalized combination regimens achieved a partial response on the latter. In fact, in the combination portion of the study, two of these patients received the same targeted therapy that they had progressed on and were resistant to earlier. However, when combined with PF-07284892, they responded to these drugs.

For example, an ALK fusion-positive NSCLC patient who had progressed on Pfizer's ALK inhibitor Lorbrena (lorlatinib) received six weeks of PF-07284892 monotherapy until progression. Then, researchers added Lorbrena to PF-07284892, and after another six weeks the patient had a partial response. The patient stayed on the combination treatment until progression at 4.5 months.

A patient with BRAF V600E-mutant colorectal cancer who had progressed on Pfizer's Braftovi (encorafenib) plus Eli Lilly's Erbitux (cetuximab) was also enrolled in the trial. When this regimen was given with PF-07284892, the patient responded for six months, three times longer than the patient's response to prior treatment with Braftovi-Erbitux.

Across other tumor types in the trials, PF-07284892 demonstrated the same response profile: limited activity as a single agent but more robust responses when combined with other drugs.

For example, a KRAS-mutant ovarian cancer patient responded to the combination of PF-07284892 with Pfizer's Mektovi (binimetinib), and a ROS1 fusion-positive pancreatic cancer patient responded to PF-07284892 and Lorbrena.

Combination targeted regimens carry the risk of increased toxicities. None of the four patients experienced dose-limiting toxicities on these PF-07284892-containing combinations, though two patients required dose modifications once the other targeted therapies were added.

"[These results] illustrate the potential of Pfizer's SHP2 inhibitor to overcome or delay targeted therapy resistance, and therefore, the potential to increase clinical benefit for patients," said Rothenberg. SHP2 inhibition can also address some potential issues with currently available targeted therapies, Rothenberg added.

"SHP2 inhibitor combination therapy may be required for oncogene-driven cancers that acquire off-target resistance to diverse targeted therapies," such as ALK or ROS1 fusion-positive lung cancers, BRAF V600E-mutant colorectal cancer, KRAS-mutant cancers, and others, Rothenberg explained.

This off-target activity can lead to the reactivation of the MAPK signaling pathway, but because a SHP2 inhibitor can turn off that pathway again, it can overcome those resistance mechanisms, allowing patients to respond, he added.

Combination regimens that include SHP2 inhibitors may also be needed for certain oncogenic drivers that are more difficult to target with just a single targeted drug, including tumors with KRAS or PIK3CA mutations, Rothenberg said.

Researchers are exploring SHP2 inhibitor combinations in KRAS-mutant tumors in several ongoing studies. BridgeBio Pharma is conducting a study of its SHP2 inhibitor BBP-398 with Bristol Myers Squibb's checkpoint inhibitor Opdivo (nivolumab) in KRAS-mutant NSCLC, and Amgen is evaluating its KRAS inhibitor Lumakras (sotorasib) with BridgeBio's BBP-398 in KRAS-mutant tumors.

Other companies developing SHP2 inhibitors include Revolution Medicines, Erasca, and Genentech, which acquired an agent from Relay Therapeutics in 2020. Pfizer also acquired PF-07284892 from Array Biopharma in its 2019 deal. All of these companies are in early-stage trials for their SHP2 inhibitors combined with other targeted therapies, including KRAS, MEK, EGFR, ERK, and checkpoint inhibitors.

While Pfizer's Phase I trial of PF-07284892 is still in early stages, the firm is already looking ahead to larger studies. Next, researchers are planning trials where they'll study PF-07284892 combination regimens from the beginning "in appropriate biomarker-selected patients, for whom concomitant inhibition with a SHP2 inhibitor may overcome or delay relevant resistance mechanisms or pathways," Rothenberg said.

Pfizer plans to continue exploring PF-07284892 in the tumor types included in the Phase I study – lung, colorectal, ovarian, and pancreatic – and may expand into others if data suggests adding a SHP2 inhibitor may provide clinical benefit.

"We hope that PF-07284892, and the unique trial design, illustrates the importance of getting the right drug to the right patients as part of the right treatment … early in the clinical development of new cancer drugs," Rothenberg said.